CA3129581A1 - Antibody-drug conjugates including antibody against human dlk1, and use thereof - Google Patents
Antibody-drug conjugates including antibody against human dlk1, and use thereof Download PDFInfo
- Publication number
- CA3129581A1 CA3129581A1 CA3129581A CA3129581A CA3129581A1 CA 3129581 A1 CA3129581 A1 CA 3129581A1 CA 3129581 A CA3129581 A CA 3129581A CA 3129581 A CA3129581 A CA 3129581A CA 3129581 A1 CA3129581 A1 CA 3129581A1
- Authority
- CA
- Canada
- Prior art keywords
- solvate
- pharmaceutically acceptable
- antibody
- acceptable salt
- antibody conjugate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940049595 antibody-drug conjugate Drugs 0.000 title abstract description 50
- 239000000611 antibody drug conjugate Substances 0.000 title abstract description 46
- 241000282414 Homo sapiens Species 0.000 title description 28
- 101150102995 dlk-1 gene Proteins 0.000 title 1
- 230000027455 binding Effects 0.000 claims abstract description 74
- 239000000427 antigen Substances 0.000 claims abstract description 65
- 102000036639 antigens Human genes 0.000 claims abstract description 65
- 108091007433 antigens Proteins 0.000 claims abstract description 65
- 101000928535 Homo sapiens Protein delta homolog 1 Proteins 0.000 claims abstract description 62
- 102100036467 Protein delta homolog 1 Human genes 0.000 claims abstract description 60
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 55
- 239000012634 fragment Substances 0.000 claims abstract description 40
- 201000011510 cancer Diseases 0.000 claims abstract description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 125000005647 linker group Chemical group 0.000 claims description 84
- -1 isoprenyl Chemical class 0.000 claims description 70
- 125000001072 heteroaryl group Chemical group 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 66
- 239000012453 solvate Substances 0.000 claims description 65
- 125000003118 aryl group Chemical group 0.000 claims description 57
- 229940127121 immunoconjugate Drugs 0.000 claims description 57
- 210000004027 cell Anatomy 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 239000013543 active substance Substances 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 44
- 150000001413 amino acids Chemical class 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 42
- 229940024606 amino acid Drugs 0.000 claims description 41
- 235000001014 amino acid Nutrition 0.000 claims description 41
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 35
- 108090000623 proteins and genes Proteins 0.000 claims description 34
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 28
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 26
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
- 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 24
- 239000000203 mixture Substances 0.000 claims description 23
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 23
- 235000018102 proteins Nutrition 0.000 claims description 23
- 102000004169 proteins and genes Human genes 0.000 claims description 23
- 125000002947 alkylene group Chemical group 0.000 claims description 22
- 150000002923 oximes Chemical class 0.000 claims description 22
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 21
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 20
- 150000007523 nucleic acids Chemical class 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 18
- 125000006552 (C3-C8) cycloalkyl group Chemical group 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
- 229960002433 cysteine Drugs 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 16
- 230000002062 proliferating effect Effects 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 108020004707 nucleic acids Proteins 0.000 claims description 15
- 102000039446 nucleic acids Human genes 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 15
- 239000003053 toxin Substances 0.000 claims description 15
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 14
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 14
- 239000004471 Glycine Substances 0.000 claims description 14
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 14
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 229920001184 polypeptide Polymers 0.000 claims description 14
- 229960001153 serine Drugs 0.000 claims description 14
- 235000004400 serine Nutrition 0.000 claims description 14
- 231100000765 toxin Toxicity 0.000 claims description 14
- 239000004475 Arginine Substances 0.000 claims description 13
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 13
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 13
- 229960003121 arginine Drugs 0.000 claims description 13
- 235000009697 arginine Nutrition 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 108090000992 Transferases Proteins 0.000 claims description 11
- 102000004357 Transferases Human genes 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 11
- 230000001656 angiogenetic effect Effects 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 10
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 10
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 10
- 239000004472 Lysine Substances 0.000 claims description 10
- 239000002246 antineoplastic agent Substances 0.000 claims description 10
- 229930195712 glutamate Natural products 0.000 claims description 10
- 229940049906 glutamate Drugs 0.000 claims description 10
- 229960003646 lysine Drugs 0.000 claims description 10
- 125000004434 sulfur atom Chemical group 0.000 claims description 10
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 9
- 229960003767 alanine Drugs 0.000 claims description 9
- 235000004279 alanine Nutrition 0.000 claims description 9
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000003827 glycol group Chemical group 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 8
- 125000006239 protecting group Chemical group 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
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 7
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 7
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 7
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
- 229940009098 aspartate Drugs 0.000 claims description 7
- 235000003704 aspartic acid Nutrition 0.000 claims description 7
- 229960005261 aspartic acid Drugs 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 7
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 7
- 229960002743 glutamine Drugs 0.000 claims description 7
- 229960002449 glycine Drugs 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 229960003104 ornithine Drugs 0.000 claims description 7
- 201000002528 pancreatic cancer Diseases 0.000 claims description 7
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 7
- 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 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-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
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-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
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 6
- 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 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 108010044540 auristatin Proteins 0.000 claims description 6
- 229930195731 calicheamicin Natural products 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 229940127089 cytotoxic agent Drugs 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
- 229960004679 doxorubicin Drugs 0.000 claims description 6
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 6
- 235000005772 leucine Nutrition 0.000 claims description 6
- 229960003136 leucine Drugs 0.000 claims description 6
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 6
- 229930182817 methionine Natural products 0.000 claims description 6
- 235000006109 methionine Nutrition 0.000 claims description 6
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 125000000172 C5-C10 aryl group Chemical group 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 108090000790 Enzymes Proteins 0.000 claims description 5
- 108010063738 Interleukins Proteins 0.000 claims description 5
- 102000015696 Interleukins Human genes 0.000 claims description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 5
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 5
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 5
- 150000001408 amides Chemical group 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 229960002885 histidine Drugs 0.000 claims description 5
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 5
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 5
- 229960002429 proline Drugs 0.000 claims description 5
- 235000013930 proline Nutrition 0.000 claims description 5
- 125000001424 substituent group Chemical group 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
- 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
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-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
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 229960005532 CC-1065 Drugs 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
- 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
- 229930189413 Esperamicin Natural products 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 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
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 4
- 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
- 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
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 4
- 239000004473 Threonine Substances 0.000 claims description 4
- 206010054094 Tumour necrosis Diseases 0.000 claims description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 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
- 229960003437 aminoglutethimide Drugs 0.000 claims description 4
- 229940121375 antifungal agent Drugs 0.000 claims description 4
- 239000003096 antiparasitic agent Substances 0.000 claims description 4
- 229960001230 asparagine Drugs 0.000 claims description 4
- 235000009582 asparagine Nutrition 0.000 claims description 4
- 210000004899 c-terminal region Anatomy 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
- 239000011203 carbon fibre reinforced carbon Substances 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
- 239000000460 chlorine Substances 0.000 claims description 4
- 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 4
- 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 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
- 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 4
- 229950006700 edatrexate Drugs 0.000 claims description 4
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 claims description 4
- 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 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 4
- 229960001101 ifosfamide Drugs 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
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 229960001428 mercaptopurine Drugs 0.000 claims description 4
- 229960004452 methionine Drugs 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- 229960001156 mitoxantrone Drugs 0.000 claims description 4
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 claims description 4
- 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
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 4
- 229960001196 thiotepa Drugs 0.000 claims description 4
- 229960002898 threonine 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
- 102000003390 tumor necrosis factor Human genes 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
- 125000000923 (C1-C30) alkyl group Chemical group 0.000 claims description 3
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 102000007644 Colony-Stimulating Factors Human genes 0.000 claims description 3
- 108010071942 Colony-Stimulating Factors Proteins 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 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
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 230000003115 biocidal effect Effects 0.000 claims description 3
- 238000012650 click reaction Methods 0.000 claims description 3
- 230000002519 immonomodulatory effect Effects 0.000 claims description 3
- 230000002163 immunogen Effects 0.000 claims description 3
- 230000004957 immunoregulator effect Effects 0.000 claims description 3
- 239000003112 inhibitor Substances 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
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 239000004474 valine Substances 0.000 claims description 3
- 229960004295 valine Drugs 0.000 claims description 3
- 235000014393 valine Nutrition 0.000 claims description 3
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 claims description 2
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 claims description 2
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 claims description 2
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 claims description 2
- 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
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 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
- 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
- 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 2
- 125000003161 (C1-C6) alkylene group Chemical group 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
- 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
- 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
- 108010059616 Activins Proteins 0.000 claims description 2
- 102000005606 Activins Human genes 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
- 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
- 229940122815 Aromatase inhibitor Drugs 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
- 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
- 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
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-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
- 102000009016 Cholera Toxin Human genes 0.000 claims description 2
- 108010049048 Cholera Toxin Proteins 0.000 claims description 2
- 102100021809 Chorionic somatomammotropin hormone 1 Human genes 0.000 claims description 2
- 229930188224 Cryptophycin Natural products 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
- 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
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 claims description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 2
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 claims description 2
- 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
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 2
- 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 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
- 238000006736 Huisgen cycloaddition reaction Methods 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
- 102000002746 Inhibins Human genes 0.000 claims description 2
- 108010004250 Inhibins Proteins 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- 102000014150 Interferons Human genes 0.000 claims description 2
- 108010002352 Interleukin-1 Proteins 0.000 claims description 2
- 108090000174 Interleukin-10 Proteins 0.000 claims description 2
- 108090000177 Interleukin-11 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
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 102100020880 Kit ligand Human genes 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
- 229940123917 Lipid kinase inhibitor Drugs 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 102000009151 Luteinizing Hormone Human genes 0.000 claims description 2
- 108010073521 Luteinizing Hormone Proteins 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
- 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
- 108091034117 Oligonucleotide Proteins 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
- 108010057150 Peplomycin Proteins 0.000 claims description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims description 2
- 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
- 108010057464 Prolactin Proteins 0.000 claims description 2
- 102000003946 Prolactin Human genes 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
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 claims description 2
- 102000003743 Relaxin Human genes 0.000 claims description 2
- 108090000103 Relaxin Proteins 0.000 claims description 2
- 108010039491 Ricin Proteins 0.000 claims description 2
- 206010039491 Sarcoma Diseases 0.000 claims description 2
- 229920000519 Sizofiran Polymers 0.000 claims description 2
- 108010039445 Stem Cell Factor Proteins 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
- 102100040247 Tumor necrosis factor Human genes 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
- 229950002684 aceglatone Drugs 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
- 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
- 150000001299 aldehydes Chemical class 0.000 claims description 2
- 125000005262 alkoxyamine group Chemical group 0.000 claims description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 2
- 229960000473 altretamine Drugs 0.000 claims description 2
- 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
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 claims description 2
- 229950000242 ancitabine Drugs 0.000 claims description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 230000000843 anti-fungal effect Effects 0.000 claims description 2
- 239000000868 anti-mullerian hormone Substances 0.000 claims description 2
- 230000002141 anti-parasite Effects 0.000 claims description 2
- 230000000840 anti-viral effect Effects 0.000 claims description 2
- 239000003429 antifungal agent Substances 0.000 claims description 2
- 229940125687 antiparasitic agent Drugs 0.000 claims description 2
- 239000000074 antisense oligonucleotide Substances 0.000 claims description 2
- 238000012230 antisense oligonucleotides Methods 0.000 claims description 2
- 239000003443 antiviral agent Substances 0.000 claims description 2
- 150000008209 arabinosides Chemical class 0.000 claims description 2
- 239000003886 aromatase inhibitor Substances 0.000 claims description 2
- 229960002756 azacitidine Drugs 0.000 claims description 2
- 229950011321 azaserine Drugs 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 229960000997 bicalutamide Drugs 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
- 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
- 229960001467 bortezomib Drugs 0.000 claims description 2
- 229940053031 botulinum toxin Drugs 0.000 claims description 2
- 229930188356 brevetoxin Natural products 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
- 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
- 229960004117 capecitabine Drugs 0.000 claims description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 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
- 229960005243 carmustine 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
- 229950007509 carzelesin Drugs 0.000 claims description 2
- 108010047060 carzinophilin Proteins 0.000 claims description 2
- 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 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 229950008249 chlornaphazine Drugs 0.000 claims description 2
- 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 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
- 229960002286 clodronic acid Drugs 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 230000000295 complement effect Effects 0.000 claims description 2
- 108010006226 cryptophycin Proteins 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
- 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
- 208000001848 dysentery Diseases 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
- 229950011487 enocitabine Drugs 0.000 claims description 2
- 229960001904 epirubicin Drugs 0.000 claims description 2
- 229950002973 epitiostanol Drugs 0.000 claims description 2
- 229930013356 epothilone Natural products 0.000 claims description 2
- 150000003883 epothilone derivatives Chemical class 0.000 claims description 2
- 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
- 229960001433 erlotinib Drugs 0.000 claims description 2
- 229940105423 erythropoietin 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
- 229950002017 esorubicin Drugs 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
- 229940126864 fibroblast growth factor 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
- 229960000961 floxuridine Drugs 0.000 claims description 2
- 229960000390 fludarabine Drugs 0.000 claims description 2
- 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 2
- 239000007850 fluorescent dye Substances 0.000 claims description 2
- 229960002949 fluorouracil Drugs 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
- 229960004783 fotemustine Drugs 0.000 claims description 2
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 claims description 2
- 229960002258 fulvestrant Drugs 0.000 claims description 2
- 229940044658 gallium nitrate Drugs 0.000 claims description 2
- 229960002584 gefitinib Drugs 0.000 claims description 2
- 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
- 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 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
- 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
- 239000003102 growth factor Substances 0.000 claims description 2
- 230000002440 hepatic effect Effects 0.000 claims description 2
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 2
- 125000005549 heteroarylene group Chemical group 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
- 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
- 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
- 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
- 229940079322 interferon Drugs 0.000 claims description 2
- 201000002313 intestinal cancer Diseases 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 229940043355 kinase inhibitor Drugs 0.000 claims description 2
- 229960004891 lapatinib Drugs 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
- 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
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 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
- 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 2
- 229950008612 mannomustine Drugs 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
- 229960004961 mechlorethamine Drugs 0.000 claims description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 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
- QRMNENFZDDYDEF-GOSISDBHSA-N methyl (8s)-8-(bromomethyl)-2-methyl-4-(4-methylpiperazine-1-carbonyl)oxy-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-1-carboxylate Chemical compound C1([C@H](CBr)CN(C1=C1)C(=O)C=2NC3=C(OC)C(OC)=C(OC)C=C3C=2)=C2C(C(=O)OC)=C(C)NC2=C1OC(=O)N1CCN(C)CC1 QRMNENFZDDYDEF-GOSISDBHSA-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
- 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
- 229960000951 mycophenolic acid Drugs 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
- 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
- 229950009266 nogalamycin Drugs 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 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
- 229950011093 onapristone Drugs 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 229960001756 oxaliplatin Drugs 0.000 claims description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 2
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 claims description 2
- 229960002340 pentostatin Drugs 0.000 claims description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 2
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 claims description 2
- 229950003180 peplomycin Drugs 0.000 claims description 2
- 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
- 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
- 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
- 229940097325 prolactin Drugs 0.000 claims description 2
- 239000003909 protein kinase inhibitor Substances 0.000 claims description 2
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 claims description 2
- 229950010131 puromycin Drugs 0.000 claims description 2
- 229960002185 ranimustine 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
- 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
- 229960003787 sorafenib 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
- 229960001603 tamoxifen Drugs 0.000 claims description 2
- 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 2
- 229960001278 teniposide 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
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 claims description 2
- 229950011457 tiamiprine Drugs 0.000 claims description 2
- 229960003087 tioguanine Drugs 0.000 claims description 2
- 229940044693 topoisomerase inhibitor 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
- 229960000303 topotecan 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
- 229960005026 toremifene Drugs 0.000 claims description 2
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 claims description 2
- 229950001353 tretamine Drugs 0.000 claims description 2
- 229960001727 tretinoin Drugs 0.000 claims description 2
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 claims description 2
- 229960001670 trilostane Drugs 0.000 claims description 2
- 229960001099 trimetrexate 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
- 229930184737 tubulysin Natural products 0.000 claims description 2
- GFNNBHLJANVSQV-UHFFFAOYSA-N tyrphostin AG 1478 Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1 GFNNBHLJANVSQV-UHFFFAOYSA-N 0.000 claims description 2
- 229950009811 ubenimex Drugs 0.000 claims description 2
- 229960001055 uracil mustard Drugs 0.000 claims description 2
- 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
- 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
- 229960002066 vinorelbine Drugs 0.000 claims description 2
- 229940053867 xeloda Drugs 0.000 claims description 2
- 229950009268 zinostatin Drugs 0.000 claims description 2
- 229960000641 zorubicin Drugs 0.000 claims description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 3
- 238000003776 cleavage reaction Methods 0.000 claims 2
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 230000007017 scission Effects 0.000 claims 2
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims 1
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims 1
- 229960005538 6-diazo-5-oxo-L-norleucine Drugs 0.000 claims 1
- 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 1
- 241001133287 Artocarpus hirsutus Species 0.000 claims 1
- 229910014276 N-Li Inorganic materials 0.000 claims 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims 1
- 229910014326 N—Li Inorganic materials 0.000 claims 1
- 239000012190 activator Substances 0.000 claims 1
- 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 1
- 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 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 claims 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims 1
- 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 1
- 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 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 1
- 230000000849 parathyroid Effects 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- 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 1
- 239000003814 drug Substances 0.000 abstract description 45
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 230000008685 targeting Effects 0.000 abstract description 5
- 239000002207 metabolite Substances 0.000 abstract description 2
- 230000002491 angiogenic effect Effects 0.000 abstract 1
- 230000003463 hyperproliferative effect Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 41
- 125000003275 alpha amino acid group Chemical group 0.000 description 33
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 17
- 238000002823 phage display Methods 0.000 description 12
- 125000006413 ring segment Chemical group 0.000 description 12
- 239000013598 vector Substances 0.000 description 12
- 108060003951 Immunoglobulin Proteins 0.000 description 11
- 102000018358 immunoglobulin Human genes 0.000 description 11
- 235000000346 sugar Nutrition 0.000 description 11
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 10
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 10
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229940125644 antibody drug Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 238000002869 basic local alignment search tool Methods 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 150000001768 cations Chemical class 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 150000001491 aromatic compounds Chemical class 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 101710119301 Protein delta homolog 1 Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 102000025171 antigen binding proteins Human genes 0.000 description 3
- 108091000831 antigen binding proteins Proteins 0.000 description 3
- 238000006664 bond formation reaction Methods 0.000 description 3
- 230000024245 cell differentiation Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 239000012829 chemotherapy agent Substances 0.000 description 3
- 239000000562 conjugate Substances 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 102000057336 human DLK1 Human genes 0.000 description 3
- 210000004408 hybridoma Anatomy 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- CTMHWPIWNRWQEG-UHFFFAOYSA-N 1-methylcyclohexene Chemical compound CC1=CCCCC1 CTMHWPIWNRWQEG-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-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
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 102000043279 ADAM17 Human genes 0.000 description 2
- 108091007505 ADAM17 Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 238000011230 antibody-based therapy Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].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 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000005488 carboaryl group Chemical group 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 2
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- QWHNJUXXYKPLQM-UHFFFAOYSA-N dimethyl cyclopentane Natural products CC1(C)CCCC1 QWHNJUXXYKPLQM-UHFFFAOYSA-N 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 229960005501 duocarmycin Drugs 0.000 description 2
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 2
- 229930184221 duocarmycin Natural products 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[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](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 2
- 239000000174 gluconic acid Substances 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 150000002632 lipids Chemical class 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- BDJAEZRIGNCQBZ-UHFFFAOYSA-N methylcyclobutane Chemical compound CC1CCC1 BDJAEZRIGNCQBZ-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methylcyclopentane Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000002891 organic anions Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 229940095574 propionic acid Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000003127 radioimmunoassay Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 241000894007 species Species 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000005030 transcription termination Effects 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 229910052720 vanadium Inorganic materials 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 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
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- OFZYBEBWCZBCPM-UHFFFAOYSA-N 1,1-dimethylcyclobutane Chemical compound CC1(C)CCC1 OFZYBEBWCZBCPM-UHFFFAOYSA-N 0.000 description 1
- PBIJFSCPEFQXBB-UHFFFAOYSA-N 1,1-dimethylcyclopropane Chemical compound CC1(C)CC1 PBIJFSCPEFQXBB-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- PUAKTHBSHFXVAG-UHFFFAOYSA-N 1,2-dimethylcyclobutene Chemical compound CC1=C(C)CC1 PUAKTHBSHFXVAG-UHFFFAOYSA-N 0.000 description 1
- SZZWLAZADBEDQP-UHFFFAOYSA-N 1,2-dimethylcyclopentene Chemical compound CC1=C(C)CCC1 SZZWLAZADBEDQP-UHFFFAOYSA-N 0.000 description 1
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VMLKTERJLVWEJJ-UHFFFAOYSA-N 1,5-naphthyridine Chemical compound C1=CC=NC2=CC=CN=C21 VMLKTERJLVWEJJ-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- MUPYMRJBEZFVMT-UHFFFAOYSA-N 1-chloro-4-dimethoxyphosphorylsulfanylbenzene Chemical compound COP(=O)(OC)SC1=CC=C(Cl)C=C1 MUPYMRJBEZFVMT-UHFFFAOYSA-N 0.000 description 1
- AVPHQXWAMGTQPF-UHFFFAOYSA-N 1-methylcyclobutene Chemical compound CC1=CCC1 AVPHQXWAMGTQPF-UHFFFAOYSA-N 0.000 description 1
- ATQUFXWBVZUTKO-UHFFFAOYSA-N 1-methylcyclopentene Chemical compound CC1=CCCC1 ATQUFXWBVZUTKO-UHFFFAOYSA-N 0.000 description 1
- SHDPRTQPPWIEJG-UHFFFAOYSA-N 1-methylcyclopropene Chemical compound CC1=CC1 SHDPRTQPPWIEJG-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- MFJCPDOGFAYSTF-UHFFFAOYSA-N 1H-isochromene Chemical compound C1=CC=C2COC=CC2=C1 MFJCPDOGFAYSTF-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- FJRPOHLDJUJARI-UHFFFAOYSA-N 2,3-dihydro-1,2-oxazole Chemical compound C1NOC=C1 FJRPOHLDJUJARI-UHFFFAOYSA-N 0.000 description 1
- ZABMHLDQFJHDSC-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazole Chemical compound C1NC=CO1 ZABMHLDQFJHDSC-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- BQTJMKIHKULPCZ-UHFFFAOYSA-N 2H-indene Chemical compound C1=CC=CC2=CCC=C21 BQTJMKIHKULPCZ-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- JZIBVTUXIVIFGC-UHFFFAOYSA-N 2H-pyrrole Chemical compound C1C=CC=N1 JZIBVTUXIVIFGC-UHFFFAOYSA-N 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- QMEQBOSUJUOXMX-UHFFFAOYSA-N 2h-oxadiazine Chemical compound N1OC=CC=N1 QMEQBOSUJUOXMX-UHFFFAOYSA-N 0.000 description 1
- BOLMDIXLULGTBD-UHFFFAOYSA-N 3,4-dihydro-2h-oxazine Chemical compound C1CC=CON1 BOLMDIXLULGTBD-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- VXIKDBJPBRMXBP-UHFFFAOYSA-N 3H-pyrrole Chemical compound C1C=CN=C1 VXIKDBJPBRMXBP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 1
- KSIJECNNZVKMJG-RXMQYKEDSA-N 5-oxo-l-norleucine Chemical compound CC(=O)CC[C@@H](N)C(O)=O KSIJECNNZVKMJG-RXMQYKEDSA-N 0.000 description 1
- 101710179738 6,7-dimethyl-8-ribityllumazine synthase 1 Proteins 0.000 description 1
- NJBMMMJOXRZENQ-UHFFFAOYSA-N 6H-pyrrolo[2,3-f]quinoline Chemical compound c1cc2ccc3[nH]cccc3c2n1 NJBMMMJOXRZENQ-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- PQJUJGAVDBINPI-UHFFFAOYSA-N 9H-thioxanthene Chemical compound C1=CC=C2CC3=CC=CC=C3SC2=C1 PQJUJGAVDBINPI-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- 101150081262 ARD4 gene Proteins 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 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
- 101100009548 Arabidopsis thaliana DHFS gene Proteins 0.000 description 1
- 101100186130 Arabidopsis thaliana NAC052 gene Proteins 0.000 description 1
- 101100529509 Arabidopsis thaliana RECQL4A gene Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000193388 Bacillus thuringiensis Species 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000912781 Carcharhinus galapagensis Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 101710094648 Coat protein Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical group OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000008961 Fibrous Dysplasia of Bone Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 108091092584 GDNA Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- 102100021181 Golgi phosphoprotein 3 Human genes 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 108010093488 His-His-His-His-His-His Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101100321817 Human parvovirus B19 (strain HV) 7.5K gene Proteins 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-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
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.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 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 1
- 101710186608 Lipoyl synthase 1 Proteins 0.000 description 1
- 101710137584 Lipoyl synthase 1, chloroplastic Proteins 0.000 description 1
- 101710090391 Lipoyl synthase 1, mitochondrial Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 1
- 101100162020 Mesorhizobium japonicum (strain LMG 29417 / CECT 9101 / MAFF 303099) adc3 gene Proteins 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000003019 Neurofibromatosis 1 Diseases 0.000 description 1
- 208000024834 Neurofibromatosis type 1 Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 108010070047 Notch Receptors Proteins 0.000 description 1
- 102000005650 Notch Receptors Human genes 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 101710141454 Nucleoprotein Proteins 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 102000015731 Peptide Hormones Human genes 0.000 description 1
- 108010038988 Peptide Hormones Proteins 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 1
- 101710083689 Probable capsid protein Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000589776 Pseudomonas putida Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- NSFWWJIQIKBZMJ-YKNYLIOZSA-N Roridin A Chemical compound C([C@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)[C@@H](O)[C@H](C)CCO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 NSFWWJIQIKBZMJ-YKNYLIOZSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 101100434411 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) ADH1 gene Proteins 0.000 description 1
- 101100203168 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) SGS1 gene Proteins 0.000 description 1
- 101100216053 Saccharomycopsis fibuligera GLA1 gene Proteins 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191965 Staphylococcus carnosus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 229930006000 Sucrose Natural products 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
- 241000282887 Suidae Species 0.000 description 1
- 101710143177 Synaptonemal complex protein 1 Proteins 0.000 description 1
- 102100036234 Synaptonemal complex protein 1 Human genes 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 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
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- CWRYPZZKDGJXCA-UHFFFAOYSA-N acenaphthene Chemical compound C1=CC(CC2)=C3C2=CC=CC3=C1 CWRYPZZKDGJXCA-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 101150102866 adc1 gene Proteins 0.000 description 1
- 101150042711 adc2 gene Proteins 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000005571 anion exchange chromatography Methods 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003302 anti-idiotype Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000009830 antibody antigen interaction Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229940097012 bacillus thuringiensis Drugs 0.000 description 1
- 239000013602 bacteriophage vector Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-L clondronate(2-) Chemical compound OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O ACSIXWWBWUQEHA-UHFFFAOYSA-L 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 239000013601 cosmid vector Substances 0.000 description 1
- 229960003624 creatine Drugs 0.000 description 1
- 239000006046 creatine Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- OOXWYYGXTJLWHA-UHFFFAOYSA-N cyclopropene Chemical compound C1C=C1 OOXWYYGXTJLWHA-UHFFFAOYSA-N 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- HGGNZMUHOHGHBJ-UHFFFAOYSA-N dioxepane Chemical compound C1CCOOCC1 HGGNZMUHOHGHBJ-UHFFFAOYSA-N 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 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
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229940046466 freeze it Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 150000002337 glycosamines Chemical group 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000010005 growth-factor like effect Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 238000012872 hydroxylapatite chromatography Methods 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000000879 imine group Chemical group 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910001412 inorganic anion Inorganic materials 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- KLEAIHJJLUAXIQ-JDRGBKBRSA-N irinotecan hydrochloride hydrate Chemical compound O.O.O.Cl.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 KLEAIHJJLUAXIQ-JDRGBKBRSA-N 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 210000003734 kidney Anatomy 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
- 208000032839 leukemia Diseases 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000003738 lymphoid progenitor cell Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 1
- VNXBKJFUJUWOCW-UHFFFAOYSA-N methylcyclopropane Chemical compound CC1CC1 VNXBKJFUJUWOCW-UHFFFAOYSA-N 0.000 description 1
- WPHGSKGZRAQSGP-UHFFFAOYSA-N methylenecyclohexane Natural products C1CCCC2CC21 WPHGSKGZRAQSGP-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 231100000324 minimal toxicity Toxicity 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- PUPNJSIFIXXJCH-UHFFFAOYSA-N n-(4-hydroxyphenyl)-2-(1,1,3-trioxo-1,2-benzothiazol-2-yl)acetamide Chemical compound C1=CC(O)=CC=C1NC(=O)CN1S(=O)(=O)C2=CC=CC=C2C1=O PUPNJSIFIXXJCH-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- GTWJETSWSUWSEJ-UHFFFAOYSA-N n-benzylaniline Chemical compound C=1C=CC=CC=1CNC1=CC=CC=C1 GTWJETSWSUWSEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- IVMHDOBGNQOUHO-UHFFFAOYSA-N oxathiane Chemical compound C1CCSOC1 IVMHDOBGNQOUHO-UHFFFAOYSA-N 0.000 description 1
- AZHVQJLDOFKHPZ-UHFFFAOYSA-N oxathiazine Chemical compound O1SN=CC=C1 AZHVQJLDOFKHPZ-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- XDJOIMJURHQYDW-UHFFFAOYSA-N phenalene Chemical compound C1=CC(CC=C2)=C3C2=CC=CC3=C1 XDJOIMJURHQYDW-UHFFFAOYSA-N 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- GJSGGHOYGKMUPT-UHFFFAOYSA-N phenoxathiine Chemical compound C1=CC=C2OC3=CC=CC=C3SC2=C1 GJSGGHOYGKMUPT-UHFFFAOYSA-N 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 210000000229 preadipocyte Anatomy 0.000 description 1
- 230000013823 prenylation Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 101150079601 recA gene Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- IMUQLZLGWJSVMV-UOBFQKKOSA-N roridin A Natural products CC(O)C1OCCC(C)C(O)C(=O)OCC2CC(=CC3OC4CC(OC(=O)C=C/C=C/1)C(C)(C23)C45CO5)C IMUQLZLGWJSVMV-UOBFQKKOSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000009131 signaling function Effects 0.000 description 1
- 102000035087 single-pass transmembrane proteins Human genes 0.000 description 1
- 108091005496 single-pass transmembrane proteins Proteins 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- YYMWVZQRBNARFZ-UHFFFAOYSA-M sodium;2-[2,3-bis(sulfanyl)propoxy]ethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCOCC(S)CS YYMWVZQRBNARFZ-UHFFFAOYSA-M 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 150000003505 terpenes Chemical group 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IFLREYGFSNHWGE-UHFFFAOYSA-N tetracene Chemical compound C1=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C21 IFLREYGFSNHWGE-UHFFFAOYSA-N 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- KHVCOYGKHDJPBZ-WDCZJNDASA-N tetrahydrooxazine Chemical compound OC[C@H]1ONC[C@@H](O)[C@@H]1O KHVCOYGKHDJPBZ-WDCZJNDASA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- GVIJJXMXTUZIOD-UHFFFAOYSA-N thianthrene Chemical compound C1=CC=C2SC3=CC=CC=C3SC2=C1 GVIJJXMXTUZIOD-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-O trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=[NH+]C(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-O 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
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
- A61K47/6851—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
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- 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
-
- 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
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/567—Framework region [FR]
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cell Biology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to: novel antibody-drug conjugates (ADC) targeting DLK1; active metabolites of the ADCs; a method for producing the ADCs; a use of the ADCs for treating and/or preventing diseases; and a use of the ADCs for producing medicaments for treating and/or preventing diseases, more specifically, hyperproliferative and/or angiogenic diseases such as cancer. More particularly, the present invention relates to an antibody-drug conjugate comprising an antibody binding to DLK1 or an antigen-binding fragment thereof, and to a pharmaceutical composition including same.
Description
ANTIBODY-DRUG CONJUGATES INCLUDING ANTIBODY
AGAINST HUMAN DLK1, AND USE THEREOF
TECHNICAL FIELD
The present invention relates to new antibody-drug conjugates (ADCs) targeting DLK1, active metabolites of such ADCs, methods for preparation of such ADCs, uses for such ADCs in treatment and/or prevention of illnesses, and uses for such ADCs in production of drugs for treatment and/or prevention of diseases, more specifically, uses for such ADCs in producing drugs for treatment and/or prevention of proliferative and/or angiogenetic diseases, for example, cancer.
More particularly, the present invention relates to an antibody-drug conjugate comprising an antibody binding with DLK1 or an antigen-binding fragment thereof, and a pharmaceutical composition comprising the same.
BACKGROUND
Cancer is a disease caused by abnormal lumps of uncontrolled cell growth in the tissues of the body, and is the result of uncontrolled cell growth in a variety of tissues. Tumors in early stage cancers may be removed through surgical and radiotherapeutic measures, and metastasized tumors are generally treated palliatively using chemotherapy.
Most chemotherapy agents administered non-orally may induce unwanted adverse effects or serious toxicity as a result of systemic administration. Accordingly, the focus of development has been on developing novel chemotherapy agents to achieve increased efficacy and minimal toxicity / adverse effects through improved and selective action of chemotherapy agents on tumor cells or immediately adjacent tissues.
An antibody-drug conjugate (ADC) is a new targeted technology where a toxin or drug is bonded to an antibody which in turn binds to an antigen, the toxin or drug released into a tumor cell, etc., to cause cell death. The technology has superior efficacy over antibody drugs, and is able to substantially reduce the risk of adverse effects compared to conventional anti-cancer agents, as it specifically delivers drugs to the target cancer cells with minimum impact to healthy cells, and only releases drugs under specific conditions.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 The basic structure of an antibody-drug conjugate is "antibody ¨ linker ¨
small molecule drug (toxin)". Here, the linker needs to play not only the functional role of linking the antibody and drug, but also ensure that the drug is released properly through antibody-drug dissociation (e.g. as a result of hydrolysis by enzyme) after being circulated through the body and reaching the target cells, and exhibits efficacy against the target cancer cells. That is, the stability of the linker plays a very important role in the efficacy and systemic toxicity of an antibody-drug conjugate (Discovery Medicine 2010, 10(53): 329-39).
The inventors of the present invention have developed and secured a patent for a linker including an effective self-immolative group, which is more stable in the plasma and in circulation, and allows a drug to be easily released and exhibit efficacy in a cancer cell (Korean Registered Patent No. 1,628,872, etc.). Meanwhile, use of monoclonal antibodies for cancer treatment is having substantial success. Monoclonal antibodies are suitable for target-oriented addressing of tumor tissue and tumor cells. Antibody-drug conjugates have become a novel and powerful option for therapy of lymphomas and solid tumors, and recently, immunoregulatory antibodies are seeing significant success in clinical trials. Development of therapeutic antibodies is based on a profound understanding of cancer serology, protein engineering technology, mechanisms of action and resistance, and interactions between immune systems and cancer cells.
Antigens which are expressed on the surface of human cancer cells are defined as a broad range of targets which are over-expressed compared to normal tissues, mutated or selectively expressed. The key problem is identifying the appropriate antigens for antibody-based therapies.
These therapeutic agents mediate changes in antigen or receptor function (i.e., as a stimulant or antagonist), regulate the immune system through Fc and T cell activation, and exhibit efficacy through the delivery of specific drugs that bind to antibodies targeting specific antigens. Molecular techniques that can alter antibody pharmacokinetics, functional function, size and immune stimulation are emerging as key elements in the development of novel antibody-based therapies.
Evidence from clinical trials of therapeutic antibodies in cancer patients highlights the importance of approaches for selecting optimized antibodies, including affinity and binding of the target antigen and antibodies, selection of antibody structure, and therapeutic approaches (blocking signaling or immune function).
Related research is in progress on antibodies whose antigen is DLK1. Human-derived DLK1 (delta-like 1 homolog (Drosophila)) is a single-pass transmembrane protein whose whole
AGAINST HUMAN DLK1, AND USE THEREOF
TECHNICAL FIELD
The present invention relates to new antibody-drug conjugates (ADCs) targeting DLK1, active metabolites of such ADCs, methods for preparation of such ADCs, uses for such ADCs in treatment and/or prevention of illnesses, and uses for such ADCs in production of drugs for treatment and/or prevention of diseases, more specifically, uses for such ADCs in producing drugs for treatment and/or prevention of proliferative and/or angiogenetic diseases, for example, cancer.
More particularly, the present invention relates to an antibody-drug conjugate comprising an antibody binding with DLK1 or an antigen-binding fragment thereof, and a pharmaceutical composition comprising the same.
BACKGROUND
Cancer is a disease caused by abnormal lumps of uncontrolled cell growth in the tissues of the body, and is the result of uncontrolled cell growth in a variety of tissues. Tumors in early stage cancers may be removed through surgical and radiotherapeutic measures, and metastasized tumors are generally treated palliatively using chemotherapy.
Most chemotherapy agents administered non-orally may induce unwanted adverse effects or serious toxicity as a result of systemic administration. Accordingly, the focus of development has been on developing novel chemotherapy agents to achieve increased efficacy and minimal toxicity / adverse effects through improved and selective action of chemotherapy agents on tumor cells or immediately adjacent tissues.
An antibody-drug conjugate (ADC) is a new targeted technology where a toxin or drug is bonded to an antibody which in turn binds to an antigen, the toxin or drug released into a tumor cell, etc., to cause cell death. The technology has superior efficacy over antibody drugs, and is able to substantially reduce the risk of adverse effects compared to conventional anti-cancer agents, as it specifically delivers drugs to the target cancer cells with minimum impact to healthy cells, and only releases drugs under specific conditions.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 The basic structure of an antibody-drug conjugate is "antibody ¨ linker ¨
small molecule drug (toxin)". Here, the linker needs to play not only the functional role of linking the antibody and drug, but also ensure that the drug is released properly through antibody-drug dissociation (e.g. as a result of hydrolysis by enzyme) after being circulated through the body and reaching the target cells, and exhibits efficacy against the target cancer cells. That is, the stability of the linker plays a very important role in the efficacy and systemic toxicity of an antibody-drug conjugate (Discovery Medicine 2010, 10(53): 329-39).
The inventors of the present invention have developed and secured a patent for a linker including an effective self-immolative group, which is more stable in the plasma and in circulation, and allows a drug to be easily released and exhibit efficacy in a cancer cell (Korean Registered Patent No. 1,628,872, etc.). Meanwhile, use of monoclonal antibodies for cancer treatment is having substantial success. Monoclonal antibodies are suitable for target-oriented addressing of tumor tissue and tumor cells. Antibody-drug conjugates have become a novel and powerful option for therapy of lymphomas and solid tumors, and recently, immunoregulatory antibodies are seeing significant success in clinical trials. Development of therapeutic antibodies is based on a profound understanding of cancer serology, protein engineering technology, mechanisms of action and resistance, and interactions between immune systems and cancer cells.
Antigens which are expressed on the surface of human cancer cells are defined as a broad range of targets which are over-expressed compared to normal tissues, mutated or selectively expressed. The key problem is identifying the appropriate antigens for antibody-based therapies.
These therapeutic agents mediate changes in antigen or receptor function (i.e., as a stimulant or antagonist), regulate the immune system through Fc and T cell activation, and exhibit efficacy through the delivery of specific drugs that bind to antibodies targeting specific antigens. Molecular techniques that can alter antibody pharmacokinetics, functional function, size and immune stimulation are emerging as key elements in the development of novel antibody-based therapies.
Evidence from clinical trials of therapeutic antibodies in cancer patients highlights the importance of approaches for selecting optimized antibodies, including affinity and binding of the target antigen and antibodies, selection of antibody structure, and therapeutic approaches (blocking signaling or immune function).
Related research is in progress on antibodies whose antigen is DLK1. Human-derived DLK1 (delta-like 1 homolog (Drosophila)) is a single-pass transmembrane protein whose whole
2 FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 chain comprises 383 amino acids. The protein has 6 EGF (epidermal growth factor-like repeat) domains in the extracellular domain.
DLK1 is generally referred to by the gene DLK1 due to its homology in amino acid sequence with Delta, a ligand of the Notch receptor which is a cell differentiation control factor, and other names by which it is referred to are Pref-1, pG2, SCP-1 and ZOG.
While DLK1 is a transmembrane protein, it is well reported as a protein where the extracellular domain is shed from the cell membrane by TACE (Tumor necrosis factor alpha converting enzyme) and functions separately.
DLK1 exhibits high expression in undifferentiated fetal cells with a high proliferation index. In particular, whereas high expression is exhibited in the liver, kidneys, skeletal muscles and brain, etc., of the fetus, expression is not seen in most tissues after birth, with expression limited to only certain cells such as preadipocytes, pancreatic islet cells, thymic stromal cells and adrenal gland cells.
As for research into the functions of DLK1, DLK1 is most researched as Pref-1 (preadipocyte factor-1) which is a factor that inhibits adipose cell differentiation. Aside from its ability to suppress adipose cell differentiation, DLK1 is reported to be able to suppress differentiation of hematopoietic stem cells, to play a role in regulating differentiation of lymphoid progenitor cells, and to be associated with wound healing.
Further, DLK1 is reported as being expressed with high frequency in various cancers or tumors. Cancers in which the expression of DLK1 has been confirmed to date include the solid cancers of neuroendocrine tumors, neuroblastoma, glioma, neurofibromatosis type 1, small cell lung cancer, liver cancer, renal cancer, ovarian cancer, colorectal cancer, breast cancer and pancreatic cancer, and the blood cancers of myelodysplastic syndrome and acute myeloid leukemia. As for research on the association between nDLK1 and cancer, there have been reports that DLK1 is over-expressed in brain cancer cells (gliomas), and that overexpressing the cDNA of DLK1 in brain cancer cells increases proliferation and migration of brain cancer cells. It has also been reported that DLK1 expression in liver cancer is elevated compared to normal liver cells, and that when DLK1 expression is reduced through siRNA tests, tumor size decreases.
To this technical background, the inventors of the present invention have worked to develop antibodies which bind specifically to DLK1, as a result developing anti-DLK1 antibody exhibiting superior binding to DLK1. The inventors have confirmed that, by applying a linker
DLK1 is generally referred to by the gene DLK1 due to its homology in amino acid sequence with Delta, a ligand of the Notch receptor which is a cell differentiation control factor, and other names by which it is referred to are Pref-1, pG2, SCP-1 and ZOG.
While DLK1 is a transmembrane protein, it is well reported as a protein where the extracellular domain is shed from the cell membrane by TACE (Tumor necrosis factor alpha converting enzyme) and functions separately.
DLK1 exhibits high expression in undifferentiated fetal cells with a high proliferation index. In particular, whereas high expression is exhibited in the liver, kidneys, skeletal muscles and brain, etc., of the fetus, expression is not seen in most tissues after birth, with expression limited to only certain cells such as preadipocytes, pancreatic islet cells, thymic stromal cells and adrenal gland cells.
As for research into the functions of DLK1, DLK1 is most researched as Pref-1 (preadipocyte factor-1) which is a factor that inhibits adipose cell differentiation. Aside from its ability to suppress adipose cell differentiation, DLK1 is reported to be able to suppress differentiation of hematopoietic stem cells, to play a role in regulating differentiation of lymphoid progenitor cells, and to be associated with wound healing.
Further, DLK1 is reported as being expressed with high frequency in various cancers or tumors. Cancers in which the expression of DLK1 has been confirmed to date include the solid cancers of neuroendocrine tumors, neuroblastoma, glioma, neurofibromatosis type 1, small cell lung cancer, liver cancer, renal cancer, ovarian cancer, colorectal cancer, breast cancer and pancreatic cancer, and the blood cancers of myelodysplastic syndrome and acute myeloid leukemia. As for research on the association between nDLK1 and cancer, there have been reports that DLK1 is over-expressed in brain cancer cells (gliomas), and that overexpressing the cDNA of DLK1 in brain cancer cells increases proliferation and migration of brain cancer cells. It has also been reported that DLK1 expression in liver cancer is elevated compared to normal liver cells, and that when DLK1 expression is reduced through siRNA tests, tumor size decreases.
To this technical background, the inventors of the present invention have worked to develop antibodies which bind specifically to DLK1, as a result developing anti-DLK1 antibody exhibiting superior binding to DLK1. The inventors have confirmed that, by applying a linker
3 FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 including an effective self-immolative group, which is more stable in the plasma and in circulation, and allows a drug to be easily released and exhibit efficacy in a cancer cell, to the anti-DLK1 antibody to further reinforce the effect of the antibody, it is possible to provide a novel antibody-drug conjugate (ADC) which targets DLK1 and is effective at treating and/or preventing cancer illnesses, and thereby completed the present invention.
DETAILED DESCRIPTION OF THE INVENTION
TECHNICAL PROBLEM
A purpose of the present invention is to provide a novel antibody-drug conjugate targeting DLK1, or a salt or solvate thereof.
Another purpose of the present invention is to provide a drug-antibody conjugate including an antibody which binds specifically to DLK1 and a drug binding thereto, and a pharmaceutical composition including the same.
Another purpose of the present invention is to provide a method for preventing or treating a proliferative, cancer or angiogenetic disease, the method comprising a step of administering an individual with an antibody-drug conjugate comprising a pharmaceutically efficacious amount of antibody which specifically binds to DLK1 and a drug which binds to the same.
Another purpose of the present invention is to provide a use for an antibody-drug conjugate comprising a pharmaceutically efficacious amount of antibody which specifically binds to DLK1 and a drug which binds to the same as a pharmaceutical composition for preventing or treating a proliferative, cancer or angiogenetic disease.
Yet another purpose of the present invention is to provide an antibody-linker-drug (toxin) system which allows a drug and/or toxin to safely reach a target cell and effectively exhibit efficacy while substantially reducing toxicity, by grafting technology for a linker including a self-immolative group which is more stable in the plasma and in circulation, and allows a drug to be easily released in a cancer cell to maximize efficacy.
TECHNICAL SOLUTION
One aspect of the present invention provides an antibody conjugate of the General Formula I, or a pharmaceutically acceptable salt or solvate thereof.
[General Formula I] Ab ¨ (X)y
DETAILED DESCRIPTION OF THE INVENTION
TECHNICAL PROBLEM
A purpose of the present invention is to provide a novel antibody-drug conjugate targeting DLK1, or a salt or solvate thereof.
Another purpose of the present invention is to provide a drug-antibody conjugate including an antibody which binds specifically to DLK1 and a drug binding thereto, and a pharmaceutical composition including the same.
Another purpose of the present invention is to provide a method for preventing or treating a proliferative, cancer or angiogenetic disease, the method comprising a step of administering an individual with an antibody-drug conjugate comprising a pharmaceutically efficacious amount of antibody which specifically binds to DLK1 and a drug which binds to the same.
Another purpose of the present invention is to provide a use for an antibody-drug conjugate comprising a pharmaceutically efficacious amount of antibody which specifically binds to DLK1 and a drug which binds to the same as a pharmaceutical composition for preventing or treating a proliferative, cancer or angiogenetic disease.
Yet another purpose of the present invention is to provide an antibody-linker-drug (toxin) system which allows a drug and/or toxin to safely reach a target cell and effectively exhibit efficacy while substantially reducing toxicity, by grafting technology for a linker including a self-immolative group which is more stable in the plasma and in circulation, and allows a drug to be easily released in a cancer cell to maximize efficacy.
TECHNICAL SOLUTION
One aspect of the present invention provides an antibody conjugate of the General Formula I, or a pharmaceutically acceptable salt or solvate thereof.
[General Formula I] Ab ¨ (X)y
4 HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Where:
Ab is an anti-DLK1 antibody or an antigen-binding fragment thereof, X is independently a chemical residue comprising at least one active agent and a linker, and;
the linker links an antibody and the active agent, and;
y is an integer from 1 through 20.
The anti-DLK1 antibody or antigen-binding fragment thereof, that is the antibody which binds to DLK1 or antigen-binding fragment of the same, comprises: a heavy chain variable region comprising at least one heavy chain CDR1 selected from the group comprising SEQ ID NO. 2, 16, 30, 44, 58, 72 and 86, at least one heavy chain CDR2 selected from the group comprising SEQ ID
NO. 4, 18, 32, 46, 60, 74 and 88, and at least one heavy chain CDR3 selected from the group comprising SEQ ID NO. 6, 20, 34, 48, 62, 76 and 90, and;
a light chain variable region comprising at least one light chain CDR1 selected from the group comprising SEQ ID No. 9, 23, 37, 51, 65, 79, 93, 115 and 121, at least one light chain CDR2 selected from the group comprising SEQ ID No. 11, 25, 39, 53, 67, 81 and 95, and at least one light chain CDR3 selected from the group comprising SEQ ID No.
13, 27, 41, 55, 69, 83, 97, 116 and 125.
The antibody according to the present invention may, for example, bind specifically to the extracellular domain of human DLK1.
The term "antibody" as used in the present specification refers to DLK1, in particular anti-DLK1 antibody which binds specifically to the extracellular domain of human DLK1 protein.
Included in the scope of the present invention is not only the complete form of the antibody which binds specifically to DLK1, but also antigen-binding fragments of the antibody molecule.
The complete antibody has a structure having 2 full length heavy chains and 2 full length light chains, the respective light chains linked to a heavy chain by a disulfide bond. The heavy chain constant regions have types gamma (y), mu (u), alpha (a), delta (6) and epsilon (6), with sub-classes gammal (y1), gamma2 (y2), gamma3 (y3), gamma4 (y1), alphal (al) and a1pha2 (a2). The light chain constant region has types kappa (x) and lambda (k).
An antigen-binding fragment of an antibody or antibody fragment refers to a fragment with the functionality to bind to an antigen, and includes Fab, F(ab'), F(ab')2 and Fv, etc. Among antibody fragments, Fab has a structure of light chain and heavy chain variable regions, a light chain constant region and a first constant region of a heavy chain (C111), and 1 antigen-binding FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 site. Fab' differs from Fab in that it has a hinge region comprising at least one cysteine residue at the C-terminal of the heavy chain CH1 domain. The F(ab)'2 antibody is formed when the cysteine residue of the hinge region of Fab' forms a disulfide bond. Fv is a minimum antibody fragment which only has a heavy chain variable region and light chain variable region, and recombinant technologies for preparing Fv fragments are disclosed in PCT International Published Patent Applications W088/10649, W088/106630, W088/07085, W088/07086 and W088/09344. A
two-chain Fv has a heavy chain variable region and light chain variable region linked by a non-covalent bond, and a single-chain Fv (scFv) generally has a heavy chain variable region and light chain variable region linked by a covalent bond through a peptide linker, or linked directly at the C-terminal, allowing it to form structures such as a dimer, as can a two-chain Fv. Such antibody fragments may be obtained by using protein hydrolyzing enzyme (for example, restriction cutting the entire antibody with papain yields Fab, and cutting with pepsin can yield F(ab)'2 fragment), and may also be prepared using gene recombinant technology.
In embodiments, the antibody according to the present invention is of the Fv form (for example, scFv), or in its complete antibody form. Further, the heavy chain constant region may be any one isotype selected from among gamma (y), mu (u), alpha (a), delta (6) and epsilon (6). For example, the constant region is Gammal (IgG1), Gamma3 (IgG3) or Gamma4 (IgG4).
The light chain constant region may be the kappa or lambda type.
The term "heavy chain" as used in the present specification refers to the full length heavy chain comprising the variable region domain VH which comprises amino acid sequences having sufficient variable region sequences to give antigen specificity and the three constant region domains CH1, CH2 and CH3, and all fragments of the same. Further the term "light chain" as used in the present specification refers to the full length light chain comprising the variable region domain VL which comprises amino acid sequences having sufficient variable region sequences to give antigen specificity and the constant region domain CL, and all fragments of the same.
The antibody of the invention includes, but is not limited to, monoclonal antibody, multispecific antibody, human antibody, humanized antibody, chimera antibody, single chain Fvs (scFV), single chain antibody, Fab fragment, F(ab') fragment, disulfide-bond Fvs (sdFV) and anti-idiotype (anti-Id) antibody, or epitope-binding fragments of the above antibodies, etc.
Monoclonal antibodies refer to antibodies obtained from a substantially homogeneous antibody group, that is, except for possible naturally occurring mutations in which individual HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 antibodies that occupy the population may be present in minor amounts.
Monoclonal antibodies are highly specific and are directed against a single antigenic site. In contrast to a conventional (polyclonal) antibody formulation which comprises different antibodies directed to different determining factors, the respective monoclonal antibodies are directed against a single determining factor on the antigen. For example, the useful monoclonal antibodies of the present invention may be prepared using the hybridoma method, or by using recombinant DNA methods on bacteria or eukaryotic animal cells or plant cells (see US Patent 4,816,567). Further, the monoclonal antibody may be isolated from a phage antibody library.
In one embodiment of the present invention, the phage display method was used to pan a natural human single chain Fv library (native human single chain Fv library) to prepare seven types of monoclonal human antibody which bind specifically to DLK1.
"Phage display" is a technique for displaying a mutant polypeptide as a fusion protein with the phage, for example, at least part of the coat protein on the surface of the phage particle. The usefulness of phage display is that large libraries of randomized protein variants may be targeted to quickly and efficiently classify sequences that bind to target antigens in high affinity. Displaying peptides and protein libraries on phages has been used to screen millions of polypeptides to identify polypeptides with specific binding properties.
Phage display technology has provided a powerful tool for generating and screening new proteins that bind to specific ligands (e.g. antigens). Using phage display technology, large libraries of protein variants may be generated and sequences that bind with high affinity to target antigens may be quickly classified. The nucleic acid encoding the mutant polypeptide is fused with a nucleic acid sequence encoding a viral coat protein, e.g. a gene III protein or a gene VIII protein.
A monophasic phage display system has been developed in which a nucleic acid sequence encoding a protein or polypeptide is fused with a nucleic acid sequence encoding a part of the gene III protein. In the 1-phage display system, the gene fusion is expressed at a low level and the wild-type gene III protein is also expressed, thereby maintaining the infectivity of the particles.
Demonstrating the expression of peptides on the fibrous phage surface and the expression of functional antibody fragments in the peripheral cytoplasm of E. coli is important in developing antibody phage display libraries. Libraries of antibodies or antigen-binding polypeptides have been prepared in a number of ways, for example by altering a single gene by inserting a random DNA
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 sequence, or by cloning a related gene sequence. The library may be screened for the expression of antibodies or antigen binding proteins with the desired characteristics.
Phage display technology has several advantages over conventional hybridomas and recombinant methods for producing antibodies with the desired characteristics.
This technique allows the generation of large antibody libraries with a variety of sequences in a short time without the use of animals. The production of hybridomas and the production of humanized antibodies may require several months of manufacturing time. In addition, since no immunity is required, the phage antibody library can generate antibodies against antigens that are toxic or have low antigenicity. Phage antibody libraries can also be used to generate and identify novel therapeutic antibodies.
Techniques for generating human antibodies from non-immunized humans, germline sequences, or sub-sensitized B cell Ig repertoires may be used, which are immunized using a phage display library. Various lymphatic tissues may be used to prepare an undetected or non-immunogenic antigen-binding library.
Techniques for identifying and separating high affinity antibodies from phage display libraries are important for new antibody separation for therapy. The separation of high affinity antibodies from the library can depend on the size of the library, the production efficiency in bacterial cells and the variety of libraries. The size of the library is reduced by inefficient folding of the antibody or antigen binding protein and inefficient production due to the presence of the stop codon. Expression in bacterial cells may be inhibited when the antibody or antigen binding domain is not properly folded. Expression may be improved by alternately mutating the residues at the surface of the variable / constant interface or the selected CDR
residues. The sequence of the framework region is one element to provide appropriate folding in the case of generating antibody phage libraries in bacterial cells.
It is important to generate various libraries of antibody or antigen binding proteins in high affinity antibody separation. CDR3 regions have been found to often participate in antigen binding.
The CDR3 region on the heavy chain varies considerably in terms of size, sequence and structural conformation, and thus various libraries may be prepared using the CDR3 region.
Also, diversity may be generated by randomizing the CDR regions of the variable heavy and light chains using all 20 amino acids at each position. The use of all 20 amino acids results in HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 an increased variability in antibody sequences and an increased chance of identifying new antibodies.
"Epitope" refers to a protein determinant to which an antibody can specifically bind.
Epitopes usually consist of a group of chemically active surface molecules, such as amino acids or sugar side chains, and generally have specific three-dimensional structural characteristics as well as specific charge characteristics. Three-dimensional epitopes and non-stereo epitopes are distinguished in that the binding to the former is lost but not to the latter in the presence of a denatured solvent.
The non-human (e.g., murine) antibody of the "humanized" form is a chimeric antibody containing minimal sequence derived from non-human immunoglobulin. In most cases, the humanized antibody is a non-human species (donor antibody), such as a mouse, a rat, a rabbit or a non-human, having a desired specificity, affinity and ability to retain a residue from the hypervariable region of the recipient and is a human immunoglobulin (acceptor antibody) that has been replaced with a residue from the hypervariable region of the primate.
The above-mentioned "human antibody" means a molecule derived from human immunoglobulin, wherein all the amino acid sequences constituting the antibody including the complementarity determining region and the structural region are composed of human immunoglobulin.
The other chain(s) may be derived from another species or may be derived from another antibody class or subgroup, such as a portion of the heavy chain and / or light chain derived from a particular species or identical or homologous to a corresponding sequence in an antibody belonging to a particular antibody class or subclass, "chimeric" antibodies (immunoglobulins) identical or homologous to the corresponding sequences in antibodies belonging to the subclass as well as fragments of said antibodies exhibiting the desired biological activity.
As used herein, an "antibody variable domain" refers to the light and heavy chain portions of an antibody molecule comprising complementarity determining regions (CDRs;
i.e., CDR1, CDR2, and CDR3), and the amino acid sequence of the framework region (FR) . VH
refers to the variable domain of the heavy chain. VL refers to the variable domain of the light chain.
"Complementarity determining regions" (CDRs; i.e., CDR1, CDR2, and CDR3) refer to the amino acid residues of an antibody variable domain that are necessary for antigen binding.
Each variable domain typically has three CDR regions identified as CDR1, CDR2 and CDR3.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 In the present invention, the antibody binding to DLK1 or an antigen-binding fragment thereof may specifically include the CDR sequences stated in Table 1 below. Of these, Korean Patent Application No. 10-2018-0107639 has confirmed that the anti-DLK1 antibodies of two types (18A5 and 27F7) and two other 18A5 mutant antibodies (18A5 LS 1A10 and 18A5 AM 1Al2) are capable of binding to cells where DLK1 is overexpressed, and may be developed into anti-DLK1 antibody-drug conjugates which can target DLK1 expressed on the surface of cancer cells to cause cancer cell apoptosis.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 [Table 1]
, __________________________________________________ =
SEQ ID
done nu Cb81 ER2 CDR2 FR3 CND FM
NO.
QvQ1. YSADSA'K
VV1G MSWV GRFTISR TREG varGQ
17811- , GUN CTh RQTPG ITKS DNsiCs-TL LGYY GTIV 99 NC QPGG SSBA KOLE GS GT YLQNINSL YGNID
, SLRU WVSS RAEDTAV V
CAAS YYC
SEQ ID NO. 1 2 3 4 5 7 N RPSGVP
QQLPG SGTSASI. 171111- SGAPG GAG GST
NW* TKVT 100 LW LC TAPRL A1TGLQA RYV vL QRvIl YD F.DRADYY
SCTGS
SEQIDNO 8 9 to 11 12 13 14 QvQL NYADSVK
VQSG 11INA v sin) GRLTIS1R vRivw weal 111A5- GA"' Q PG GRN "Nsic"rn 0c QpGa KC,117 SFQ 1.4 INSL T Tvss stens a .4Ir 111 . µN " 67' RAEDTAV
SEAS ' ________________________________________________________________ ,sEct ID NO 15 141 17 11 19 2$ 21 IMQK SLQSAvAS
TQSPS I. MAN
RFSGsGS QD I PAS- ELSA'S QQKP GAA. GrEFILri ()WY ITGGG
v M
ssLQ= FEDF IK
VN1TC tor,Liv ANYYC
RAs , \
ANY
SEQ ID NO 22 23 24 25 20 27 2$
QMQL GYADSVK
VQSG XII1vvv caurnsR TKGP WGQ
20D3- GGIN RQA PG 1SWN DNAKNS1. GLA1 HC Bey V
QPGRS . KGLE SGS1 YLQYINSL GICVY .re GTQ 103 ss LRLSC A WVSG RAEDTAV ENS a AAS YYC
¨
FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 t _____ . r ___________________________________________________ -1 - D1QM TL li NGV P
, TQSPS 1 LAWY SRFSGSAS FGQG ' 21103- SVSAS I QR1S QQKP n LC ' YGDR SW GRApK SAS crprru SSLQPEDF QQGH I TtiLD 104 SFPVT
' VT1TC LLIII , i AIINC
RAS
SEQ ID NO , 36 37 38 39 40 41 42 QVQL ' TYADSVK , ' VESG MNWV ' GRFTISR ARGY
21011- GGLV GFTF RQAPG 1SPD DNAK WGQNTL , SPKYP laa SSY
IIC ( QPGG KGI.V GSSI YLQININSL 1 TVGL GTE! air*P
W TVSS ' , SIR IS WVSR RAEDTAV DV
CAAS __ r YYC ;
SEQ ID NO. 43 44 45 46 47 45 49 DIVNIT ' NRFSGVP
, QSPLS ' ESLL LTWL DRFSGSC , veer", ' iptletel 211/11- 1, SPVTL USN QQRP ' AGTDFTL v 'gm4W1 -, 1 TKVII 1"
LC GQPAS GNT GQPPR KIS QITRVET
' INT ISCRS V LI.III EDVGµlir 1K
h , $ C
i SEQ ID NO , SO ' 51 32 53 1 54 . 55 . 54 , . _ QVQL i LYAQKFQ 1 ' VOSG 1111WV1 t rn $ I GRVTMT ARLN WGQ
21F9- AEVK GYSL QAPR new 1 EDTSTDT ' YFEST ' GTM iai HC KPGAS
SEFP MG111 ""µ.¨ 1 AYWIELSS ' DYWV VTV'S ""
VRVSC WilIGG TLIPSZDTA DAFDI $
ICVS I VYYC : ' f 4 SEQ ID NO, 57 58 lip 0 'a a 43 '. _____________________________________________________________________ , QRPSGVP
QLVLT , VQWY . DRFSGSID
2IF9- '' QPYSV SGSI QQRP gnat . SMNsAst QSYD FG`'"
Lc, SESPG
ASNF GSAPT m's." T1SGVMT SGSS TKLT 108 CTRS i C
_________________________________________________________________ = X
SEQ ID NO. 64 65 66 67 i 411 69 711 1 , i I-FHBOSTON5259862.1 Date Regue/Date Received 2021-08-09 QMQL I YVADSVIC .
VESG 3L'SWV GRFTISR
GFNF .ARD4;) WGII
27F7- GGLV RQAPG 1SST DNAKSSL.
Y GIIDV TVSS
SITLS WLAH RAEDTAV .
C'DAT , YY'C" ' , .
SEQ ID
71. 72: 73 74 75 . 76 . 77 ' NR.PSGVP
QL11õ,T
VDWY DRFSGSK ' .27F7 QPSSV SSNI QSYD ' F.GGG
- QQLPG SGTSASL .
SGAPG GAG GNT SSL.SA. ThIT 110 LC TAPKL AITGLQA QRVTI YD
, LIY EDDSDYY
,SCTGS
C
., SEQ ID
NO 7$ 74 ' 80 II 82 83 84 . , .QVQ,L, YVADSVIC ' AREG ,.
V"ESG NIIIW'V G,RFTISR
. SYDV WGQ , 35E2- GGVV GFTF RQAPG 'nrsc DNSICNTL
AITYT GAIN' HC QPGR.S SSYA KGLE GST YLQNEVSL . 111 IRIGG TVSS
LRLSC WVAV ItAEDIAV .
VF'Dli AAS YY'C , .õ.
SEQ ID
S5 84 ' 17 88 89 90 91 DIQA1 ,, , SLQSGVP , TQSPS ' VAWY
SRESGSG FGPG
35E2.. SVSAS QGIS QQKP QQA.N
LC VGT3R DW GICAõP SFPLT
ISNLQPE pc v""rtrc . .KLL1Y
D'FATYYC
RAS
, SEQ ID
NO. 92 93 . 94 95 96 97 98 QVQL NYADSVK
õ
18A5 17()SG Gn: '51H10.17 / - GRLTLSR von, 11, urftri , .LS,..li GAVV , ' RQAPG ' DNS-lei-IL .7.- - --"c QPG11 If SFQ1µLNSL . ' YG K . DI TVSS
-BC SI,.RI.S . 'Wlõ,AV . RAEDTAA' , CFAS ' YYC , SEQ ID
NO.
16 ' 17 18 19 20 21 , FIII30STON5259862.1 Date Recue/Date Received 2021-08-09 SLQSGVP
1 QSPS LAWVi SI,S AS QGTS QQKP QQSY
LS 1 A A AS SGTDFT1 LG OR SA 1 CKAP I I Pi. 1 TKVF 126 RAS I KHAN
I lliõ111 AC II
, __________________________________________________________ 1 ____ SEQ ID I
-- +-QVQL NY AD
18 A5 VW; NIHNNT GRI,TISR
(.FK ISM) N-RDW 11-(';(,) A NI I (,,;(.,1 V RQ1PC 1INSK\ 11, 1,12 Q14.(i II; K(4.1: 1 t l R1 W R s. S
CA-1S il..NN' K SFQN1NSI.
11311 : 1V
INC SN AI- ( ;I 1 N 127 Il 1)1 LASS
119 16 ' 1 *7 18 19 211 21 No.
NI KM-AT
18,15_ TQSPS L.µWY
SRFSGSG ()QS' 171-,C;f;
k A 1 i FLSAS IIDIS (:)()KS
_ sAS s( ,1111,SI, I IA 1 1 KL1. 128 i Al2 \ GDR SS C.I.A1' 11SSLQIIE I 1k , I Lt \111(' Kt L11 DI-All Nt RAS , 1 , SEQ11) 121/ 121 j 122 39 123 124 125 A "framework region" (FR) is a variable domain residue other than a CDR
residue. Each variable domain typically has four FRs identified as FR1, FR2, FR3, and FR4.
Embodiments of the present invention may comprise: at least one heavy chain FR1 selected from the group comprising SEQ ID No. 1, 15, 29, 43, 57, 71, 85 and 119; at least one heavy chain FR2 selected from the group comprising SEQ ID No. 3, 17, 31, 45, 59, 73 and 87; at least one heavy chain FR3 selected from the group comprising SEQ ID No. 5, 19, 33, 47, 61, 75 and 89; at least one heavy chain FR4 selected from the group comprising SEQ ID No. 7, 21, 35, 49, 63, 77 and 91; at least one light chain FR1 selected from the group comprising SEQ ID
No. 8, 22, 36, 50, 64, 78, 92, 117 and 120; at least one light chain FR2 selected from the group comprising SEQ ID
No. 10, 24, 38, 52, 66, 80, 94 and 122; at least one light chain FR3 selected from the group comprising SEQ ID No. 12, 26, 40, 54, 68, 82, 96, 118 and 123, and; at least one light chain FR4 selected from the group comprising SEQ ID No. 14, 28, 42, 56, 70, 84, 98 and 125.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 An "Fv" fragment is an antibody fragment that contains complete antibody recognition and binding sites. This region consists of one heavy chain variable domain and one light chain variable domain, for example, dimers substantially tightly covalently associated with scFv.
A "Fab" fragment contains the variable and constant domains of the light chain and the variable and first constant domain (CH1) of the heavy chain. F(ab')2 antibody fragments generally comprise a pair of Fab fragments covalently linked by their hinge cysteine near their carboxy ends.
A "single chain Fv" or "scFv" antibody fragment comprises the VH and VL
domains of an antibody, which domains are within a single polypeptide chain. The Fv polypeptide may further comprise a polypeptide linker between the VH domain and the VL domain such that the scFv can form the desired structure for antigen binding.
The antibody according to the present invention may be monovalent or divalent, and comprises a single chain or a double chain.
Functionally, the binding affinity of the antibody to the extracellular domain of DLK1 is in a range of 10-5M to 10-12M. For example, the binding affinity is 10-6M to 10-12M, 10-7M to 10-M
'2", 108M to 10'2M, 109M to 10'2M, 105M to 10"M, 106M to 10"M, 107M to 10"M, 10-81\4 to 10"M, 10-9M to 10-11m, 10-10A4 to 10M, -H¨¨, 10-5M to 10-0M 1 10-6M to 10-1 M, 10-7M to 10 M-10", 10-8M to 10' M, 10-9M to 10' M, 10-5M to 10-9M, 10-6M to 10-9M, 10-7M to 10-9M, 10-8M
to 10-9M, 10-5M to 10-8M, 10-6M to 10-8M, 10-7M to 10-8M, 10-5M to 10-7M, 10-6M to 10-7M or 10-5M to 10-6M.
Further, the antibodies of the present invention are antibodies with increased affinity for the antigen. The term "affinity" refers to the ability to specifically recognize and bind to specific sites of an antigen. High specificity, together with the specificity of these antibodies, is an important factor in the immune response. Any of various analyses known to the art, for example radioimmunoassays (RIA) and ELISA may be used to determine affinity, which may be expressed as various quantitative values. The affinity of an antibody to an antigen may generally be represented by the dissociation constant (Kd) of a specific antibody-antigen interaction. A lower Kd value indicates higher affinity of an antibody to an antigen. For example, the Kd value of the 18A5 antibody of the present invention is 0.52, and that of the 27F7 antibody is 0.22. This indicates these are high-affinity antibodies which bind with specificity to human DLK1.
The antibody binding to the extracellular domain of DLK1, or antigen-binding fragment thereof, may comprise a heavy chain variable region including a sequence that has at least 90%
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 sequence homology with a sequence selected from the group comprising SEQ ID
No. 99, 101, 103, 105, 107, 109, 111 and 127. The antibody binding to the extracellular domain of DLK1, or antigen-binding fragment, thereof, may comprise a heavy chain variable region selected from the group comprising SEQ ID No. 99, 101, 103, 105, 107, 109, 111 and 127.
Further, the antibody binding to the extracellular domain of DLK1, or antigen-binding fragment thereof, may comprise a light chain variable region including a sequence that has at least 90% sequence homology with a sequence selected from the group comprising SEQ
ID No. 100, 102, 104, 106, 108, 110, 112, 126 and 128. The antibody binding to the extracellular domain of DLK1, or antigen-binding fragment, thereof, may comprise a light chain variable region selected from the group comprising SEQ ID No. 100, 102, 104, 106, 108, 110, 112, 126 and 128.
The antibody or antibody fragment of the present invention may contain, within the scope of specifically recognizing DLK1, the sequence of the anti-DLK1 antibody of the present invention described herein as well as biological equivalents thereof. For example, additional changes may be made to the amino acid sequence of the antibody to further improve the binding affinity and /
or other biological properties of the antibody. Such modifications include, for example, deletion, insertion and / or substitution of the amino acid sequence residues of the antibody. Such amino acid variations are made based on the relative similarity of the amino acid side chain substituents, such as hydrophobicity, hydrophilicity, charge, size, and the like. By analysis of the size, shape and type of amino acid side chain substituents, arginine, lysine and histidine are both positively charged residues; Alanine, glycine and serine have similar sizes;
Phenylalanine, tryptophan and tyrosine have similar shapes. Thus, based on these considerations, arginine, lysine and histidine;
alanine, glycine and serine; and phenylalanine, tryptophan and tyrosine are biologically functional equivalents.
Considering the mutation having the above-mentioned biological equivalent activity, the antibody of the present invention or the nucleic acid molecule encoding the same is interpreted to include a sequence showing substantial identity with the sequences under SEQ
ID NO. The above-mentioned substantial identity is determined by aligning the above-described sequence of the present invention with any other sequence as much as possible and analyzing the aligned sequence using an algorithm commonly used in the art, with a homology of at least 90%, and most preferably at least 95% homology, at least 96%, at least 97%, at least 98%, or at least 99%.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Alignment methods for sequence comparison are well known in the art. The NCBI
Basic Local Alignment Search Tool (BLAST) is accessible from NBCI and may be used in conjunction with sequence analysis programs such as blastp, blasm, blastx, tblastn and tblastx on the Internet.
BLSAT is available at www.ncbi.nlm.nih.gov/BLAST/. A comparison of sequence homology using this program may be found at www.ncbi.nlm.nih.gov/BLAST/blast_help.html.
Based on this, the antibody or antigen-binding fragment thereof of the present invention is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% compared to the specified sequence or all described in the specification. Such homology may be determined by sequence comparison and / or alignment by methods known in the art. For example, sequence comparison algorithms (i.e., BLAST or BLAST 2.0), manual alignment, visual inspection may be used to determine the percent sequence homology of nucleic acids or proteins of the invention.
In another aspect, the present invention relates to a nucleic acid encoding the antibody or antigen-binding fragment thereof.
The nucleic acid encoding the antibody or antigen-binding fragment thereof of the present invention may be isolated to recombinantly produce the antibody or antigen-binding fragment thereof. The nucleic acid is isolated and inserted into a replicable vector for further cloning (amplification of DNA) or for further expression. Based on this, the present invention relates to a vector comprising the nucleic acid in another aspect.
"Nucleic acid" is meant to encompass DNA (gDNA and cDNA) and RNA molecules inclusively, and the nucleotides that are the basic building blocks of nucleic acids include natural nucleotides as well as analogs with modified sugar or base sites. The sequences of nucleic acids encoding heavy and light chain variable regions of the invention may be modified. Such modifications include addition, deletion, or non-conservative or conservative substitutions of nucleotides.
The DNA encoding the antibody is readily isolated or synthesized using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to the DNA
encoding the heavy and light chains of the antibody). Many vectors are available. Vector components generally include, but are not limited to, one or more of the following: signal sequence, origin of replication, one or more marker genes, enhancer elements, promoters, and transcription termination sequences.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 As used in the present specification, the term "vector" refers to a plasmid vector as a means for expressing a gene of interest in a host cell; cosmid vector; viral vectors such as bacteriophage vectors, adenovirus vectors, retrovirus vectors, and adeno-associated virus vectors, and the like.
The nucleic acid encoding the antibody in the vector is operably linked with a promoter.
"Operatively linked" means a functional binding between a nucleic acid expression control sequence (e.g., an array of promoters, signal sequences, or transcriptional regulator binding sites) and another nucleic acid sequence, whereby the regulatory sequence is the other nucleic acid. To control transcription and / or translation of the sequence.
In the case of a prokaryotic cell as a host, powerful promoters capable of promoting transcription (e.g., tac promoter, lac promoter, lacUV5 promoter, 1pp promoter, pLX, promoter, pRk promoter, rac5 promoter, amp promoter, recA promoter, SP6 promoter, trp promoter and T7 promoter, etc.), ribosome binding sites for initiation of translation, and transcription / translation termination sequences. Also, for example, when the eukaryotic cell is a host, a promoter derived from the genome of the mammalian cell (e.g., a metallothionine promoter, a I3-actin promoter, a human hemoglobin promoter and a human muscle creatine promoter) or a mammal Promoters derived from animal viruses (e.g., adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, cytomegalovirus (CMV) promoter, tk promoter of HSV, mouse breast tumor virus (MMTV) promoter, LTR promoter of HIV) , promoter of the Moroni virus, promoter of the Epsteinbar virus (EBV) and Loose Sacoma virus (RSV) promoter) may be used, and generally has a polyadenylation sequence as a transcription termination sequence.
In some cases, the vector may be fused with other sequences to facilitate purification of the antibody expressed therefrom. Sequences to be fused include, for example, glutathione S-transferase (Pharmacia, USA), maltose binding protein (NEB, USA), FLAG (IBI, USA) and 6x His (hexahi sti dine; Qui agen, USA).
Such vectors include antibiotic resistance genes commonly used in the art as selection markers and include, for example, resistance genes against ampicillin, gentamicin, carbenicillin, chloramphenicol, streptomycin, kanamycin, geneticin, neomycin and tetracycline.
In another aspect, the present invention relates to a cell transformed with the above-mentioned vector. The cells used to produce the antibodies of the invention may be prokaryote, yeast or higher eukaryote cells, but are not limited thereto.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Bacterial strains such as Escherichia coli, Bacillus subtilis and Bacillus thuringiensis, Streptomyces and Pseudomonas (e.g. Pseudomonas putida), and prokaryotic host cells such as Proteus mirabilis and Staphylococcus (e.g., Staphylococcus carnosus) may be used.
However, animal cells are of the greatest interest, and examples of useful host cell lines are, but are not limited to, COS-7, BHK, CHO, CHOK1, DXB-11, DG-44, CHO / -DHFR, CV1, COS-7, HEK293, BHK, TM4, VERO, HELA, MDCK, BRL 3A, W138, Hep G2, SK-Hep, MMT, TRI, MRC 5, F54, 3T3, RIN, A549, PC12, K562, PER.C6, 5P2/0, NS-0, U205, or HT1080.
In another aspect, the present invention relates to a method for preparing the above-stated antibodies or antigen-binding fragments thereof, the method comprising: (a) a step of culturing the cells; and (b) a step of recovering the antibody or antigen-binding fragment thereof from the cultured cells.
The cells may be cultured in various media. Commercially available media may be used without limitation as the culture medium. All other necessary supplements known to those skilled in the art may be included at appropriate concentrations. Culture conditions, such as temperature, pH, and the like, are already in use with host cells selected for expression, which will be apparent to those skilled in the art.
In the recovery of the antibody or antigen-binding fragment thereof, impurities may be removed by, for example, centrifugation or ultrafiltration, and the result may be purified using, for example, affinity chromatography or the like. Other purification techniques such as anion or cation exchange chromatography, hydrophobic interaction chromatography, hydroxylapatite chromatography and the like may be used.
In one aspect of the present invention, the linker between the antibody and the active agent may be cleavable.
In one aspect of the present invention, the linker has the structure of Chemical Formula Ha below:
[Chemical Formula Ha]
(Z),, R1 2o 422-L.W
=
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Where:
G is a sugar, a sugar acid or a sugar derivative;
W is -C(0)-, -C(0)NR'-, -C(0)0-, -S(0)2NR'-, -P(0)R"NR'-, -S(0)NR'-, or -P02NR'-; In a case where C(0), S or P is linked directly with the phenyl ring, R' and R" are, respectively and independently, hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C1-C8) alkoxy, (C1-C8) alkylthio, mono- or di-(C1-C8) alkylamino, (C3-C2o) heteroaryl, or (C6-C2o) aryl;
Each Z is, respectively and independently, (Ci-C8) alkyl, halogen, cyano or nitro;
n is an integer of 0 through 3;
m is 0 or 1;
L is absent, or;
Contains at least one branching unit (BR) and at least one connection unit;
Ri and R2 are, respectively and independently, hydrogen, (C1-C8) alkyl or (C3-C8) cycloalkyl, or the Ri and R2, together with the carbon atoms to which they are bound, form a (C3-C8) cycloalkyl ring, and;
In the above formula, `¨' denotes a region which binds to an antibody, and *
denotes a region which binds to a drug or a toxin.
In one aspect of the present invention, the sugar or sugar acid is a monosaccharide.
In one aspect of the present invention, G is a glucuronic acid moiety or a compound of the structure of Chemical Formula (Ma) below:
[Chemical Formula (Ma)]
IS
R4...ort., "
0, -..*R4 Where:
R3 is a hydrogen or carboxyl protective group, and;
Each R4 is, respectively and independently, a hydrogen or hydroxyl protective group.
In one aspect of the present invention, R3 is hydrogen, and each R4 is hydrogen.
FuBosToN5259862.1 Date Recue/Date Received 2021-08-09 Further Ri and R2 are respectively hydrogen.
Further, each Z is, respectively and independently, (Ci-C8) alkyl, halogen, cyano or nitro.
Further, W is -C(0)-, -C(0)NR'- or -C(0)0-. More specifically, W is -C(0)NR'-, where C(0) is linked to a phenyl ring, and NR' is linked to L.
Further, n is 0, 1, 2 or 3, specifically 0, 1 or 2, and more specifically 0.
More specifically, G is a compound of the structure of chemical formula (Ma) below:
[Chemical Formula (Ma)]
o Where:
R3 is a hydrogen or carboxyl protective group;
Each R4 is, respectively and independently, a hydrogen or hydroxyl protective group, and;
W is -C(0)NR'-, where C(0) is linked to a phenyl ring, and NR' is linked to L, each Z is (Ci-C8) alkyl, halogen, cyano or nitro, n is 0, m is 1, and Ri and R2 are respectively hydrogen.
In one aspect of the present invention, at least one branching unit is an alkylene having 1 to 100 carbon atoms, where the carbon atoms of the alkylene may be substituted by one or more heteroatoms selected from a group comprised of N, 0 and S, and the alkylene may further be substituted with one or more alkyls having 1 to 20 carbon atoms.
Specifically, at least one branching unit is Ci-050 alkylene or a 1 to 50 atom heteroalkylene, and may satisfy at least one of the following:
(i) the branching unit comprises at least one unsaturated bond;
(ii) 2 atoms in the branching unit are the same as in a substituent, this completing a heteroarylene;
(iii) the branching unit is a 1 to 50 atom heteroalkylene, and;
(iv) the alkylene is substituted by at least one C1_20 alkyl.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Further, the at least one branching unit is a nitrogen-comprising 1-50 atom heteroalkylene, the linker comprises at least 2 atoms of a hydrophilic amino acid, and the nitrogen may form a peptide bond with the carbonyl of a hydrophilic amino acid.
In one aspect of the present invention, the at least one branching unit is a hydrophilic amino acid.
In one aspect of the present invention, the hydrophilic amino acid may be arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine.
Further, the hydrophilic amino acid may covalently bond an oxime of a linker to a polyethylene glycol unit of the linker.
In one aspect of the present invention, the hydrophilic amino acid may be an amino acid including a side chain having a moiety which has electric charge in aqueous solution at a neutral pH.
In one aspect of the present invention, the hydrophilic amino acid is aspartate or glutamate.
In one aspect of the present invention, the hydrophilic amino acid is ornithine or lysine.
In one aspect of the present invention, the at least one branching unit is -C(0)-, -C(0)NR'--C(0)O-, -S(0)2NR'-, -P(0)R"NR'-, -S(0)NR'-, or -P02NR'-, and R' and R" are, respectively and independently, hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C1-C8) alkoxy, (C1-C8) alkylthio, mono- or di-(C1-C8) alkylamino, (C3-C2o) heteroaryl, or (C6-C2o) aryl.
In one aspect of the present invention, the at least one branching unit is -C(0)NR'-, and R' is hydrogen.
In one aspect of the present invention, at least one connecting unit is represented by General Formula VIII or General Formula IX:
[General Formula VIII]
-(CH2)r(V(CH2)p)q-[General Formula IX]
-(CH2CH2X),-Where: V is a single bond, -0-, -S-, -NR21-, -C(0)N-R22_, NR23C(0)-, NR24S02-, or -S02NR25-;
X is -0-, C i-C8 alkylene or -NR21-;
R21 to R25 are, independently and respectively hydrogen, (C1-C6) alkyl, (C1-C6) alkyl (C6-C2o) aryl, or (C1-C6) alkyl (C3-C2o) heteroaryl;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 r is an integer of 0 to 10;
p is an integer of 0 to 10;
q is an integer of 1 to 20, and;
w is an integer of 1 to 20.
In one aspect of the present invention, q may be 4 to 20, more specifically 6 to 20. Further, q may be 2 to 12, more specifically 2, 5 or 11. Further, may be 2. Further, p may be 2. Further, V
may be -0-.
More specifically, r may be 2, p may be 2, q may be 2, 5 or 11, and V may be -0-.
Further, in one aspect of the present invention, X may be -0-. Further, w may be an integer of 6 to 20.
More specifically, X may be -0-, and w may be 6 to 20.
In one aspect of the present invention, the at least one connecting unit comprises at least one polyethylene glycol unit represented by 1 0 or 4- '-+' , where n is 1 to 12.
In one aspect of the present invention, the at least one connecting unit may be 1 to 12 -OCH2CH2- units, 3 to 12 -OCH2CH2- units, 5 to 12 -OCH2CH2- units, 6 to 12 -OCH2CH2- units, or 3 -OCH2CH2- units.
In one aspect of the present invention, at least one connection unit is -(CH2CH2X)w-, Where X is a single bond, -0-, (C1-C8) alkylene, or -NR21-;
R21 is hydrogen, (C1-C6) alkyl, (C1-C6) alkyl (C6-C2o) aryl, or (C1-C6) alkyl (C3-C2o) heteroaryl, and;
w is an integer of 1 to 20, specifically 1, 3, 6 or 12.
In one aspect of the present invention, X is -0-, and w is an integer of 6 to 20.
In one aspect of the present invention, the linker further comprises binding units formed by 1,3-dipolar cycloaddition reactions, hetero-diels reactions, nucleophilic substitution reactions, non-aldol type carbonyl reactions, additions to carbon-carbon multiple bonds, oxidation reactions or click reactions.
In one aspect of the present invention, the binding unit is formed by a reaction between acetylene and azide, or a reaction between aldehyde or a ketone group and hydrazine or alkoxyamine.
In one aspect of the present invention, the binding unit is:
or FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 C-F-1 rre..1 Li. L
11/4 f -RcrL-1./A
Where, Li is a single bond or an alkylene having 1 to 30 carbon atoms;
Rii is hydrogen or an alkyl having 1 to 10 carbon atoms, specifically methyl.
In one aspect of the present invention, Li is a single bond, an alkylene having 11 carbon atoms, or an alkylene having 12 carbon atoms.
Further, in one aspect of the invention, the binding unit comprises Li (CH2MV(CH2)p)cr N
N
Or Li __________________________ (CH2)r(V(C1-12)p)cr NN
V is a single bond, -0-, -S-, -NR21-, -C(0)NR22-, NR23C(0)-, NR24S02-, or -S02NR25-;
R21 to R25 are, independently and respectively hydrogen, C1-C6 alkyl, C1-C6 alkyl C6-C2o aryl, or C1-C6 alkyl C3-C2o heteroaryl;
r is an integer of 1 to 10;
p is an integer of 0 to 10;
q is an integer of 1 to 20, and;
L1 is a single bond.
In one aspect of the present invention, r may be 2 or 3. Further, p may be 1 or 2. Further, q may be 1 through 6.
More specifically, in the binding unit, r may be 2 or 3; p may be 1 or 2, and;
q may be 1 through 6.
Further, in one aspect of the present invention, the binding unit may be HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 C) so..
0 tCom HOA
0J..
6.
N
s."
1404 0 14=-1.iN
Ab , or;
o2H
HO
-0 *
, where:
UGH
rai o where Ab is an anti-DLK1 antibody; B is an active agent, and; n is an integer of 0 to 20.
In one aspect of the present invention, the branching unit is Or In one aspect of the present invention, the linker may comprise 3 to 50 heteroalkylenes 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 to Ab, or;
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.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, the linker may additionally contain at least one r, g isoprenyl unit having the structure - , where n is at least 2.
In one aspect of the preset invention, at least one isoprenyl unit is an isoprenoid transferase substrate or a product of isoprenoid transferase.
In one aspect of the present invention, the isoprenyl unit of the linker binds covalently with an antibody through a thioether bond, and the thioether bond includes a sulfur atom of cysteine.
Further, the isoprenyl unit may covalently bind the oxime included in the linker to an antibody.
In one aspect of the present invention, the antibody includes an amino acid motif recognized by isoprenoid transferase, and the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the antibody binding to DLK1 or antigen-binding fragment thereof includes an amino acid motif recognized by isoprenoid transferase, and the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the amino acid motif is a sequence selected from a group comprised of CXX, CXC, XCXC, XXCC and CYYX, where C denotes cysteine; Y
in each case independently denotes an aliphatic amino acid; X in each case independently denotes glutamine, glutamate, serine, cysteine, methionine, alanine or leucine, and;
the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the amino acid motif is a CYYX
sequence, and Y in each case is independently alanine, isoleucine, leucine, methionine or valine.
In one aspect of the present invention, the amino acid motif is a CVIM or CVLL
sequence.
In one aspect of the present invention, at least one of the 1 to 10 amino acids preceding the amino acid motif may, respectively and independently, be selected from among glycine, arginine, aspartic acid and serine. For example, in one aspect of the present invention, at least one of the 7 amino acids preceding the amino acid motif are glycine. Alternatively, at least 3 of the 7 amino acids preceding the amino acid motif are, respectively and independently, selected from among glycine, arginine, aspartic acid and serine. Alternatively, 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.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, the antibody may include the amino acid sequence GGGGGGGC VIM.
In one aspect of the present invention, L comprises at least one branch linker covalently bonded to Ab, i) the respective branch linkers comprise a branched unit covalently bonded to Ab by a primary linker (PL);
ii) the respective branch linkers bind a first active agent to a branched unit, and comprise a first branch (B1) comprising a second linker (SL) and a cleaving group (CG), and;
iii) the respective branch linkers comprise a) a second branch (B2) wherein a second active agent is covalently bonded to a branched unit by a second linker (SL) and a cleaving group (CG), or b) a second branch wherein a polyethylene glycol moiety is covalently bonded to a branched unit, and the respective cleaving groups are hydrolyzed to release an active agent from an antibody conjugate.
L3.1' L4, õ
G;ss In one aspect of the present invention, the branch linker is or ="""v L2, L3 and L4 are, respectively and independently, direct bonds or -CnH2n-, n is an integer of 1 to 30, cssL
G1' G2 and G3 are, respectively and independently, a direct bond, R3 1.<AN'Llf N '4.4221> N 5ss' Or ,and;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 R3 is hydrogen or C1-30 alky.
More specifically, the branch linker comprises z.....H 0 HO õ
0 40 0;
4-, [ , 0 OH
0 N-h'e(9,11 H
0 N-4.--Cli"--") ' H n HO,C 0, il i Ail HO* -OHIV 0 EV
y ,,,t1 [_ , B and B' indicate active agents which may be different or identical;
n indicates, respectively and independently, an integer of 0 to 30;
f indicates, respectively and independently, an integer of 0 to 30, and;
L indicates a bond to Ab.
In one aspect of the present invention, n is an integer of 1 to 20, more specifically an integer of 1 to 10, or 4 to 20.
In one aspect of the present invention, L comprises oxime, and at least one polyethylene glycol unit covalently binds the oxime to an active agent.
In one aspect of the present invention, the cleaving group may be cleaved within a target cell, and the cleaving group may release one or more active agents.
In one aspect of the present invention, the linker comprises at least one branch linker covalently bonded to Ab, and comprises at least two active agents covalently linked to the branch linker.
Specifically, 1 branch linker may bind with Ab.
Further, two or more branch linkers may bind to Ab, and the respective branch linkers may bind to at least two active agents. More specifically, 3 branch linkers may bind to Ab.
Alternatively, 4 branch linker may bind to Ab.
In one aspect of the present invention, the respective branch linkers bind to at least two identical or different active agents. In one aspect of the present invention, the respective active agents are bonded to the branch linker by a cleavable bond.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, the respective branch linkers comprise a branched unit, the respective active agents are bonded to the branched unit through a second linker, and the branched units are bonded to an antibody by a first linker.
In one aspect of the present invention, the branched unit may be a nitrogen atom. Further, the branched unit may be an amide, and the first linker or the second linker may comprise a carbonyl of the amide. Alternatively, the branched unit may be a lysine unit.
In yet another aspect of the present invention, the linker may comprise:
(a) at least one branching unit; (b) at least one connection unit; (c) at least one binding unit (BU), and; at least one trigger unit (TU).
Here, the connection unit connects the trigger unit and binding unit, the trigger unit and the branching unit, or the branching unit and the binding unit;
the at least one trigger unit may release at least one drug or toxin, and the branching unit links a connection unit and trigger unit, or a connection unit and another connection unit.
In one aspect of the present invention, the trigger unit has the structure of Chemical Formula (IIb) below:
[Chemical Formula (IIb)]
(Z)n Where:
G is a sugar, a sugar acid or a sugar derivative;
W is -C(0)-, -C(0)NR'-, -C(0)0-, -S(0)2NR'-, -P(0)R"NR'-, -S(0)NR'-, or -P02NR'-; In a case where C(0), S or P is linked directly with the phenyl ring, R' and R" are, respectively and independently, hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C1-C8) alkoxy, (Ci-C8) alkylthio, mono- or di-(C1-C8) alkylamino, (C3-C2o) heteroaryl, or (C6-C2o) aryl, and W is linked to a connection unit or a branching unit;
Each Z is, respectively and independently, (Ci-C8) alkyl, halogen, cyano or nitro;
n is an integer of 1 through 3;
m is 0 or 1;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Ri and R2 are, respectively and independently, hydrogen, (C1-C8) alkyl or (C3-C8) cycloalkyl, or the Ri and R2, together with the carbon atoms to which they are bound, form a (C3-C8) cycloalkyl ring.
In one aspect of the present invention, the sugar or sugar acid is a monosaccharide.
In one aspect of the present invention, G is a compound having the structure of Chemical Formula (Ma) below:
[Chemical Formula (Ma)]
R4 "C)1,1) R4' 0 0 0,R4 Where:
R3 is a hydrogen or carboxyl protective group, and;
Each R4 is, respectively and independently, a hydrogen or hydroxyl protective group.
In one aspect of the present invention, R3 is hydrogen, and each R4 is hydrogen.
In one aspect of the present invention, W is -C(0)NR'-, where C(0) is linked to a phenyl ring, and NR' is linked to L.
In one aspect of the present invention, Z is hydrogen.
In one aspect of the present invention, Ri and R2 are respectively hydrogen.
In one aspect of the present invention, the connection unit is represented as -(C112),(V(C112)p)q-, -((a12)pV)q-, -(C112),(V(C112)p),X-, -((a12)pV)q(C112),-, -Y((C112)pV)q- or -(C112),(V(C112)p)qYCH2-, Where:
r is an integer of 0 to 10;
p is an integer of 1 to 10;
q is an integer of 1 to 20;
V and Y are, independently and respectively a single bond, -0-, -S-, -NR21-, -C(0)NR22-, NR23C(0)-, NR24S02-, Or -S02NR25- and;
FI1B0ST0N5259862 .1 Date Recue/Date Received 2021-08-09 R21 to R25 are, independently and respectively hydrogen, (C1-C6) alkyl, (C1-C6) alkyl (C6-C2o) aryl, or (C1-C6) alkyl (C3-C2o) heteroaryl.
In one aspect of the present invention, r is 2.
In one aspect of the present invention, p is 2.
In one aspect of the present invention, q is an integer of 6 to 20.
In one aspect of the present invention, q is 2, 5 or 11.
In one aspect of the present invention, V and Y are, respectively and independently, -0-.
s cs ' N
jvIA, 41, ' N
=L
2 3,, 41(2 Or -/L1N.N , #
.
NN
Where:
Li, L2 and L3 are, respectively and independently, a direct bond or -CnH2n-;
n is an integer of 1 through 30;
Where:
It N
G1, G2 and G3 are, respectively and independently, a direct bond, R3 o R41 R4 R3 0 Or R3 is hydrogen or C1-C30 alkyl;
R4 is hydrogen or L4-COOR5; L4 is a direct bond or -CnH2n-; n is an integer of 1 to 10, and R5 is hydrogen or C1-C30 alkyl.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, the branching unit is or risi N N -N7' /\
N=N N=N N=N
RI, I-2 Where Li is a direct bond or an alkylene having 1 to 30 carbon atoms;
Rii is hydrogen or an alkyl having 1 to 10 carbon atoms, specifically methyl;
L2 is an alkylene having 1 to 30 carbon atoms, and;
the branching unit links a connection unit and an antibody.
In one aspect of the present invention, Li is an alkylene having 12 carbon atoms.
In one aspect of the present invention, Rii is methyl.
In one aspect of the present invention, L2 is an alkylene having 11 carbon atoms.
In one aspect of the present invention, the branched unit is AN
=."-<
Or In one aspect of the present invention, the isoprenyl unit of the linker binds covalently with an antibody through a thioether bond, and the thioether bond includes a sulfur atom of cysteine.
In one aspect of the present invention, the antibody includes an amino acid motif recognized by isoprenoid transferase, and the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the amino acid motif is a sequence selected from a group comprised of CXX, CXC, XCXC, XXCC and CYYX, where C denotes cysteine; Y
in each case independently denotes an aliphatic amino acid; X in each case independently denotes glutamine, glutamate, serine, cysteine, methionine, alanine or leucine, and;
the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the amino acid motif is a CYYX
sequence, and Y in each case is independently alanine, isoleucine, leucine, methionine or valine.
In one aspect of the present invention, the amino acid motif is a CVIM or CVLL
sequence.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, at least one of the 7 amino acids preceding the amino acid motif may, respectively and independently, be selected from among glycine, arginine, aspartic acid and serine.
In one aspect of the present invention, at least 3 of the 7 amino acids preceding the amino acid motif are, respectively and independently, selected from among glycine, arginine, aspartic acid and serine.
Alternatively, 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.
In one aspect of the present invention, the antibody may include the amino acid sequence GGGGGGGC VIM.
Furtherõ in one aspect of the present invention, the active agent may be a chemotherapeutic agent or a toxin.
Further, the active agent may be an immunoregulatory compound, anti-cancer agent, antiviral, antibacterial, antifungal, antiparasitic or a combination of these, and the active agents listed below may be selectively used:
(a) erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787/ZK 222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, teimethylolomelamine, bullatacin, bullataciionone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotoxin, fotemustine, lomustine, nimustine, ranimustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, esperamicin, neocarzinostatin chromophore, aclacinomysins, actinomycin, antrymycin, azaserine, bleomycins, catcinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6-diazo-
Ab is an anti-DLK1 antibody or an antigen-binding fragment thereof, X is independently a chemical residue comprising at least one active agent and a linker, and;
the linker links an antibody and the active agent, and;
y is an integer from 1 through 20.
The anti-DLK1 antibody or antigen-binding fragment thereof, that is the antibody which binds to DLK1 or antigen-binding fragment of the same, comprises: a heavy chain variable region comprising at least one heavy chain CDR1 selected from the group comprising SEQ ID NO. 2, 16, 30, 44, 58, 72 and 86, at least one heavy chain CDR2 selected from the group comprising SEQ ID
NO. 4, 18, 32, 46, 60, 74 and 88, and at least one heavy chain CDR3 selected from the group comprising SEQ ID NO. 6, 20, 34, 48, 62, 76 and 90, and;
a light chain variable region comprising at least one light chain CDR1 selected from the group comprising SEQ ID No. 9, 23, 37, 51, 65, 79, 93, 115 and 121, at least one light chain CDR2 selected from the group comprising SEQ ID No. 11, 25, 39, 53, 67, 81 and 95, and at least one light chain CDR3 selected from the group comprising SEQ ID No.
13, 27, 41, 55, 69, 83, 97, 116 and 125.
The antibody according to the present invention may, for example, bind specifically to the extracellular domain of human DLK1.
The term "antibody" as used in the present specification refers to DLK1, in particular anti-DLK1 antibody which binds specifically to the extracellular domain of human DLK1 protein.
Included in the scope of the present invention is not only the complete form of the antibody which binds specifically to DLK1, but also antigen-binding fragments of the antibody molecule.
The complete antibody has a structure having 2 full length heavy chains and 2 full length light chains, the respective light chains linked to a heavy chain by a disulfide bond. The heavy chain constant regions have types gamma (y), mu (u), alpha (a), delta (6) and epsilon (6), with sub-classes gammal (y1), gamma2 (y2), gamma3 (y3), gamma4 (y1), alphal (al) and a1pha2 (a2). The light chain constant region has types kappa (x) and lambda (k).
An antigen-binding fragment of an antibody or antibody fragment refers to a fragment with the functionality to bind to an antigen, and includes Fab, F(ab'), F(ab')2 and Fv, etc. Among antibody fragments, Fab has a structure of light chain and heavy chain variable regions, a light chain constant region and a first constant region of a heavy chain (C111), and 1 antigen-binding FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 site. Fab' differs from Fab in that it has a hinge region comprising at least one cysteine residue at the C-terminal of the heavy chain CH1 domain. The F(ab)'2 antibody is formed when the cysteine residue of the hinge region of Fab' forms a disulfide bond. Fv is a minimum antibody fragment which only has a heavy chain variable region and light chain variable region, and recombinant technologies for preparing Fv fragments are disclosed in PCT International Published Patent Applications W088/10649, W088/106630, W088/07085, W088/07086 and W088/09344. A
two-chain Fv has a heavy chain variable region and light chain variable region linked by a non-covalent bond, and a single-chain Fv (scFv) generally has a heavy chain variable region and light chain variable region linked by a covalent bond through a peptide linker, or linked directly at the C-terminal, allowing it to form structures such as a dimer, as can a two-chain Fv. Such antibody fragments may be obtained by using protein hydrolyzing enzyme (for example, restriction cutting the entire antibody with papain yields Fab, and cutting with pepsin can yield F(ab)'2 fragment), and may also be prepared using gene recombinant technology.
In embodiments, the antibody according to the present invention is of the Fv form (for example, scFv), or in its complete antibody form. Further, the heavy chain constant region may be any one isotype selected from among gamma (y), mu (u), alpha (a), delta (6) and epsilon (6). For example, the constant region is Gammal (IgG1), Gamma3 (IgG3) or Gamma4 (IgG4).
The light chain constant region may be the kappa or lambda type.
The term "heavy chain" as used in the present specification refers to the full length heavy chain comprising the variable region domain VH which comprises amino acid sequences having sufficient variable region sequences to give antigen specificity and the three constant region domains CH1, CH2 and CH3, and all fragments of the same. Further the term "light chain" as used in the present specification refers to the full length light chain comprising the variable region domain VL which comprises amino acid sequences having sufficient variable region sequences to give antigen specificity and the constant region domain CL, and all fragments of the same.
The antibody of the invention includes, but is not limited to, monoclonal antibody, multispecific antibody, human antibody, humanized antibody, chimera antibody, single chain Fvs (scFV), single chain antibody, Fab fragment, F(ab') fragment, disulfide-bond Fvs (sdFV) and anti-idiotype (anti-Id) antibody, or epitope-binding fragments of the above antibodies, etc.
Monoclonal antibodies refer to antibodies obtained from a substantially homogeneous antibody group, that is, except for possible naturally occurring mutations in which individual HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 antibodies that occupy the population may be present in minor amounts.
Monoclonal antibodies are highly specific and are directed against a single antigenic site. In contrast to a conventional (polyclonal) antibody formulation which comprises different antibodies directed to different determining factors, the respective monoclonal antibodies are directed against a single determining factor on the antigen. For example, the useful monoclonal antibodies of the present invention may be prepared using the hybridoma method, or by using recombinant DNA methods on bacteria or eukaryotic animal cells or plant cells (see US Patent 4,816,567). Further, the monoclonal antibody may be isolated from a phage antibody library.
In one embodiment of the present invention, the phage display method was used to pan a natural human single chain Fv library (native human single chain Fv library) to prepare seven types of monoclonal human antibody which bind specifically to DLK1.
"Phage display" is a technique for displaying a mutant polypeptide as a fusion protein with the phage, for example, at least part of the coat protein on the surface of the phage particle. The usefulness of phage display is that large libraries of randomized protein variants may be targeted to quickly and efficiently classify sequences that bind to target antigens in high affinity. Displaying peptides and protein libraries on phages has been used to screen millions of polypeptides to identify polypeptides with specific binding properties.
Phage display technology has provided a powerful tool for generating and screening new proteins that bind to specific ligands (e.g. antigens). Using phage display technology, large libraries of protein variants may be generated and sequences that bind with high affinity to target antigens may be quickly classified. The nucleic acid encoding the mutant polypeptide is fused with a nucleic acid sequence encoding a viral coat protein, e.g. a gene III protein or a gene VIII protein.
A monophasic phage display system has been developed in which a nucleic acid sequence encoding a protein or polypeptide is fused with a nucleic acid sequence encoding a part of the gene III protein. In the 1-phage display system, the gene fusion is expressed at a low level and the wild-type gene III protein is also expressed, thereby maintaining the infectivity of the particles.
Demonstrating the expression of peptides on the fibrous phage surface and the expression of functional antibody fragments in the peripheral cytoplasm of E. coli is important in developing antibody phage display libraries. Libraries of antibodies or antigen-binding polypeptides have been prepared in a number of ways, for example by altering a single gene by inserting a random DNA
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 sequence, or by cloning a related gene sequence. The library may be screened for the expression of antibodies or antigen binding proteins with the desired characteristics.
Phage display technology has several advantages over conventional hybridomas and recombinant methods for producing antibodies with the desired characteristics.
This technique allows the generation of large antibody libraries with a variety of sequences in a short time without the use of animals. The production of hybridomas and the production of humanized antibodies may require several months of manufacturing time. In addition, since no immunity is required, the phage antibody library can generate antibodies against antigens that are toxic or have low antigenicity. Phage antibody libraries can also be used to generate and identify novel therapeutic antibodies.
Techniques for generating human antibodies from non-immunized humans, germline sequences, or sub-sensitized B cell Ig repertoires may be used, which are immunized using a phage display library. Various lymphatic tissues may be used to prepare an undetected or non-immunogenic antigen-binding library.
Techniques for identifying and separating high affinity antibodies from phage display libraries are important for new antibody separation for therapy. The separation of high affinity antibodies from the library can depend on the size of the library, the production efficiency in bacterial cells and the variety of libraries. The size of the library is reduced by inefficient folding of the antibody or antigen binding protein and inefficient production due to the presence of the stop codon. Expression in bacterial cells may be inhibited when the antibody or antigen binding domain is not properly folded. Expression may be improved by alternately mutating the residues at the surface of the variable / constant interface or the selected CDR
residues. The sequence of the framework region is one element to provide appropriate folding in the case of generating antibody phage libraries in bacterial cells.
It is important to generate various libraries of antibody or antigen binding proteins in high affinity antibody separation. CDR3 regions have been found to often participate in antigen binding.
The CDR3 region on the heavy chain varies considerably in terms of size, sequence and structural conformation, and thus various libraries may be prepared using the CDR3 region.
Also, diversity may be generated by randomizing the CDR regions of the variable heavy and light chains using all 20 amino acids at each position. The use of all 20 amino acids results in HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 an increased variability in antibody sequences and an increased chance of identifying new antibodies.
"Epitope" refers to a protein determinant to which an antibody can specifically bind.
Epitopes usually consist of a group of chemically active surface molecules, such as amino acids or sugar side chains, and generally have specific three-dimensional structural characteristics as well as specific charge characteristics. Three-dimensional epitopes and non-stereo epitopes are distinguished in that the binding to the former is lost but not to the latter in the presence of a denatured solvent.
The non-human (e.g., murine) antibody of the "humanized" form is a chimeric antibody containing minimal sequence derived from non-human immunoglobulin. In most cases, the humanized antibody is a non-human species (donor antibody), such as a mouse, a rat, a rabbit or a non-human, having a desired specificity, affinity and ability to retain a residue from the hypervariable region of the recipient and is a human immunoglobulin (acceptor antibody) that has been replaced with a residue from the hypervariable region of the primate.
The above-mentioned "human antibody" means a molecule derived from human immunoglobulin, wherein all the amino acid sequences constituting the antibody including the complementarity determining region and the structural region are composed of human immunoglobulin.
The other chain(s) may be derived from another species or may be derived from another antibody class or subgroup, such as a portion of the heavy chain and / or light chain derived from a particular species or identical or homologous to a corresponding sequence in an antibody belonging to a particular antibody class or subclass, "chimeric" antibodies (immunoglobulins) identical or homologous to the corresponding sequences in antibodies belonging to the subclass as well as fragments of said antibodies exhibiting the desired biological activity.
As used herein, an "antibody variable domain" refers to the light and heavy chain portions of an antibody molecule comprising complementarity determining regions (CDRs;
i.e., CDR1, CDR2, and CDR3), and the amino acid sequence of the framework region (FR) . VH
refers to the variable domain of the heavy chain. VL refers to the variable domain of the light chain.
"Complementarity determining regions" (CDRs; i.e., CDR1, CDR2, and CDR3) refer to the amino acid residues of an antibody variable domain that are necessary for antigen binding.
Each variable domain typically has three CDR regions identified as CDR1, CDR2 and CDR3.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 In the present invention, the antibody binding to DLK1 or an antigen-binding fragment thereof may specifically include the CDR sequences stated in Table 1 below. Of these, Korean Patent Application No. 10-2018-0107639 has confirmed that the anti-DLK1 antibodies of two types (18A5 and 27F7) and two other 18A5 mutant antibodies (18A5 LS 1A10 and 18A5 AM 1Al2) are capable of binding to cells where DLK1 is overexpressed, and may be developed into anti-DLK1 antibody-drug conjugates which can target DLK1 expressed on the surface of cancer cells to cause cancer cell apoptosis.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 [Table 1]
, __________________________________________________ =
SEQ ID
done nu Cb81 ER2 CDR2 FR3 CND FM
NO.
QvQ1. YSADSA'K
VV1G MSWV GRFTISR TREG varGQ
17811- , GUN CTh RQTPG ITKS DNsiCs-TL LGYY GTIV 99 NC QPGG SSBA KOLE GS GT YLQNINSL YGNID
, SLRU WVSS RAEDTAV V
CAAS YYC
SEQ ID NO. 1 2 3 4 5 7 N RPSGVP
QQLPG SGTSASI. 171111- SGAPG GAG GST
NW* TKVT 100 LW LC TAPRL A1TGLQA RYV vL QRvIl YD F.DRADYY
SCTGS
SEQIDNO 8 9 to 11 12 13 14 QvQL NYADSVK
VQSG 11INA v sin) GRLTIS1R vRivw weal 111A5- GA"' Q PG GRN "Nsic"rn 0c QpGa KC,117 SFQ 1.4 INSL T Tvss stens a .4Ir 111 . µN " 67' RAEDTAV
SEAS ' ________________________________________________________________ ,sEct ID NO 15 141 17 11 19 2$ 21 IMQK SLQSAvAS
TQSPS I. MAN
RFSGsGS QD I PAS- ELSA'S QQKP GAA. GrEFILri ()WY ITGGG
v M
ssLQ= FEDF IK
VN1TC tor,Liv ANYYC
RAs , \
ANY
SEQ ID NO 22 23 24 25 20 27 2$
QMQL GYADSVK
VQSG XII1vvv caurnsR TKGP WGQ
20D3- GGIN RQA PG 1SWN DNAKNS1. GLA1 HC Bey V
QPGRS . KGLE SGS1 YLQYINSL GICVY .re GTQ 103 ss LRLSC A WVSG RAEDTAV ENS a AAS YYC
¨
FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 t _____ . r ___________________________________________________ -1 - D1QM TL li NGV P
, TQSPS 1 LAWY SRFSGSAS FGQG ' 21103- SVSAS I QR1S QQKP n LC ' YGDR SW GRApK SAS crprru SSLQPEDF QQGH I TtiLD 104 SFPVT
' VT1TC LLIII , i AIINC
RAS
SEQ ID NO , 36 37 38 39 40 41 42 QVQL ' TYADSVK , ' VESG MNWV ' GRFTISR ARGY
21011- GGLV GFTF RQAPG 1SPD DNAK WGQNTL , SPKYP laa SSY
IIC ( QPGG KGI.V GSSI YLQININSL 1 TVGL GTE! air*P
W TVSS ' , SIR IS WVSR RAEDTAV DV
CAAS __ r YYC ;
SEQ ID NO. 43 44 45 46 47 45 49 DIVNIT ' NRFSGVP
, QSPLS ' ESLL LTWL DRFSGSC , veer", ' iptletel 211/11- 1, SPVTL USN QQRP ' AGTDFTL v 'gm4W1 -, 1 TKVII 1"
LC GQPAS GNT GQPPR KIS QITRVET
' INT ISCRS V LI.III EDVGµlir 1K
h , $ C
i SEQ ID NO , SO ' 51 32 53 1 54 . 55 . 54 , . _ QVQL i LYAQKFQ 1 ' VOSG 1111WV1 t rn $ I GRVTMT ARLN WGQ
21F9- AEVK GYSL QAPR new 1 EDTSTDT ' YFEST ' GTM iai HC KPGAS
SEFP MG111 ""µ.¨ 1 AYWIELSS ' DYWV VTV'S ""
VRVSC WilIGG TLIPSZDTA DAFDI $
ICVS I VYYC : ' f 4 SEQ ID NO, 57 58 lip 0 'a a 43 '. _____________________________________________________________________ , QRPSGVP
QLVLT , VQWY . DRFSGSID
2IF9- '' QPYSV SGSI QQRP gnat . SMNsAst QSYD FG`'"
Lc, SESPG
ASNF GSAPT m's." T1SGVMT SGSS TKLT 108 CTRS i C
_________________________________________________________________ = X
SEQ ID NO. 64 65 66 67 i 411 69 711 1 , i I-FHBOSTON5259862.1 Date Regue/Date Received 2021-08-09 QMQL I YVADSVIC .
VESG 3L'SWV GRFTISR
GFNF .ARD4;) WGII
27F7- GGLV RQAPG 1SST DNAKSSL.
Y GIIDV TVSS
SITLS WLAH RAEDTAV .
C'DAT , YY'C" ' , .
SEQ ID
71. 72: 73 74 75 . 76 . 77 ' NR.PSGVP
QL11õ,T
VDWY DRFSGSK ' .27F7 QPSSV SSNI QSYD ' F.GGG
- QQLPG SGTSASL .
SGAPG GAG GNT SSL.SA. ThIT 110 LC TAPKL AITGLQA QRVTI YD
, LIY EDDSDYY
,SCTGS
C
., SEQ ID
NO 7$ 74 ' 80 II 82 83 84 . , .QVQ,L, YVADSVIC ' AREG ,.
V"ESG NIIIW'V G,RFTISR
. SYDV WGQ , 35E2- GGVV GFTF RQAPG 'nrsc DNSICNTL
AITYT GAIN' HC QPGR.S SSYA KGLE GST YLQNEVSL . 111 IRIGG TVSS
LRLSC WVAV ItAEDIAV .
VF'Dli AAS YY'C , .õ.
SEQ ID
S5 84 ' 17 88 89 90 91 DIQA1 ,, , SLQSGVP , TQSPS ' VAWY
SRESGSG FGPG
35E2.. SVSAS QGIS QQKP QQA.N
LC VGT3R DW GICAõP SFPLT
ISNLQPE pc v""rtrc . .KLL1Y
D'FATYYC
RAS
, SEQ ID
NO. 92 93 . 94 95 96 97 98 QVQL NYADSVK
õ
18A5 17()SG Gn: '51H10.17 / - GRLTLSR von, 11, urftri , .LS,..li GAVV , ' RQAPG ' DNS-lei-IL .7.- - --"c QPG11 If SFQ1µLNSL . ' YG K . DI TVSS
-BC SI,.RI.S . 'Wlõ,AV . RAEDTAA' , CFAS ' YYC , SEQ ID
NO.
16 ' 17 18 19 20 21 , FIII30STON5259862.1 Date Recue/Date Received 2021-08-09 SLQSGVP
1 QSPS LAWVi SI,S AS QGTS QQKP QQSY
LS 1 A A AS SGTDFT1 LG OR SA 1 CKAP I I Pi. 1 TKVF 126 RAS I KHAN
I lliõ111 AC II
, __________________________________________________________ 1 ____ SEQ ID I
-- +-QVQL NY AD
18 A5 VW; NIHNNT GRI,TISR
(.FK ISM) N-RDW 11-(';(,) A NI I (,,;(.,1 V RQ1PC 1INSK\ 11, 1,12 Q14.(i II; K(4.1: 1 t l R1 W R s. S
CA-1S il..NN' K SFQN1NSI.
11311 : 1V
INC SN AI- ( ;I 1 N 127 Il 1)1 LASS
119 16 ' 1 *7 18 19 211 21 No.
NI KM-AT
18,15_ TQSPS L.µWY
SRFSGSG ()QS' 171-,C;f;
k A 1 i FLSAS IIDIS (:)()KS
_ sAS s( ,1111,SI, I IA 1 1 KL1. 128 i Al2 \ GDR SS C.I.A1' 11SSLQIIE I 1k , I Lt \111(' Kt L11 DI-All Nt RAS , 1 , SEQ11) 121/ 121 j 122 39 123 124 125 A "framework region" (FR) is a variable domain residue other than a CDR
residue. Each variable domain typically has four FRs identified as FR1, FR2, FR3, and FR4.
Embodiments of the present invention may comprise: at least one heavy chain FR1 selected from the group comprising SEQ ID No. 1, 15, 29, 43, 57, 71, 85 and 119; at least one heavy chain FR2 selected from the group comprising SEQ ID No. 3, 17, 31, 45, 59, 73 and 87; at least one heavy chain FR3 selected from the group comprising SEQ ID No. 5, 19, 33, 47, 61, 75 and 89; at least one heavy chain FR4 selected from the group comprising SEQ ID No. 7, 21, 35, 49, 63, 77 and 91; at least one light chain FR1 selected from the group comprising SEQ ID
No. 8, 22, 36, 50, 64, 78, 92, 117 and 120; at least one light chain FR2 selected from the group comprising SEQ ID
No. 10, 24, 38, 52, 66, 80, 94 and 122; at least one light chain FR3 selected from the group comprising SEQ ID No. 12, 26, 40, 54, 68, 82, 96, 118 and 123, and; at least one light chain FR4 selected from the group comprising SEQ ID No. 14, 28, 42, 56, 70, 84, 98 and 125.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 An "Fv" fragment is an antibody fragment that contains complete antibody recognition and binding sites. This region consists of one heavy chain variable domain and one light chain variable domain, for example, dimers substantially tightly covalently associated with scFv.
A "Fab" fragment contains the variable and constant domains of the light chain and the variable and first constant domain (CH1) of the heavy chain. F(ab')2 antibody fragments generally comprise a pair of Fab fragments covalently linked by their hinge cysteine near their carboxy ends.
A "single chain Fv" or "scFv" antibody fragment comprises the VH and VL
domains of an antibody, which domains are within a single polypeptide chain. The Fv polypeptide may further comprise a polypeptide linker between the VH domain and the VL domain such that the scFv can form the desired structure for antigen binding.
The antibody according to the present invention may be monovalent or divalent, and comprises a single chain or a double chain.
Functionally, the binding affinity of the antibody to the extracellular domain of DLK1 is in a range of 10-5M to 10-12M. For example, the binding affinity is 10-6M to 10-12M, 10-7M to 10-M
'2", 108M to 10'2M, 109M to 10'2M, 105M to 10"M, 106M to 10"M, 107M to 10"M, 10-81\4 to 10"M, 10-9M to 10-11m, 10-10A4 to 10M, -H¨¨, 10-5M to 10-0M 1 10-6M to 10-1 M, 10-7M to 10 M-10", 10-8M to 10' M, 10-9M to 10' M, 10-5M to 10-9M, 10-6M to 10-9M, 10-7M to 10-9M, 10-8M
to 10-9M, 10-5M to 10-8M, 10-6M to 10-8M, 10-7M to 10-8M, 10-5M to 10-7M, 10-6M to 10-7M or 10-5M to 10-6M.
Further, the antibodies of the present invention are antibodies with increased affinity for the antigen. The term "affinity" refers to the ability to specifically recognize and bind to specific sites of an antigen. High specificity, together with the specificity of these antibodies, is an important factor in the immune response. Any of various analyses known to the art, for example radioimmunoassays (RIA) and ELISA may be used to determine affinity, which may be expressed as various quantitative values. The affinity of an antibody to an antigen may generally be represented by the dissociation constant (Kd) of a specific antibody-antigen interaction. A lower Kd value indicates higher affinity of an antibody to an antigen. For example, the Kd value of the 18A5 antibody of the present invention is 0.52, and that of the 27F7 antibody is 0.22. This indicates these are high-affinity antibodies which bind with specificity to human DLK1.
The antibody binding to the extracellular domain of DLK1, or antigen-binding fragment thereof, may comprise a heavy chain variable region including a sequence that has at least 90%
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 sequence homology with a sequence selected from the group comprising SEQ ID
No. 99, 101, 103, 105, 107, 109, 111 and 127. The antibody binding to the extracellular domain of DLK1, or antigen-binding fragment, thereof, may comprise a heavy chain variable region selected from the group comprising SEQ ID No. 99, 101, 103, 105, 107, 109, 111 and 127.
Further, the antibody binding to the extracellular domain of DLK1, or antigen-binding fragment thereof, may comprise a light chain variable region including a sequence that has at least 90% sequence homology with a sequence selected from the group comprising SEQ
ID No. 100, 102, 104, 106, 108, 110, 112, 126 and 128. The antibody binding to the extracellular domain of DLK1, or antigen-binding fragment, thereof, may comprise a light chain variable region selected from the group comprising SEQ ID No. 100, 102, 104, 106, 108, 110, 112, 126 and 128.
The antibody or antibody fragment of the present invention may contain, within the scope of specifically recognizing DLK1, the sequence of the anti-DLK1 antibody of the present invention described herein as well as biological equivalents thereof. For example, additional changes may be made to the amino acid sequence of the antibody to further improve the binding affinity and /
or other biological properties of the antibody. Such modifications include, for example, deletion, insertion and / or substitution of the amino acid sequence residues of the antibody. Such amino acid variations are made based on the relative similarity of the amino acid side chain substituents, such as hydrophobicity, hydrophilicity, charge, size, and the like. By analysis of the size, shape and type of amino acid side chain substituents, arginine, lysine and histidine are both positively charged residues; Alanine, glycine and serine have similar sizes;
Phenylalanine, tryptophan and tyrosine have similar shapes. Thus, based on these considerations, arginine, lysine and histidine;
alanine, glycine and serine; and phenylalanine, tryptophan and tyrosine are biologically functional equivalents.
Considering the mutation having the above-mentioned biological equivalent activity, the antibody of the present invention or the nucleic acid molecule encoding the same is interpreted to include a sequence showing substantial identity with the sequences under SEQ
ID NO. The above-mentioned substantial identity is determined by aligning the above-described sequence of the present invention with any other sequence as much as possible and analyzing the aligned sequence using an algorithm commonly used in the art, with a homology of at least 90%, and most preferably at least 95% homology, at least 96%, at least 97%, at least 98%, or at least 99%.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Alignment methods for sequence comparison are well known in the art. The NCBI
Basic Local Alignment Search Tool (BLAST) is accessible from NBCI and may be used in conjunction with sequence analysis programs such as blastp, blasm, blastx, tblastn and tblastx on the Internet.
BLSAT is available at www.ncbi.nlm.nih.gov/BLAST/. A comparison of sequence homology using this program may be found at www.ncbi.nlm.nih.gov/BLAST/blast_help.html.
Based on this, the antibody or antigen-binding fragment thereof of the present invention is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% compared to the specified sequence or all described in the specification. Such homology may be determined by sequence comparison and / or alignment by methods known in the art. For example, sequence comparison algorithms (i.e., BLAST or BLAST 2.0), manual alignment, visual inspection may be used to determine the percent sequence homology of nucleic acids or proteins of the invention.
In another aspect, the present invention relates to a nucleic acid encoding the antibody or antigen-binding fragment thereof.
The nucleic acid encoding the antibody or antigen-binding fragment thereof of the present invention may be isolated to recombinantly produce the antibody or antigen-binding fragment thereof. The nucleic acid is isolated and inserted into a replicable vector for further cloning (amplification of DNA) or for further expression. Based on this, the present invention relates to a vector comprising the nucleic acid in another aspect.
"Nucleic acid" is meant to encompass DNA (gDNA and cDNA) and RNA molecules inclusively, and the nucleotides that are the basic building blocks of nucleic acids include natural nucleotides as well as analogs with modified sugar or base sites. The sequences of nucleic acids encoding heavy and light chain variable regions of the invention may be modified. Such modifications include addition, deletion, or non-conservative or conservative substitutions of nucleotides.
The DNA encoding the antibody is readily isolated or synthesized using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to the DNA
encoding the heavy and light chains of the antibody). Many vectors are available. Vector components generally include, but are not limited to, one or more of the following: signal sequence, origin of replication, one or more marker genes, enhancer elements, promoters, and transcription termination sequences.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 As used in the present specification, the term "vector" refers to a plasmid vector as a means for expressing a gene of interest in a host cell; cosmid vector; viral vectors such as bacteriophage vectors, adenovirus vectors, retrovirus vectors, and adeno-associated virus vectors, and the like.
The nucleic acid encoding the antibody in the vector is operably linked with a promoter.
"Operatively linked" means a functional binding between a nucleic acid expression control sequence (e.g., an array of promoters, signal sequences, or transcriptional regulator binding sites) and another nucleic acid sequence, whereby the regulatory sequence is the other nucleic acid. To control transcription and / or translation of the sequence.
In the case of a prokaryotic cell as a host, powerful promoters capable of promoting transcription (e.g., tac promoter, lac promoter, lacUV5 promoter, 1pp promoter, pLX, promoter, pRk promoter, rac5 promoter, amp promoter, recA promoter, SP6 promoter, trp promoter and T7 promoter, etc.), ribosome binding sites for initiation of translation, and transcription / translation termination sequences. Also, for example, when the eukaryotic cell is a host, a promoter derived from the genome of the mammalian cell (e.g., a metallothionine promoter, a I3-actin promoter, a human hemoglobin promoter and a human muscle creatine promoter) or a mammal Promoters derived from animal viruses (e.g., adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, cytomegalovirus (CMV) promoter, tk promoter of HSV, mouse breast tumor virus (MMTV) promoter, LTR promoter of HIV) , promoter of the Moroni virus, promoter of the Epsteinbar virus (EBV) and Loose Sacoma virus (RSV) promoter) may be used, and generally has a polyadenylation sequence as a transcription termination sequence.
In some cases, the vector may be fused with other sequences to facilitate purification of the antibody expressed therefrom. Sequences to be fused include, for example, glutathione S-transferase (Pharmacia, USA), maltose binding protein (NEB, USA), FLAG (IBI, USA) and 6x His (hexahi sti dine; Qui agen, USA).
Such vectors include antibiotic resistance genes commonly used in the art as selection markers and include, for example, resistance genes against ampicillin, gentamicin, carbenicillin, chloramphenicol, streptomycin, kanamycin, geneticin, neomycin and tetracycline.
In another aspect, the present invention relates to a cell transformed with the above-mentioned vector. The cells used to produce the antibodies of the invention may be prokaryote, yeast or higher eukaryote cells, but are not limited thereto.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Bacterial strains such as Escherichia coli, Bacillus subtilis and Bacillus thuringiensis, Streptomyces and Pseudomonas (e.g. Pseudomonas putida), and prokaryotic host cells such as Proteus mirabilis and Staphylococcus (e.g., Staphylococcus carnosus) may be used.
However, animal cells are of the greatest interest, and examples of useful host cell lines are, but are not limited to, COS-7, BHK, CHO, CHOK1, DXB-11, DG-44, CHO / -DHFR, CV1, COS-7, HEK293, BHK, TM4, VERO, HELA, MDCK, BRL 3A, W138, Hep G2, SK-Hep, MMT, TRI, MRC 5, F54, 3T3, RIN, A549, PC12, K562, PER.C6, 5P2/0, NS-0, U205, or HT1080.
In another aspect, the present invention relates to a method for preparing the above-stated antibodies or antigen-binding fragments thereof, the method comprising: (a) a step of culturing the cells; and (b) a step of recovering the antibody or antigen-binding fragment thereof from the cultured cells.
The cells may be cultured in various media. Commercially available media may be used without limitation as the culture medium. All other necessary supplements known to those skilled in the art may be included at appropriate concentrations. Culture conditions, such as temperature, pH, and the like, are already in use with host cells selected for expression, which will be apparent to those skilled in the art.
In the recovery of the antibody or antigen-binding fragment thereof, impurities may be removed by, for example, centrifugation or ultrafiltration, and the result may be purified using, for example, affinity chromatography or the like. Other purification techniques such as anion or cation exchange chromatography, hydrophobic interaction chromatography, hydroxylapatite chromatography and the like may be used.
In one aspect of the present invention, the linker between the antibody and the active agent may be cleavable.
In one aspect of the present invention, the linker has the structure of Chemical Formula Ha below:
[Chemical Formula Ha]
(Z),, R1 2o 422-L.W
=
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Where:
G is a sugar, a sugar acid or a sugar derivative;
W is -C(0)-, -C(0)NR'-, -C(0)0-, -S(0)2NR'-, -P(0)R"NR'-, -S(0)NR'-, or -P02NR'-; In a case where C(0), S or P is linked directly with the phenyl ring, R' and R" are, respectively and independently, hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C1-C8) alkoxy, (C1-C8) alkylthio, mono- or di-(C1-C8) alkylamino, (C3-C2o) heteroaryl, or (C6-C2o) aryl;
Each Z is, respectively and independently, (Ci-C8) alkyl, halogen, cyano or nitro;
n is an integer of 0 through 3;
m is 0 or 1;
L is absent, or;
Contains at least one branching unit (BR) and at least one connection unit;
Ri and R2 are, respectively and independently, hydrogen, (C1-C8) alkyl or (C3-C8) cycloalkyl, or the Ri and R2, together with the carbon atoms to which they are bound, form a (C3-C8) cycloalkyl ring, and;
In the above formula, `¨' denotes a region which binds to an antibody, and *
denotes a region which binds to a drug or a toxin.
In one aspect of the present invention, the sugar or sugar acid is a monosaccharide.
In one aspect of the present invention, G is a glucuronic acid moiety or a compound of the structure of Chemical Formula (Ma) below:
[Chemical Formula (Ma)]
IS
R4...ort., "
0, -..*R4 Where:
R3 is a hydrogen or carboxyl protective group, and;
Each R4 is, respectively and independently, a hydrogen or hydroxyl protective group.
In one aspect of the present invention, R3 is hydrogen, and each R4 is hydrogen.
FuBosToN5259862.1 Date Recue/Date Received 2021-08-09 Further Ri and R2 are respectively hydrogen.
Further, each Z is, respectively and independently, (Ci-C8) alkyl, halogen, cyano or nitro.
Further, W is -C(0)-, -C(0)NR'- or -C(0)0-. More specifically, W is -C(0)NR'-, where C(0) is linked to a phenyl ring, and NR' is linked to L.
Further, n is 0, 1, 2 or 3, specifically 0, 1 or 2, and more specifically 0.
More specifically, G is a compound of the structure of chemical formula (Ma) below:
[Chemical Formula (Ma)]
o Where:
R3 is a hydrogen or carboxyl protective group;
Each R4 is, respectively and independently, a hydrogen or hydroxyl protective group, and;
W is -C(0)NR'-, where C(0) is linked to a phenyl ring, and NR' is linked to L, each Z is (Ci-C8) alkyl, halogen, cyano or nitro, n is 0, m is 1, and Ri and R2 are respectively hydrogen.
In one aspect of the present invention, at least one branching unit is an alkylene having 1 to 100 carbon atoms, where the carbon atoms of the alkylene may be substituted by one or more heteroatoms selected from a group comprised of N, 0 and S, and the alkylene may further be substituted with one or more alkyls having 1 to 20 carbon atoms.
Specifically, at least one branching unit is Ci-050 alkylene or a 1 to 50 atom heteroalkylene, and may satisfy at least one of the following:
(i) the branching unit comprises at least one unsaturated bond;
(ii) 2 atoms in the branching unit are the same as in a substituent, this completing a heteroarylene;
(iii) the branching unit is a 1 to 50 atom heteroalkylene, and;
(iv) the alkylene is substituted by at least one C1_20 alkyl.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Further, the at least one branching unit is a nitrogen-comprising 1-50 atom heteroalkylene, the linker comprises at least 2 atoms of a hydrophilic amino acid, and the nitrogen may form a peptide bond with the carbonyl of a hydrophilic amino acid.
In one aspect of the present invention, the at least one branching unit is a hydrophilic amino acid.
In one aspect of the present invention, the hydrophilic amino acid may be arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine.
Further, the hydrophilic amino acid may covalently bond an oxime of a linker to a polyethylene glycol unit of the linker.
In one aspect of the present invention, the hydrophilic amino acid may be an amino acid including a side chain having a moiety which has electric charge in aqueous solution at a neutral pH.
In one aspect of the present invention, the hydrophilic amino acid is aspartate or glutamate.
In one aspect of the present invention, the hydrophilic amino acid is ornithine or lysine.
In one aspect of the present invention, the at least one branching unit is -C(0)-, -C(0)NR'--C(0)O-, -S(0)2NR'-, -P(0)R"NR'-, -S(0)NR'-, or -P02NR'-, and R' and R" are, respectively and independently, hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C1-C8) alkoxy, (C1-C8) alkylthio, mono- or di-(C1-C8) alkylamino, (C3-C2o) heteroaryl, or (C6-C2o) aryl.
In one aspect of the present invention, the at least one branching unit is -C(0)NR'-, and R' is hydrogen.
In one aspect of the present invention, at least one connecting unit is represented by General Formula VIII or General Formula IX:
[General Formula VIII]
-(CH2)r(V(CH2)p)q-[General Formula IX]
-(CH2CH2X),-Where: V is a single bond, -0-, -S-, -NR21-, -C(0)N-R22_, NR23C(0)-, NR24S02-, or -S02NR25-;
X is -0-, C i-C8 alkylene or -NR21-;
R21 to R25 are, independently and respectively hydrogen, (C1-C6) alkyl, (C1-C6) alkyl (C6-C2o) aryl, or (C1-C6) alkyl (C3-C2o) heteroaryl;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 r is an integer of 0 to 10;
p is an integer of 0 to 10;
q is an integer of 1 to 20, and;
w is an integer of 1 to 20.
In one aspect of the present invention, q may be 4 to 20, more specifically 6 to 20. Further, q may be 2 to 12, more specifically 2, 5 or 11. Further, may be 2. Further, p may be 2. Further, V
may be -0-.
More specifically, r may be 2, p may be 2, q may be 2, 5 or 11, and V may be -0-.
Further, in one aspect of the present invention, X may be -0-. Further, w may be an integer of 6 to 20.
More specifically, X may be -0-, and w may be 6 to 20.
In one aspect of the present invention, the at least one connecting unit comprises at least one polyethylene glycol unit represented by 1 0 or 4- '-+' , where n is 1 to 12.
In one aspect of the present invention, the at least one connecting unit may be 1 to 12 -OCH2CH2- units, 3 to 12 -OCH2CH2- units, 5 to 12 -OCH2CH2- units, 6 to 12 -OCH2CH2- units, or 3 -OCH2CH2- units.
In one aspect of the present invention, at least one connection unit is -(CH2CH2X)w-, Where X is a single bond, -0-, (C1-C8) alkylene, or -NR21-;
R21 is hydrogen, (C1-C6) alkyl, (C1-C6) alkyl (C6-C2o) aryl, or (C1-C6) alkyl (C3-C2o) heteroaryl, and;
w is an integer of 1 to 20, specifically 1, 3, 6 or 12.
In one aspect of the present invention, X is -0-, and w is an integer of 6 to 20.
In one aspect of the present invention, the linker further comprises binding units formed by 1,3-dipolar cycloaddition reactions, hetero-diels reactions, nucleophilic substitution reactions, non-aldol type carbonyl reactions, additions to carbon-carbon multiple bonds, oxidation reactions or click reactions.
In one aspect of the present invention, the binding unit is formed by a reaction between acetylene and azide, or a reaction between aldehyde or a ketone group and hydrazine or alkoxyamine.
In one aspect of the present invention, the binding unit is:
or FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 C-F-1 rre..1 Li. L
11/4 f -RcrL-1./A
Where, Li is a single bond or an alkylene having 1 to 30 carbon atoms;
Rii is hydrogen or an alkyl having 1 to 10 carbon atoms, specifically methyl.
In one aspect of the present invention, Li is a single bond, an alkylene having 11 carbon atoms, or an alkylene having 12 carbon atoms.
Further, in one aspect of the invention, the binding unit comprises Li (CH2MV(CH2)p)cr N
N
Or Li __________________________ (CH2)r(V(C1-12)p)cr NN
V is a single bond, -0-, -S-, -NR21-, -C(0)NR22-, NR23C(0)-, NR24S02-, or -S02NR25-;
R21 to R25 are, independently and respectively hydrogen, C1-C6 alkyl, C1-C6 alkyl C6-C2o aryl, or C1-C6 alkyl C3-C2o heteroaryl;
r is an integer of 1 to 10;
p is an integer of 0 to 10;
q is an integer of 1 to 20, and;
L1 is a single bond.
In one aspect of the present invention, r may be 2 or 3. Further, p may be 1 or 2. Further, q may be 1 through 6.
More specifically, in the binding unit, r may be 2 or 3; p may be 1 or 2, and;
q may be 1 through 6.
Further, in one aspect of the present invention, the binding unit may be HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 C) so..
0 tCom HOA
0J..
6.
N
s."
1404 0 14=-1.iN
Ab , or;
o2H
HO
-0 *
, where:
UGH
rai o where Ab is an anti-DLK1 antibody; B is an active agent, and; n is an integer of 0 to 20.
In one aspect of the present invention, the branching unit is Or In one aspect of the present invention, the linker may comprise 3 to 50 heteroalkylenes 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 to Ab, or;
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.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, the linker may additionally contain at least one r, g isoprenyl unit having the structure - , where n is at least 2.
In one aspect of the preset invention, at least one isoprenyl unit is an isoprenoid transferase substrate or a product of isoprenoid transferase.
In one aspect of the present invention, the isoprenyl unit of the linker binds covalently with an antibody through a thioether bond, and the thioether bond includes a sulfur atom of cysteine.
Further, the isoprenyl unit may covalently bind the oxime included in the linker to an antibody.
In one aspect of the present invention, the antibody includes an amino acid motif recognized by isoprenoid transferase, and the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the antibody binding to DLK1 or antigen-binding fragment thereof includes an amino acid motif recognized by isoprenoid transferase, and the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the amino acid motif is a sequence selected from a group comprised of CXX, CXC, XCXC, XXCC and CYYX, where C denotes cysteine; Y
in each case independently denotes an aliphatic amino acid; X in each case independently denotes glutamine, glutamate, serine, cysteine, methionine, alanine or leucine, and;
the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the amino acid motif is a CYYX
sequence, and Y in each case is independently alanine, isoleucine, leucine, methionine or valine.
In one aspect of the present invention, the amino acid motif is a CVIM or CVLL
sequence.
In one aspect of the present invention, at least one of the 1 to 10 amino acids preceding the amino acid motif may, respectively and independently, be selected from among glycine, arginine, aspartic acid and serine. For example, in one aspect of the present invention, at least one of the 7 amino acids preceding the amino acid motif are glycine. Alternatively, at least 3 of the 7 amino acids preceding the amino acid motif are, respectively and independently, selected from among glycine, arginine, aspartic acid and serine. Alternatively, 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.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, the antibody may include the amino acid sequence GGGGGGGC VIM.
In one aspect of the present invention, L comprises at least one branch linker covalently bonded to Ab, i) the respective branch linkers comprise a branched unit covalently bonded to Ab by a primary linker (PL);
ii) the respective branch linkers bind a first active agent to a branched unit, and comprise a first branch (B1) comprising a second linker (SL) and a cleaving group (CG), and;
iii) the respective branch linkers comprise a) a second branch (B2) wherein a second active agent is covalently bonded to a branched unit by a second linker (SL) and a cleaving group (CG), or b) a second branch wherein a polyethylene glycol moiety is covalently bonded to a branched unit, and the respective cleaving groups are hydrolyzed to release an active agent from an antibody conjugate.
L3.1' L4, õ
G;ss In one aspect of the present invention, the branch linker is or ="""v L2, L3 and L4 are, respectively and independently, direct bonds or -CnH2n-, n is an integer of 1 to 30, cssL
G1' G2 and G3 are, respectively and independently, a direct bond, R3 1.<AN'Llf N '4.4221> N 5ss' Or ,and;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 R3 is hydrogen or C1-30 alky.
More specifically, the branch linker comprises z.....H 0 HO õ
0 40 0;
4-, [ , 0 OH
0 N-h'e(9,11 H
0 N-4.--Cli"--") ' H n HO,C 0, il i Ail HO* -OHIV 0 EV
y ,,,t1 [_ , B and B' indicate active agents which may be different or identical;
n indicates, respectively and independently, an integer of 0 to 30;
f indicates, respectively and independently, an integer of 0 to 30, and;
L indicates a bond to Ab.
In one aspect of the present invention, n is an integer of 1 to 20, more specifically an integer of 1 to 10, or 4 to 20.
In one aspect of the present invention, L comprises oxime, and at least one polyethylene glycol unit covalently binds the oxime to an active agent.
In one aspect of the present invention, the cleaving group may be cleaved within a target cell, and the cleaving group may release one or more active agents.
In one aspect of the present invention, the linker comprises at least one branch linker covalently bonded to Ab, and comprises at least two active agents covalently linked to the branch linker.
Specifically, 1 branch linker may bind with Ab.
Further, two or more branch linkers may bind to Ab, and the respective branch linkers may bind to at least two active agents. More specifically, 3 branch linkers may bind to Ab.
Alternatively, 4 branch linker may bind to Ab.
In one aspect of the present invention, the respective branch linkers bind to at least two identical or different active agents. In one aspect of the present invention, the respective active agents are bonded to the branch linker by a cleavable bond.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, the respective branch linkers comprise a branched unit, the respective active agents are bonded to the branched unit through a second linker, and the branched units are bonded to an antibody by a first linker.
In one aspect of the present invention, the branched unit may be a nitrogen atom. Further, the branched unit may be an amide, and the first linker or the second linker may comprise a carbonyl of the amide. Alternatively, the branched unit may be a lysine unit.
In yet another aspect of the present invention, the linker may comprise:
(a) at least one branching unit; (b) at least one connection unit; (c) at least one binding unit (BU), and; at least one trigger unit (TU).
Here, the connection unit connects the trigger unit and binding unit, the trigger unit and the branching unit, or the branching unit and the binding unit;
the at least one trigger unit may release at least one drug or toxin, and the branching unit links a connection unit and trigger unit, or a connection unit and another connection unit.
In one aspect of the present invention, the trigger unit has the structure of Chemical Formula (IIb) below:
[Chemical Formula (IIb)]
(Z)n Where:
G is a sugar, a sugar acid or a sugar derivative;
W is -C(0)-, -C(0)NR'-, -C(0)0-, -S(0)2NR'-, -P(0)R"NR'-, -S(0)NR'-, or -P02NR'-; In a case where C(0), S or P is linked directly with the phenyl ring, R' and R" are, respectively and independently, hydrogen, (C1-C8) alkyl, (C3-C8) cycloalkyl, (C1-C8) alkoxy, (Ci-C8) alkylthio, mono- or di-(C1-C8) alkylamino, (C3-C2o) heteroaryl, or (C6-C2o) aryl, and W is linked to a connection unit or a branching unit;
Each Z is, respectively and independently, (Ci-C8) alkyl, halogen, cyano or nitro;
n is an integer of 1 through 3;
m is 0 or 1;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Ri and R2 are, respectively and independently, hydrogen, (C1-C8) alkyl or (C3-C8) cycloalkyl, or the Ri and R2, together with the carbon atoms to which they are bound, form a (C3-C8) cycloalkyl ring.
In one aspect of the present invention, the sugar or sugar acid is a monosaccharide.
In one aspect of the present invention, G is a compound having the structure of Chemical Formula (Ma) below:
[Chemical Formula (Ma)]
R4 "C)1,1) R4' 0 0 0,R4 Where:
R3 is a hydrogen or carboxyl protective group, and;
Each R4 is, respectively and independently, a hydrogen or hydroxyl protective group.
In one aspect of the present invention, R3 is hydrogen, and each R4 is hydrogen.
In one aspect of the present invention, W is -C(0)NR'-, where C(0) is linked to a phenyl ring, and NR' is linked to L.
In one aspect of the present invention, Z is hydrogen.
In one aspect of the present invention, Ri and R2 are respectively hydrogen.
In one aspect of the present invention, the connection unit is represented as -(C112),(V(C112)p)q-, -((a12)pV)q-, -(C112),(V(C112)p),X-, -((a12)pV)q(C112),-, -Y((C112)pV)q- or -(C112),(V(C112)p)qYCH2-, Where:
r is an integer of 0 to 10;
p is an integer of 1 to 10;
q is an integer of 1 to 20;
V and Y are, independently and respectively a single bond, -0-, -S-, -NR21-, -C(0)NR22-, NR23C(0)-, NR24S02-, Or -S02NR25- and;
FI1B0ST0N5259862 .1 Date Recue/Date Received 2021-08-09 R21 to R25 are, independently and respectively hydrogen, (C1-C6) alkyl, (C1-C6) alkyl (C6-C2o) aryl, or (C1-C6) alkyl (C3-C2o) heteroaryl.
In one aspect of the present invention, r is 2.
In one aspect of the present invention, p is 2.
In one aspect of the present invention, q is an integer of 6 to 20.
In one aspect of the present invention, q is 2, 5 or 11.
In one aspect of the present invention, V and Y are, respectively and independently, -0-.
s cs ' N
jvIA, 41, ' N
=L
2 3,, 41(2 Or -/L1N.N , #
.
NN
Where:
Li, L2 and L3 are, respectively and independently, a direct bond or -CnH2n-;
n is an integer of 1 through 30;
Where:
It N
G1, G2 and G3 are, respectively and independently, a direct bond, R3 o R41 R4 R3 0 Or R3 is hydrogen or C1-C30 alkyl;
R4 is hydrogen or L4-COOR5; L4 is a direct bond or -CnH2n-; n is an integer of 1 to 10, and R5 is hydrogen or C1-C30 alkyl.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, the branching unit is or risi N N -N7' /\
N=N N=N N=N
RI, I-2 Where Li is a direct bond or an alkylene having 1 to 30 carbon atoms;
Rii is hydrogen or an alkyl having 1 to 10 carbon atoms, specifically methyl;
L2 is an alkylene having 1 to 30 carbon atoms, and;
the branching unit links a connection unit and an antibody.
In one aspect of the present invention, Li is an alkylene having 12 carbon atoms.
In one aspect of the present invention, Rii is methyl.
In one aspect of the present invention, L2 is an alkylene having 11 carbon atoms.
In one aspect of the present invention, the branched unit is AN
=."-<
Or In one aspect of the present invention, the isoprenyl unit of the linker binds covalently with an antibody through a thioether bond, and the thioether bond includes a sulfur atom of cysteine.
In one aspect of the present invention, the antibody includes an amino acid motif recognized by isoprenoid transferase, and the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the amino acid motif is a sequence selected from a group comprised of CXX, CXC, XCXC, XXCC and CYYX, where C denotes cysteine; Y
in each case independently denotes an aliphatic amino acid; X in each case independently denotes glutamine, glutamate, serine, cysteine, methionine, alanine or leucine, and;
the thioether bond includes a sulfur atom of the cysteine of the amino acid motif.
In one aspect of the present invention, the amino acid motif is a CYYX
sequence, and Y in each case is independently alanine, isoleucine, leucine, methionine or valine.
In one aspect of the present invention, the amino acid motif is a CVIM or CVLL
sequence.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 In one aspect of the present invention, at least one of the 7 amino acids preceding the amino acid motif may, respectively and independently, be selected from among glycine, arginine, aspartic acid and serine.
In one aspect of the present invention, at least 3 of the 7 amino acids preceding the amino acid motif are, respectively and independently, selected from among glycine, arginine, aspartic acid and serine.
Alternatively, 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.
In one aspect of the present invention, the antibody may include the amino acid sequence GGGGGGGC VIM.
Furtherõ in one aspect of the present invention, the active agent may be a chemotherapeutic agent or a toxin.
Further, the active agent may be an immunoregulatory compound, anti-cancer agent, antiviral, antibacterial, antifungal, antiparasitic or a combination of these, and the active agents listed below may be selectively used:
(a) erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787/ZK 222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, teimethylolomelamine, bullatacin, bullataciionone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotoxin, fotemustine, lomustine, nimustine, ranimustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, esperamicin, neocarzinostatin chromophore, aclacinomysins, actinomycin, antrymycin, azaserine, bleomycins, catcinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6-diazo-
5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 pyrrolino-doxorubucin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tudercidin, ubenimex, zinostatin, zorubicin, 5-fluoDLKacil, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thiguianine, ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone, propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide,mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatrexate, defofamine, democolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaqizuone, 2,2', 2"-trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, docetaxel, chlorambucil, gemcitabine,
6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS
2000, difluoromethylornithine, retinoic acid, capecitabine, or pharmaceutically acceptable salts, solvates or acids thereof;
(b) monokine, lympokine, traditional polypeptide hormone, parathyroid hormone, thyroxine, relaxin, pDLKelaxin, glycoprotein hormone, follicle stimulating hormone, thyroid stimulating hormone, luteinizing hormone, hepatic growth factor fibroblast growth factor, prolactin, placental lactogen, tumor necrosis factor, tumor necrosis factor-a, tumor necrosis factor-I3, Mullerian inhibiting substance, mouse gonadotropin associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, osteoinductive factor, interferon, interferon-a, interferon-I3, interferon-y, colony stimulating factor (C SF), macrophage-CSF, granulocyte-macrophage-CSF), granulocyte-FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 macrophage-CSF, granulocyte-CSF, interleukin (IL), IL-1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, I L-12, tumor necrosis factor, TNF-a, TNF-I3, polypeptide factor, LIF, kit ligand, or mixtures thereof;
(c) diphtheria toxin, botulinum toxin, tetanus toxin, dysentery toxin, cholera toxin, amanitin, a-amatinin, pyrrolobenzodiazepine, pyrrolobenzodiazepine derivative, indolinobenzodiazepine, pyridobenzodiazepine, tetrodotoxin, brevetoxin, ciguatoxin, ricin, AM toxin, auristatin, tubulysin, geldanamycin, maytansinoid, calicheamicin, daunomycin, doxorubicin, methotrexate, vindesine, SG2285, dolastatin, dolastatin analog, auristatin, cryptophycin, camptothecin, rhizoxin, rhizoxin derivatives, CC-1065, CC-1065 analogs or derivatives, duocarmycin, enediyne antibiotic, esperamicin, epothilone, toxoid, or mixtures thereof;
(d) affinity ligand, where the affinity ligand is a substrate, inhibitor, active agent, neurotransmitter, radioactive isotope, or mixtures thereof;
(e) radioactive label, 32P, 35S, fluorescent dye, electron dense reagent, enzyme, biotin, streptavidin, dioxigenin, hapten, immunogenic protein, nucleic acid molecule with a sequence complementary to a target, or mixtures thereof;
(f) immunomodulatory compound, anti-cancer agent, anti-viral agent, anti-bacterial agent, anti-fungal agent, anti-parasitic agent, or mixtures thereof;
(g) tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone or toremifene;
(h) 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole or anastrozole (i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine;
(j) aromatase inhibitor;
(k) protein kinase inhibitor;
(1) lipid kinase inhibitor;
(m) antisense oligonucleotide;
(n) ribozyme;
(o) vaccine, and;
(p) anti-angiogenic agent.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Yet another aspect of the present invention provides, in relation to the preparation of a drug for prevention or treatment of a proliferative, cancer or angiogenetic disease, a use of an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof.
Yet another aspect of the present invention provides a method for drug for prevention or treatment of a proliferative, cancer or angiogenetic disease by administering an individual with a pharmaceutical composition for prevention or treatment of a proliferative, cancer or angiogenetic disease, the pharmaceutical composition comprising an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, wherein the pharmaceutical composition is mixed and administered with at least one anti-proliferative, cytostatic or cytotoxic substance.
Yet another aspect of the present invention provides an antibody-drug conjugate of the General Formula Ia below:
[General Formula Ia.]
Ab-(Linker-D), Where:
Ab is an anti-DLK1 antibody;
Linker is a linker;
D is a pyrrolobenzodiazepine dimer as an active agent, and;
the linker and the antibody are linked through the N10 or N10' position of the pyrrolobenzodiazepine dimer.
Here, a pyrrolobenzodiazepine dimer prodrug, a pharmaceutically acceptable salt or solvate of the same, where: at the N10 and N10' positions of the pyrrolobenzodiazepine dimer, respectively and independently, are attached any one selected from the group comprised of -C(0)0*, -S(0)0*, -C(0)*, -C(0)NR*, -S(0)2NR*, -(P(0)R')NR*, -S(0)NR* and -P02NR*
groups;
where * is a region where a linker is attached;
where R and R' are respectively and independently H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, substituted or unsubstituted C1_8 alkyl, substituted or unsubstituted C3_8 cycloalkyl, substituted or unsubstituted C1-8 alkoxy, substituted or unsubstituted C1-8 alkylthio, substituted or unsubstituted C3_20 heteroaryl, substituted or unsubstituted C5_20 aryl, or mono- or di-C1-8 alkylamino, and;
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 where, in a case where the C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1_8 alkylthio, C3_20 heteroaryl or C5-20 aryl is substituted, the substitution is by a substitution group selected from a group comprising H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, halo, C1-6 alkyl, C1-6 alkoxy and C6-12 aryl.
A pyrrolobenzodiazepine dimer prodrug, pharmaceutically acceptable salt or solvate thereof, may be used as an active agent.
In one aspect of the present invention, a pyrrolobenzodiazepine dimer precursor is provided. In a case of administering in the form of the precursor according to the present invention, there are advantages over conventional PBD drugs in that: additional reactions are necessary for conversion to an efficacious drug upon exposure to blood, preventing the potential for adverse reactions which may arise when the linker is dissolved unexpectedly; in that toxicity to normal cells is reduced, and in that the drug is more stable.
Further, when preparing antibody-drug conjugates, whereas antibody-drug conjugate prepared using conventional methods has high impurity content, and the exposed imine group is subject to nucleophile attack, posing a risk of a drug of an undesirable structure being generated.
On the other hand, an antibody-drug conjugate prepared using the method according to the present invention has an advantage of ease of isolation due to high purity, and further improved physical properties over conventional PBD or PBD dimer.
In one aspect of the present invention, the pyrrolobenzodiazepine dimer precursor is a pyrrolobenzodiazepine dimer precursor characterized in that it has the structure of General Formula X or General Formula XI below, or a pharmaceutically acceptable salt or solvate thereof:
[General Formula X]
RX5 X Rx3 Rx3 X
N Rx4, Rx4 N ;
Rxi, -=
" Rx2. Rx2 -RX1 RX7' Rx7 [General Formula XI]
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 za, zb' r Ir X zb RX3 1 za WO . , " 1 L N.........\\/y", Rm.
., 101 N .-RX71 0 R". Rx2 0 RXT
In the above formulae:
The dotted lines denote the possible existence of double bonds between Cl and C2, between C2 and C3, between C' 1 and C'2, or between C'2 and C'3;
01 and Rx1' are independently selected from H, OH, =0, =CH2 CN, Rm ORm, =CH-Rm', =C(Rm')2, 0-S02-Rm, CO2Rm, CORm, halo and dihalo;
Rm' is selected from among Rm, CO2Rm, CORm, CHO, CO2H and halo;
each Rm is independently selected from a group comprised of C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5-2o aryl, C5-2o heteroaryl, C3_6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl and 5 to 7 membered heteroaryl;
Rx2, Rx2', Rx3, Rx3', Rx5 and Rx5' are independently selected from among H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm2, NO2, Me3SN and halo;
Rx4 and Rx4' are independently selected from among H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm2, NO2, Me3SN, halo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl, 5 to 7 membered heteroaryl, -CN, -NCO, -ORn, -0C(0)R", -0C(0)NRnir, -OS(0)R", -OS(0)2R", -SRn, -S(0)R", -S(0)2R, -S(0)NRnRn', -S(0)2NRnRn', -0S(0)NRnRn', -0S(0)2NRnRn', -NRnRn', -NRnC(0)R , -NRnC(0)0R , -NRnC(0)NR R ', -NRn S (0 )Rn, -NRnS(0)2R , -NRnS(0)NR 1r, -NRnS(0)2NR Ir, -C(0)R'1, -C(0)0R'1 and -C(0)NRnRn';
Rx and Rx are independently selected from among H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, C1_8 alkyl, C3_8 cycloalkyl, C1_8 alkoxy, C1-8 alkylthio, C3_20 heteroaryl, C5_20 aryl or mono- or di-C1_8 alkylamino;
Y and Y' are independently selected from 0, S and N(H);
Rx6 is independently selected from C3_12 alkylene, C3_12 alkenylene, or C3_12 heteroalkylene;
Rx7 and Rx7' are independently selected from among H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6_10 aryl, 5 to 7 membered heteroaryl, -OW, -0C(0)W, -0C(0)NR1r, -0S(0)W, -0S(0)2W, -SW, -S(0)W, -S(0)2W, -S(0)NR rlr, -S(0)2NR1e, -OS(0)NW W', -0S(0)2NW RI', -NR1r, -NWC(0)Rs, -FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 NWC(0)0Rs, -NWC(0)NRsRs', -NR,S(0)Rs, -NR,S(0)2Rs, -NR,S(0)NRsir, -NR,S(0)2NRsRs, -C(0)W, -C(0)0Rs or -C(0)NRan;
each RI., RI'', Rs and Rs' is independently selected from H, C1-7 alkyl, C2_7 alkenyl, C2_7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl and 5 to 7 membered heteroaryl;
each Rx8 and Rx8' is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 heteroalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, 5 to 7 membered heteroaryl, -S(0)Rm, -S(0)2Rm, -S(0)NRmR", -S(0)2NRmRm', -NRmRm', -NRmC(0)Rm, -NRmC(0)0Rn, -NRmC(0)NR -NRmS(0)Rn, -NRmS(0)2Rn, -NRmS(0)NRnRn', -NRmS(0)2NRnRn', -C(0)Rm, -C(0)0Rm and -C(0)NRmR";
Za is selected from among ORx12a, RN xl2aRX12a, or SRx12a;
Zb is selected from among ORx13a, RN xuaRxi3a, or SRx13a;
Za' is selected from among ORx12a, RN xl2aRX12a, or SRx12a;
Zb' is selected from among ORx13a', RN xua'Rxna', or SRx13a';
each RX12a, XR 12a', RX13a' and R' is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-10 aryl, 5 to 7 membered heteroaryl, -C(0)Rx151, -C(0)0Rx151 and -C(0)NRx15a 1RX 5, and;
each Rx15a and R815a' is independently selected from C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5-20 aryl, C5_20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, and 5 to 7 membered heteroaryl, and:
The Rx13a and Rx14a optionally join the atoms to which they are attached to form 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, or 3 to 7 membered heteroaryl, and the 013' and Rxma' optionally join theatoms to which they are attached to form 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, or 3 to 7 membered heteroaryl, and;
each of the Rn, Re', R , R ', RP and RP' is independently selected from among H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, and to 7 membered heteroaryl.
Further, the Rm is independently selected from a group comprised of C1_12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C5_20 aryl, C5-20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl and 5 to 7 membered heteroaryl, and;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 the Rm is additionally substituted with of C1-12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5_20 aryl, C5_20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl or 5 to 7 membered heteroaryl.
Furtherõ Rx4 and V' are independently selected from among H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRmRm', NO2, Me3Sn, halo, C1_6 alkyl C1-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl, 5 to 7 membered heteroaryl, -CN, -NCO, -ORn, -0C(0)R, -0C(0)NRnRn', -OS(0)R, -OS(0)2R, -SR, -S(0)R, -S(0)2R, -S(0)NRnRn', -S(0)2NRnRn', -0S(0)NRnRn', -0S(0)2NRnRm, -NRnRn', -NRnC(0)R , -NRnC(0)0R , -NRnC(0)NR R ', -NRnS(0)R , -NRnS(0)2R , -NRnS(0)NR R"',-NRnS(0)2NR R ', -C(0)R, -C(0)0R'1 and -C(0)NRnRn', and;
The Rx4 or Rx4' is C1_6 alkyl, C1-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl or 5 to 7 membered heteroaryl, and additionally is substituted with at least one C1_6 alkyl, C1_6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, 5 to 7 membered heteroaryl, -OR, -0C(0)RP, -0C(0)NRPRP', -0S(0)RP, -0S(0)2RP, -SR, -S(0)RP, -S(0)2RP, -S(0)NRPRP', -S(0)2NRPRP', -0S(0)NRPRP', -0S(0)2NRPRP', -NRPRP', -NRPC(0)Rq, -NRPC(0)0Rq, -NRPC(0)NRqRq', -NRPS(0)Rq, -NRPS(0)2Rq, -NRPS(0)NRqRq', -NRPS(0)2NRqRq', -C(0)RP, -C(0)OR' or -C(0)NRPRP.
Further, the Rx7 and Rx7' are independently selected from among H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6_10 aryl, 5 to 7 membered heteroaryl, -OW, -0C(0)W, -0C(0)NR an, -0S(0)W, -0S(0)2W, -SW, -S(0)W, -S(0)2W, -S(0)NW R11, -S(0)2NR le, -0S(0)NW R11, -0S(0)2NW R11, -NRall, -NWC(0)Rs, -NWC(0)0Rs, -NWC(0)NRsRs', -NWS(0)Rs, -NWS(0)2Rs, -NWS(0)NRsRs', -NWS(0)2NRsRs, -C(0)W, -C(0)ORS or -C(0)NRIr ;
Rx7 and Rx7' are independently selected from among C1-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6_10 aryl, or 5 to 7 membered heteroaryl, and are additionally substituted by C1_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6_10 aryl, 5 to 7 membered heteroaryl, -OR% -0C(0)Rt, -0C(0)NRtRt', -0S(0)Rt, -0S(0)2Rt, -SRt, -S(0)Rt, -S(0)2Rt, -S(0)NRtRt', -S(0)2NRtRt', -0S(0)NleR t', -0S(0)2NRtRt', -NRtRt', -NRtC(0)Ru, -NRtC(0)01V,-NRtC(0)NRuR"', -FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 NRtS(0)1V, -NRtS(0)2Ru, -NRtS(0)NIVR', -NRtS(0)2NIV R', -C(0)Rt, -C(0)0Rt or -C(0)NRtRt', and;
The Rr, Rr', Rs, Rs', Rt, Rt', RU and R"' are independently selected from among H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, and to 7 membered heteroaryl.
Further, 01 and Rxr are independently selected from R", and;
WI' is selected from among C1-6 alkyl, C2_6 alkenyl, C5-7 aryl and C3_6 heteroaryl.
Further, 02, Rx2', Rx3, Rx3', Rx5 and Rx57 are independently selected from H
or OH.
Further, Rx4 and Rx4' are independently selected from R", and;
WI' is C1_6 alkoxy.
Further, the Rx4 and Rx4' are independently any one selected from a group comprised of methoxy, ethoxy and butoxy. .
Further, the Y and Y7 are 0.
Furtherõ the Rx6 is C3-12 alkylene, C3-12 alkenylene or C3-12 heteroalkylene, with the Rx6 substituted by -NH2, -NHR", -NHC(0)1r, -NHC(0)R", -NHC(0)CH2-[OCH2CH2]-R , or -[CH2CH2O]n-R ;
The Rxx is H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, C1_8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, C3_20 heteroaryl, C5_20 aryl or mono- or di-C1_8 alkyl amino, and;
n is an integer of 1 through 6.
Further, in one aspect of the present invention, the active agent is a pyrrolobenzodiazepine dimer denoted by General Formula XII or General Formula XIII;
[General Formula XII]
31 G WA.'Ab i 1 x. x Rot I Rx3* Rxs I Rxs H
, , -Rxe=Y si N H
, 4. N lb 0 Rx40 4 -- r., Rx2. Rx2 0 7.
1x7. 10 RAT
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 [General Formula XIII]
A
GI W "Ab G
* WI, itt Rx76 Xa' X8 4. 1 x 'I' z Ner Z 11.1_,_"'RX6_y , N Oil R _______________________________________________ N R x 8 Fem -= - ,, v., op RxT= . IN---* Rx2 0 Rx7 The Xa. and Xa' are independently selected from between a bond or C1_6 alkylene;
Zx' and Zx are independently selected from among hydrogen, C1-8 alkyl, halogen, cyano, 0 IVR C () 0 "RI" ' nitro, õ."."," , or -(C112).-0C113;
The respective R"' R9 and R1 are selected from among hydrogen, C1-8 alkyl, C2-6 alkenyl and C1_6 alkoxy, and;
m is an integer of 0 to 12.
The Zx' and Zx are independently any one selected from a group comprised of hydrogen, R Sal 0 0 0 ii y -Rioo 4106 and -(C112).-OCH3;
, The respective R80' R9 and R1 are selected from among hydrogen, C1_3 alkyl and C1-3 alkoxy;
m is an integer of 1 to 6 and;
the active agent is any one selected from a group comprised of:
N...õ0,-...
,h.Tisl OW , HO :.0 7 Ho:c70 iiim 6 H ...e..0 0 ,y =
HO I Z OH
I.J.L.r 400...."......"%õ0 40-11%
N ) 0 In Me FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 0 N .....õ.,,,, 0 ,fis1H :
H0.0 0 * a Tit 0.,t0 HO:07 ifit HO' -. OH 19.LIFI
0,-...,õ,,,,,,..,0 Me0 H
00:M e 0 HOC- oso H 0:C 0 e HO s= " OH . =. 4111 H 0 = ' OH
H 0 ....0,0 IH 0 0 OM e M e0 WI t:NS
O Or H H
0 N '-''NOMe 0 N..{.,.õ=-=,04NH2 H 0:C 0 vfl HO:C7 iiit 3 H 0 '. H .. OH 411 e 0 H 0 .' H '' OH 111111P0 , t_LZ.N iso ID ....."4""'N...,== 40.--5 N OM e Me )4 0 0 ,õ.^.. ow 0 H
HO:C 0 HOIC,4&.)0 . H :1114 HOILX:H 411 HO 'OH ktt0+"',-, 4--Am )4sf."."0--ki Hi I $ 14 0,4,0 0 = 0 HO 1 Y al FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H H
0 N ,.,,,,,,..ome 0 HO:C 7 . HOC 7.
0 ,0 H0 r 1 OH
* 0 H
OMe H H
0 N "0 Me 0 H 0:C 4V aiii HO:CV,,0 0 HO .. .. OH W HO' -OH
01 0,õ 0 H 0 i 1 OH
N -,Nb,,, H
W 0 Me hie0 H H .
0 N ,....õ-,..ome 0 N .-VO4-=,..õõ, N3 H 0:C 0 44f) .. * HOC 46,1Cf,,,,,r,P oir HOc,r, ". OH HO 's .'. OH
0 =,.."..,"N/1:) *
N 0 Me Nie0 N o=N =
0 N õ,..,õ",,, opvie 0 N ,,,..)---,/^==
HOC ,,1(.10)0P HOC 0 HO ' '' OH I. HO ' .. 0 OH
HO I I OH
* *
0 Me /4.1e0 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H H
0 N ''=-"-'0Me 0 HO:Cy0 yp Air HOC q 0 2 HO oy. OH 11111 HO OH
OH 0o OH 0...,.0 0 Me WO
H H =
O '`.,..*% OM e 0 N ,.... N3 HO . K 0:C 4,cr0 le s. ..
HO r 1 ,y. OH
LL,Z-N -N 00 0,...õ,,...,...õ,.."0 N
OM e M e0 N
0 =
H H =
0 N ."*.' OM e 0 H 0:C 0 HOC sci3O
HO y ... .' OH 41111) H
s 0 ,,0 HOOH.
.õ, HO Ie, OH 00 I OH
N
N
OM e M N e 0 11 I H
H H .
0 N ,_ ....., HO OH 1.1 H".044X1OH 111411 H 0 0 OH 0 ,,, 0 HO I I OH
,--=tI las 0 , ....
N 0 Me Me0 1 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H H - .
0 N õ,,NOM e 0 N..........."-No4NH:
HO H 02C *
'A'37 0 H . H 0 0 H
H 0 0 h 0 0 HO I I OH
0,,.,..õ,,,õ.._/0 N Ohl e M e0 0 Tyiti 0 t:,'"AN 'N(A1N H H
N
H 0 N ....,0 4... Hz 0., HO
00,,,,, 0 ,,,,. 0 H 0 1 i CH
0,,,,,,,,õõ,õ,..,,,,..,0 * N......1 , N OM.
H H
0 N ,_ ,o--.,, 0 N -.........,/N.0 +N H2 ' HO 2C y0 yP 0 HO 2C
110 ..0 H HO qc. H *
OH O,.0 OH 0 0 N N
H , iial 0 .õ...,.... 0 .
IA e M eo h4e0 0 M e H H H 0 , 0 N _ .0,-.
OM e 0 N
HO2C,7 H 02C 7) H 0 = 011 III H 0 - OH
OH 0 ,0 H 0 ,.õ 0 NI OH
IL:j.z.,:" NI I*1 0,,..,...,õ.0 401 ...... .., 41'r OM e M e0 N
0 or FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Hill H H H t=
0 N ,,...,0 me 0 N..õ..õ,,N,.,,N
HO.0 0 0 HOIC,*r:::13 * 0 O /
H07jc)70H * HO ' ''CoH
OH 0,,,.0 OH 0,,,, 0 N
H. 110c 110 LZtii 4: OM. r H , P
H H H ; 0 13 N'se''OMe 0 N
HO:CT:13,0 igki HO:C0 0 O /
0 ,0 H 0 ... 0 gli N 0 ..,..,...-õ,....õ."..õ 0 F.14.-44, Wi We Me 1" / let-1 H H .
O N --... OW 0 HO:p 470 la HOCI47 HO '. "..OH s'41111 HO . ,. oillt CH
HO I I CH
N tiot 0,,y,.."0 *
NH
N., ONie L Me) O r0 0 H H .
O N ."=.'" 0 IA e 0 N'%==="*.s%0M e HO 2C y.:õ.ip an HO 2C1A,(144) õI
HO.'0 H "lij HO . ...0 H
NH
..k N 0.1 IA e i M e0 O r'''.0 0 0 'O '%.s.%=)`).NH 2 Date Recue/Date Received 2021-08-09 0.KH:
0 , 0 me0---4 --HOC r" 0 yAOH 10 ,.0011 1104k:
H070.1 4 CO
lir v;
H = ,..,00 S 0 = CNI
Ali j-1 0,;0 011e VP
Heo 0 , ,,,ome 0, H 0:C 0 _,41 H 02C 7 air Ho"0õ
H
Tiro . 0 HO 4. .1:IH illij 0 *,.. 1 ('o III1 0 i OP) y.o oti õdo:
OM e 0 N....ome 0 v 3 H 0:C 0 Al HO:C 0 id*
H 0 ' "OH IP
H
4V) yo Ho. ..coity H 01,0 r"0 NN NH 0 ...pOM e IA e0 0 .õ,,,,,,.......0"....d. 0 iii ..... 0 O,:#i N4 H , and;
' OM e 0 HOC idii H 02C 0 idit,= 3 HOOH 1.*1 HO %OH !Illi 0 y0 H 0,1õ =
1 on N
N lir OM e IA e0 N
'= 0 Fl IBOSTON5259862.1 Date Recue/Date Received 2021-08-09 , N 7_1:N0"v Nr"."0"400.....0"XrNA N N
KikCilio 111* Hosccro 0 H 011;) OHUI
HO OH
In the present specification, "conjugates" refers to cell binding agents that are covalently linked to one or more molecules of a cytotoxic compound. Here, "cell binding agent" is a molecule having affinity for a biological target, for example, a ligand, protein, antibody, specifically a monoclonal antibody, protein or antibody fragment, and the binding agent serves to direct the biologically active compound to the biological target. In one aspect of the present invention, the conjugate may be designed to target tumor cells through cell surface antigens.
The antigen may be a cell surface antigen that is overexpressed or expressed in an abnormal cell type. Specifically, the target antigen may be expressed only on proliferative cells (e.g., tumor cells). Target antigens may be selected based on different expression, usually between proliferative and normal tissues. In the present invention, a ligand is bonded to a linker.
In the present specification, "antibody" refers to an immunoglobulin molecule which, through at least 1 antigen recognizing site located in the variable region of the immunoglobulin molecule, can bind with specificity to a target, for example a carbohydrate, polynucleotide, lipid or polypeptide, etc. The term "antibody" as used in the present specification encompasses not only complete monoclonal or polyclonal antibody, but also a given antigen-binding part (for example, "antigen-binding fragment") of a complete antibody having the capacity to bind with specificity to a certain antigen) or a single chain thereof, a fused protein comprising antibody, or any other modified arrangement of immunoglobulin molecule comprising an antigen recognizing site, non-limiting examples of which are: Fab; Fab'; F(ab')2Fd fragment; Fv fragment;
single domain antibody (dAb) fragment; isolated complementarity determining region (CDR);
single chain (scFv) and single domain antibody (e.g. shark and camel antibody), a maxibody, a minibody, an intrabody, a diabody, a triabody, a tetrabody, a v-NAR, or a bis-scFv (See e.g. the literature [Hollinger and Hudson, 2005, Nature Biotechnology 23(9): 1126-1136]".
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Antibodies include any category of antibody, for example IgG, IgA or IgM (or sub-categories thereof), and the antibody does not need to be of a specific type.
Depending on the amino acid sequence of the constant domain of the heavy chain of the antibody, an immunoglobulin may be assigned to different categories. There exist five major types of immunoglobulin: IgA, IgD, IgE, IgG and IgM, of which a number may be additionally categorized into sub-categories (isotypes), for example, IgGl, IgG2, IgG3, IgG4, IgAl and IgA2. The heavy chain (HC) constant domains corresponding to different categories are respectively referred to as, respectively, alpha, delta, epsilon, gamma and mu. The subunit structures and three-dimensional configuration of different categories of immunoglobulin are widely known to the art. The antibody of the present invention may be prepared using techniques widely known to related arts, for example, recombinant techniques, phage display techniques, synthesis techniques, combinations of the foregoing techniques, or other techniques readily known to related arts.
In the present specification, "isolated antibody" refers to an antibody which does not substantially comprise a different antibody having specificity to another antigen, which may substantially not comprise other cellular material and/or chemical substances.
In the present specification, "biological target" refers to an antigen located on the surface of a tumor, cancer cell or extracellular matrix.
In the present specification, "linker" refers to a compound which covalently bonds a cytotoxic compound to a ligand. In one aspect of the present invention, the linker disclosed in PCT/US2016/063564 and PCT/US2016/063595 may be used as the linker.
In the present specification, "therapeutic agent" refers to an agent that exerts cytotoxicity, cell proliferation inhibition and / or immunomodulatory effects on cancer cells or activated immune cells. Examples of therapeutic agents include cytotoxic agents, chemotherapeutic agents, cell proliferation inhibitors, and immunomodulators.
In the present specification, "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer.
In the present specification, "subject" is intended to include human and non-human animals, particularly mammals. Examples of subjects include human subjects, e.g., disorders, such as those described herein, e.g., human patients with cancer or normal subjects. "Non-human animal" is used in all vertebrate animals, such as non-mammals (e.g., Chickens, amphibians, reptiles) and mammals such as non-human primates, livestock and / or animals (e.g., sheep, dogs, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 cats, cows, pigs, etc.) and rodents (e.g., mice, rats, hamsters, guinea pigs, etc.). In certain embodiments, the subject is a human patient. In certain examples, the subject is a human patient.
In the present specification, "treating" or "treating" refers to both therapeutic treatment and prophylactic or preventative measures. A subject in need of treatment includes a subject already having a disorder, and a subject susceptible to a disorder or a subject to be prevented from disorder.
Thus, when used in reference to a subject in need of the disease or treatment, the term encompasses an inhibition or slowing of disease progression, remission of disease, prevention of symptoms, reduction of disease and / or symptom severity, but is not limited to these.
In the present specification, "administer" or "administering" refers to providing and / or contacting and / or delivering a compound or compounds by any suitable route to achieve the desired effect. Administration may be by oral, sublingual, parenteral (e.g.
intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraarterial, intrathecal, intrasternal, intraspinal, Rectal, nasal, buccal, rectal, vaginal, nasal, ophthalmic, inhaled and implanted.
In the present specification, "unsubstituted or substituted" refers to a parent group which may be unsubstituted or substituted, "substituted" refers to a parent group having at least 1 substituent group, and substituent group refers to a chemical part which is covalently bonded to a parent group or fused to a parent group.
In the present specification, "halo" refers to fluorine, chlorine, bromine or iodine, etc.
In the present specification, "alkyl" is a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic or alicyclic, saturated or unsaturated (unsaturated, fully unsaturated) hydrocarbon compound. Examples of saturated alkyls include methyl, ethyl, Butyl, n-pentyl (amyl), n-hexyl, n-heptyl and the like, saturated cyclic alkyl groups such as methyl, ethyl, Isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and neopentyl, etc.
In the present invention, "alkoxy" refers to -OR where R is an alkyl group, and examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy, etc.
In the present invention, "aryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having a ring atom.
In the present invention, "alkenyl" is an alkyl having at least one carbon-carbon double bond. Examples of unsaturated alkenyl groups are ethenyl (vinyl, -CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl, isopropenyl, butenyl, pentenyl and hexenyl, etc.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 In the present invention, "alkynyl" is an alkyl group having at least one carbon-carbon triple bond, and examples of unsaturated alkynyl group include ethynyl and 2-propynyl, etc.
In the present invention, "carboxy" refers to -C(=0)0H.
In the present invention, "formyl" refers to -C(=0)H.
In the present invention, "aryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound. For example, "C5_7 aryl" is a moiety having from 5 to 7 ring atoms, which is a monovalent moiety obtained by removing a hydrogen atom from the aromatic ring atoms of an aromatic compound, and "C5_10 aryl" is a moiety having from 5 to 10 ring atoms, which is a monovalent moiety obtained by removing a hydrogen atom from the aromatic ring atoms of an aromatic compound. Here, the prefixes (C57, C5-10, etc.) refer to the number of ring atoms or a range for the number of ring atoms, regardless of whether they are carbon atoms or hetero atoms. For example, "C5_6 aryl" relates to an aryl group having 5 or 6 ring atoms. Here, the ring atoms may be all carbon atoms as in a "carboaryl group". Examples of a carboaryl group include, but are not limited to, those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene and pyrene. Examples of aryl groups that include a fused ring wherein at least one is an aromatic ring include, but are not limited to, groups derived from indane, indene, isoindene, tetralin, acenaphthene, fluorene, phenalene, acesphenanthrene and aseantrene. Alternatively, the ring atoms may contain one or more heteroatoms as in a "heteroaryl group".
In the present invention, " heteroaryl "refers to aryl containing one or more heteroatoms, such as pyridine, pyrimidine, benzothiophene, furyl, dioxolanyl, pyrrolyl, oxazolyl, pyridyl, pyridazinyl, More specifically benzofuran, isobenzofuran, indole, isoindole, indolizine, indolin, isoindoline, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, benzodioxole, benzofuran, benzotriazole, benzothiofuran, benzothiazole, C9 having two fused rings derived from benzothiazole, chromene, iso-chromene, chroman, is-chroman, benzodioxane, quinoline, isoquinoline, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, Cio having two fused rings derived from pteridin, CH having two fused rings derived from benzodiazepine, carbazole, dibenzofuran, dibenzothiophene, carboline, pyrimidine, C13 having three fused rings derived from pyridoindole, acridine, xanthene, thioxanthene, phenoxathiine, phenazine, phenoxazine, phenothiazine, HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 thianthrene, phenanthridine, phenanthroline, and C14 having three fused rings derived from phenazine.
In the present invention, "cycloalkyl" refers to an alkyl group which is a cycloalkyl group, and relates to a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound. Examples of cycloalkyl groups include, but are not limited to, those derived from:
Saturated single ring hydrocarbon compounds: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane and methylcyclohexane;
Unsaturated single ring hydrocarbon compounds: cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene and methylcyclohexene;
and saturated heterocyclic hydrocarbon compounds: norcaran, norphenen, and norbornene.
In the present invention, "heterocyclyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound.
In the present invention, the prefixes (e.g., C1_12 , C 3 _8, etc.) refer to the number of ring atoms or a range for the number of ring atoms, regardless of whether they are carbon atoms or hetero atoms. For example, the term "C3-6 heterocyclyl" used in the present specification relates to a heterocyclyl group having 3 to 6 ring atoms.
Examples of single ring heterocyclyl groups include, but are not limited to, those derived from:
Ni: aziridine, azetidine, pyrrolidine, pyrroline, 2H- or 3H-pyrrole, piperidine, dihydropyridine, tetrahydropyridine, azepine;
N2: imidazolidine, pyrazolidine, imidazoline, pyrazoline, piperazine;
01: oxirane, oxetane, oxolane, oxol, oxane, dihydropyran, pyran, oxepine;
02: dioxolane, dioxane and dioxepane;
03: trioxane;
N101: tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, Si: thiiran, thiethan, thiolan, thian, tiepan;
Ni Si: thiazoline, thiazolidine, thiomorpholine;
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 N201: oxadiazine;
01Si: oxathiol, oxathian, and;
N101 Si : oxathiazine.
In the present invention, "prodrug" refers to compounds which, under in vivo physiological conditions (e.g. enzymatic oxidation, reduction and/or hydrolysis), may, by action of enzyme or gastric acid, be converted directly or indirectly into a pyrrolobenzodiazepine drug.
In the present invention, "pharmaceutically acceptable salt" may be an acid addition salt formed by pharmaceutically acceptable free acid, where the free acid is an organic acid or an inorganic acid.
The organic acids include, but are not limited to, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methane sulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid and aspartic acid. Also, the inorganic acids include, but are not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
For example, if the compound has a functional group which is an anion or may be an inion (e.g. -COOH may be -000-), a suitable cation may be used for forming a salt.
Examples of suitable inorganic cations include, but are not limited to, Na + and K ' alkaline earth cations such as Ca2+ and Mg2 ' and other cations such as A13 ' Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 ) and substituted ammonium ions (e.g. NH3R+, NH2R2+, NHR3+, NR4+).
Some examples of suitable substituted ammonium ions are derived from the following:
ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine , phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a typical quaternary ammonium ion is N(CH3)4 .
If the compound has a functional group which may be a cation or a cation (e.g., -NH2 may be -NH3), a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfuric acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Examples of suitable organic anions include, but are not limited to, those derived from organic acids such as: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, But are not limited to, disulfonic acid, ethanesulfonic acid, fumaric acid, glutaronic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, But are not limited to, malic acid, methanesulfonic acid, mucilous acid, oleic acid, oxalic acid, palmitic acid, pamic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid and tartaric acid, etc. Examples of suitable multimeric organic anions include, but are not limited to, those derived from the following multimeric acids: tannic acid, carboxymethylcellulose, etc.
In the present invention, "solvate" refers to a molecular complex between a compound according to the present invention and solvent molecules, examples of which include but are not limited to water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine or the compound according to the present invention bonded to a mixed solvent thereof.
It may be convenient or desirable to prepare, purify and/or handle solvates corresponding to active compounds. In the present specification, the term "solvate" is used in its conventional sense to refer to solutes (e.g. active compounds and salts of active compounds) and complexes of solvents. When the solvent is water, the solvate may conveniently be referred to as a hydrate, such as monohydrate, dihydrate or trihydrate, etc.
The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carrier include large macromolecules that are slowly metabolized, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, lipid aggregates, and the like.
Such pharmaceutically acceptable carriers may be appropriately selected and used by a person skilled in the art.
The composition comprising a pharmaceutically acceptable carrier may be of various oral or parenteral formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrating agent, or a surfactant is usually used.
Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain at least one excipient such as starch, calcium carbonate, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 sucrose or lactose, gelatin, . In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used.
Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are commonly used simple diluents.
Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
The pharmaceutical composition may be in the form of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze- It can have one formulation.
For intravenous, intradermal or hypodermic injection, the active ingredient may be in the form of an acceptable aqueous solution for parenteral administration, be pyrogen-free, and have the appropriate pH, isotonicity and stability. A person skilled in the art may prepare an appropriate solution using an isotonic vehicle such as sodium chloride solution, Ringer's solution or Ringer's lactate solution, and preservatives, stabilizers, buffers, anti-oxidants and other additives may be included as necessary. Solid forms suitable for injection may also be prepared as emulsions or in the form of polypeptide encapsulated in liposome.
As used herein, the phrase "effective amount" or "therapeutically effective amount" refers to the amount required to achieve the desired therapeutic result (for dose and duration and means of administration). An effective amount is at least the minimum amount of active agent required to confer a therapeutic benefit to a subject, and is less than the toxic amount. For example, the amount administered may be in a range of approximately 10Ong to approximately 100mg/kg per patient, more typically approximately lug/kg to approximately 10mg/kg. In a case where an active compound is a salt, ester, amide or prodrug, the dose is calculated based on the parent compound, and accordingly the actual weight used also increases proportionally. The pyrrolobenzodiazepine compound according to the present invention may be formulated to comprise 0.1mg to 3000mg, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 lmg to 2000mg, or 10mg to 1000mg of active ingredient per unit dosage form, but is not limited thereto. The active ingredient may be administered to give an active compound peak plasma concentration of approximately 0.05 pM to 100[M, 1 [tM to 50uM, or 5pM to 30pM. For example, optionally it may be administered by intravenous injection of a solution of 0.1 w/v% to 5 w/v%
active ingredient in saline solution.
In a pharmaceutical composition, the concentration of the active compound is determined by the absorption, inactivation and excretion rates of the drug, and other factors known not persons skilled in the art. The dose administered may vary depending on the severity of symptoms or the disease. Further, the dose and administration therapy for a specific patient may be adjusted according to the professional judgment of an administration supervisor, giving general consideration to the degree of the patient's symptoms and illness, need for the drug, age, and reactivity to the drug, etc. The range of concentrations stated in the present invention are only intended as an example, and the manner of carrying out the claimed composition is not limited hereto. Furtherõ the active ingredient may be administered once, or smaller doses may be administered across multiple administrations.
The prodrug compound, or prodrug-linker compound, or prodrug-linker-ligand conjugate compound may be used to treat proliferative diseases, in particular cancer.
The term "proliferative disease" refers to excessive, abnormal, undesired or unregulated cell growth either in vitro or in vivo, such as hyperplasia or cytogenesis. Non-limiting examples of proliferative disease include neoplasm, tumor, cancer, leukemia, psoriasis, bone disease, fibrous dysplasia and pharyngeal arteriosclerosis. Non-limiting examples of cancer are lung cancer, small cell lung carcinoma, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma and melanoma.
Benefits of the invention The antibody-drug conjugate according to the present invention, by comprising an anti-DLK1 antibody which binds with specificity to DLK1-expressing cells and is internalized into a cell exhibits the benefits of being able to deliver a drug effectively, selectively and with specificity, and allowing for a drug to bind stably to an antibody to exhibit the intended cytotoxicity while maintaining in vivo stability. In particular, by grafting technology for a linker including a self-immolative group, the present invention provides a drug-linker-ligand system which allows a drug HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 and/or toxin to stably reach a target cell and effectively exhibit a drug effect while having substantially reduced toxicity.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a diagram confirming the efficacy of the ADC according to the present invention in a patient-derived tumor animal model.
BEST MODE(S) FOR CARRYING OUT THE INVENTION
In the following, the present invention is described in further detail through embodiments and experimental examples.
The following embodiments and experimental examples are intended to aid in understanding the present invention, and are not intended to limit the scope of the present invention thereto.
<Example 1> Preparation of compounds 1, 2, 3 and 4 Ho C; 01,1 0 OA kik IAE
Ile Ih.."
z ;,31-1:, 0 0- ri ##%%#4#' 0.".'&P.Ct 'Ng. .T1FA
it #h.
I
r op 0 HO,L. A, 0: Olit 0 M PAE
HQ : 0, 1511 r 4 : A
:1LN MN +00",. 4 N 1-11 :2 HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 "QA 4 OA MMAE
0 N."-====,-"Ho % .
H H
.,",,....,k0 ,....,,X, 0 ,,,,..%)."...,,,ON,,,,-,..Ø14 H2 ' HO2C 00 4 H 0 .TFA
fivy e t.coH 4 01, NIMAE
4,410 H 0 õ eatt 0 * 0 AM MAE
H 0 i OH H H H
HO2Cy H ' H
0 N 0..."0,,,õ,,z-N +..".0+ NH2 H 0. 0 2C 0 0 .TPA
HO '' .. OH SI ".---M MAE
.y.,õ
Compounds 1, 2, 3 and 4 were prepared using the method stated in International Patent Publication W02017-089895.
In compounds 1, 2, 3 and 4, the structure of MMAE is as follows.
MIME
HO Pi ri I ,....4,,..: I .... 0 .....0 0 <Example 2> Preparation of compounds 5, 6, 7 and 8 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 0 it-,=*"OM e 0 H Ni0 .õ,..,... ..+NH2 .TFA
Fro 2Cy0 yD An HO2C7 iiii 6 HO *.Y.OH IIIF HO '. .. OH 'Pli OH = ,,,.0 H 0 ..... =
0,0 ilo Na OM e M e0 = 0 NIN
0 , 11. me 044+12 0, HD2C7 HO2C7 A . WA
HO " 'OH I* HD
H
HO a Y0 0 kr a OH
N N
ON, IA 00 = 0 0 1L ,OM, 0 --"*.- OM e HO2CV=00 41 14027 a HO ' ." OH HO ..0 H 41114IP
H 0 .....0 H 0 ..,o HO r 1 OH
0 õ,...õ.........õ..",.."0 N---S H
ome meo ir ,N --'-j=,' ,
2000, difluoromethylornithine, retinoic acid, capecitabine, or pharmaceutically acceptable salts, solvates or acids thereof;
(b) monokine, lympokine, traditional polypeptide hormone, parathyroid hormone, thyroxine, relaxin, pDLKelaxin, glycoprotein hormone, follicle stimulating hormone, thyroid stimulating hormone, luteinizing hormone, hepatic growth factor fibroblast growth factor, prolactin, placental lactogen, tumor necrosis factor, tumor necrosis factor-a, tumor necrosis factor-I3, Mullerian inhibiting substance, mouse gonadotropin associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, osteoinductive factor, interferon, interferon-a, interferon-I3, interferon-y, colony stimulating factor (C SF), macrophage-CSF, granulocyte-macrophage-CSF), granulocyte-FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 macrophage-CSF, granulocyte-CSF, interleukin (IL), IL-1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, I L-12, tumor necrosis factor, TNF-a, TNF-I3, polypeptide factor, LIF, kit ligand, or mixtures thereof;
(c) diphtheria toxin, botulinum toxin, tetanus toxin, dysentery toxin, cholera toxin, amanitin, a-amatinin, pyrrolobenzodiazepine, pyrrolobenzodiazepine derivative, indolinobenzodiazepine, pyridobenzodiazepine, tetrodotoxin, brevetoxin, ciguatoxin, ricin, AM toxin, auristatin, tubulysin, geldanamycin, maytansinoid, calicheamicin, daunomycin, doxorubicin, methotrexate, vindesine, SG2285, dolastatin, dolastatin analog, auristatin, cryptophycin, camptothecin, rhizoxin, rhizoxin derivatives, CC-1065, CC-1065 analogs or derivatives, duocarmycin, enediyne antibiotic, esperamicin, epothilone, toxoid, or mixtures thereof;
(d) affinity ligand, where the affinity ligand is a substrate, inhibitor, active agent, neurotransmitter, radioactive isotope, or mixtures thereof;
(e) radioactive label, 32P, 35S, fluorescent dye, electron dense reagent, enzyme, biotin, streptavidin, dioxigenin, hapten, immunogenic protein, nucleic acid molecule with a sequence complementary to a target, or mixtures thereof;
(f) immunomodulatory compound, anti-cancer agent, anti-viral agent, anti-bacterial agent, anti-fungal agent, anti-parasitic agent, or mixtures thereof;
(g) tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone or toremifene;
(h) 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole or anastrozole (i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine;
(j) aromatase inhibitor;
(k) protein kinase inhibitor;
(1) lipid kinase inhibitor;
(m) antisense oligonucleotide;
(n) ribozyme;
(o) vaccine, and;
(p) anti-angiogenic agent.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Yet another aspect of the present invention provides, in relation to the preparation of a drug for prevention or treatment of a proliferative, cancer or angiogenetic disease, a use of an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof.
Yet another aspect of the present invention provides a method for drug for prevention or treatment of a proliferative, cancer or angiogenetic disease by administering an individual with a pharmaceutical composition for prevention or treatment of a proliferative, cancer or angiogenetic disease, the pharmaceutical composition comprising an antibody-drug conjugate or a pharmaceutically acceptable salt or solvate thereof as an active ingredient, wherein the pharmaceutical composition is mixed and administered with at least one anti-proliferative, cytostatic or cytotoxic substance.
Yet another aspect of the present invention provides an antibody-drug conjugate of the General Formula Ia below:
[General Formula Ia.]
Ab-(Linker-D), Where:
Ab is an anti-DLK1 antibody;
Linker is a linker;
D is a pyrrolobenzodiazepine dimer as an active agent, and;
the linker and the antibody are linked through the N10 or N10' position of the pyrrolobenzodiazepine dimer.
Here, a pyrrolobenzodiazepine dimer prodrug, a pharmaceutically acceptable salt or solvate of the same, where: at the N10 and N10' positions of the pyrrolobenzodiazepine dimer, respectively and independently, are attached any one selected from the group comprised of -C(0)0*, -S(0)0*, -C(0)*, -C(0)NR*, -S(0)2NR*, -(P(0)R')NR*, -S(0)NR* and -P02NR*
groups;
where * is a region where a linker is attached;
where R and R' are respectively and independently H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, substituted or unsubstituted C1_8 alkyl, substituted or unsubstituted C3_8 cycloalkyl, substituted or unsubstituted C1-8 alkoxy, substituted or unsubstituted C1-8 alkylthio, substituted or unsubstituted C3_20 heteroaryl, substituted or unsubstituted C5_20 aryl, or mono- or di-C1-8 alkylamino, and;
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 where, in a case where the C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1_8 alkylthio, C3_20 heteroaryl or C5-20 aryl is substituted, the substitution is by a substitution group selected from a group comprising H, OH, N3, CN, NO2, SH, NH2, ONH2, NNH2, halo, C1-6 alkyl, C1-6 alkoxy and C6-12 aryl.
A pyrrolobenzodiazepine dimer prodrug, pharmaceutically acceptable salt or solvate thereof, may be used as an active agent.
In one aspect of the present invention, a pyrrolobenzodiazepine dimer precursor is provided. In a case of administering in the form of the precursor according to the present invention, there are advantages over conventional PBD drugs in that: additional reactions are necessary for conversion to an efficacious drug upon exposure to blood, preventing the potential for adverse reactions which may arise when the linker is dissolved unexpectedly; in that toxicity to normal cells is reduced, and in that the drug is more stable.
Further, when preparing antibody-drug conjugates, whereas antibody-drug conjugate prepared using conventional methods has high impurity content, and the exposed imine group is subject to nucleophile attack, posing a risk of a drug of an undesirable structure being generated.
On the other hand, an antibody-drug conjugate prepared using the method according to the present invention has an advantage of ease of isolation due to high purity, and further improved physical properties over conventional PBD or PBD dimer.
In one aspect of the present invention, the pyrrolobenzodiazepine dimer precursor is a pyrrolobenzodiazepine dimer precursor characterized in that it has the structure of General Formula X or General Formula XI below, or a pharmaceutically acceptable salt or solvate thereof:
[General Formula X]
RX5 X Rx3 Rx3 X
N Rx4, Rx4 N ;
Rxi, -=
" Rx2. Rx2 -RX1 RX7' Rx7 [General Formula XI]
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 za, zb' r Ir X zb RX3 1 za WO . , " 1 L N.........\\/y", Rm.
., 101 N .-RX71 0 R". Rx2 0 RXT
In the above formulae:
The dotted lines denote the possible existence of double bonds between Cl and C2, between C2 and C3, between C' 1 and C'2, or between C'2 and C'3;
01 and Rx1' are independently selected from H, OH, =0, =CH2 CN, Rm ORm, =CH-Rm', =C(Rm')2, 0-S02-Rm, CO2Rm, CORm, halo and dihalo;
Rm' is selected from among Rm, CO2Rm, CORm, CHO, CO2H and halo;
each Rm is independently selected from a group comprised of C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5-2o aryl, C5-2o heteroaryl, C3_6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl and 5 to 7 membered heteroaryl;
Rx2, Rx2', Rx3, Rx3', Rx5 and Rx5' are independently selected from among H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm2, NO2, Me3SN and halo;
Rx4 and Rx4' are independently selected from among H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRm2, NO2, Me3SN, halo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl, 5 to 7 membered heteroaryl, -CN, -NCO, -ORn, -0C(0)R", -0C(0)NRnir, -OS(0)R", -OS(0)2R", -SRn, -S(0)R", -S(0)2R, -S(0)NRnRn', -S(0)2NRnRn', -0S(0)NRnRn', -0S(0)2NRnRn', -NRnRn', -NRnC(0)R , -NRnC(0)0R , -NRnC(0)NR R ', -NRn S (0 )Rn, -NRnS(0)2R , -NRnS(0)NR 1r, -NRnS(0)2NR Ir, -C(0)R'1, -C(0)0R'1 and -C(0)NRnRn';
Rx and Rx are independently selected from among H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, C1_8 alkyl, C3_8 cycloalkyl, C1_8 alkoxy, C1-8 alkylthio, C3_20 heteroaryl, C5_20 aryl or mono- or di-C1_8 alkylamino;
Y and Y' are independently selected from 0, S and N(H);
Rx6 is independently selected from C3_12 alkylene, C3_12 alkenylene, or C3_12 heteroalkylene;
Rx7 and Rx7' are independently selected from among H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6_10 aryl, 5 to 7 membered heteroaryl, -OW, -0C(0)W, -0C(0)NR1r, -0S(0)W, -0S(0)2W, -SW, -S(0)W, -S(0)2W, -S(0)NR rlr, -S(0)2NR1e, -OS(0)NW W', -0S(0)2NW RI', -NR1r, -NWC(0)Rs, -FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 NWC(0)0Rs, -NWC(0)NRsRs', -NR,S(0)Rs, -NR,S(0)2Rs, -NR,S(0)NRsir, -NR,S(0)2NRsRs, -C(0)W, -C(0)0Rs or -C(0)NRan;
each RI., RI'', Rs and Rs' is independently selected from H, C1-7 alkyl, C2_7 alkenyl, C2_7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl and 5 to 7 membered heteroaryl;
each Rx8 and Rx8' is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 heteroalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, 5 to 7 membered heteroaryl, -S(0)Rm, -S(0)2Rm, -S(0)NRmR", -S(0)2NRmRm', -NRmRm', -NRmC(0)Rm, -NRmC(0)0Rn, -NRmC(0)NR -NRmS(0)Rn, -NRmS(0)2Rn, -NRmS(0)NRnRn', -NRmS(0)2NRnRn', -C(0)Rm, -C(0)0Rm and -C(0)NRmR";
Za is selected from among ORx12a, RN xl2aRX12a, or SRx12a;
Zb is selected from among ORx13a, RN xuaRxi3a, or SRx13a;
Za' is selected from among ORx12a, RN xl2aRX12a, or SRx12a;
Zb' is selected from among ORx13a', RN xua'Rxna', or SRx13a';
each RX12a, XR 12a', RX13a' and R' is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-10 aryl, 5 to 7 membered heteroaryl, -C(0)Rx151, -C(0)0Rx151 and -C(0)NRx15a 1RX 5, and;
each Rx15a and R815a' is independently selected from C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5-20 aryl, C5_20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, and 5 to 7 membered heteroaryl, and:
The Rx13a and Rx14a optionally join the atoms to which they are attached to form 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, or 3 to 7 membered heteroaryl, and the 013' and Rxma' optionally join theatoms to which they are attached to form 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, or 3 to 7 membered heteroaryl, and;
each of the Rn, Re', R , R ', RP and RP' is independently selected from among H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, and to 7 membered heteroaryl.
Further, the Rm is independently selected from a group comprised of C1_12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C5_20 aryl, C5-20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl and 5 to 7 membered heteroaryl, and;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 the Rm is additionally substituted with of C1-12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5_20 aryl, C5_20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl or 5 to 7 membered heteroaryl.
Furtherõ Rx4 and V' are independently selected from among H, Rm, OH, ORm, SH, SRm, NH2, NHRm, NRmRm', NO2, Me3Sn, halo, C1_6 alkyl C1-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl, 5 to 7 membered heteroaryl, -CN, -NCO, -ORn, -0C(0)R, -0C(0)NRnRn', -OS(0)R, -OS(0)2R, -SR, -S(0)R, -S(0)2R, -S(0)NRnRn', -S(0)2NRnRn', -0S(0)NRnRn', -0S(0)2NRnRm, -NRnRn', -NRnC(0)R , -NRnC(0)0R , -NRnC(0)NR R ', -NRnS(0)R , -NRnS(0)2R , -NRnS(0)NR R"',-NRnS(0)2NR R ', -C(0)R, -C(0)0R'1 and -C(0)NRnRn', and;
The Rx4 or Rx4' is C1_6 alkyl, C1-6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl or 5 to 7 membered heteroaryl, and additionally is substituted with at least one C1_6 alkyl, C1_6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, 5 to 7 membered heteroaryl, -OR, -0C(0)RP, -0C(0)NRPRP', -0S(0)RP, -0S(0)2RP, -SR, -S(0)RP, -S(0)2RP, -S(0)NRPRP', -S(0)2NRPRP', -0S(0)NRPRP', -0S(0)2NRPRP', -NRPRP', -NRPC(0)Rq, -NRPC(0)0Rq, -NRPC(0)NRqRq', -NRPS(0)Rq, -NRPS(0)2Rq, -NRPS(0)NRqRq', -NRPS(0)2NRqRq', -C(0)RP, -C(0)OR' or -C(0)NRPRP.
Further, the Rx7 and Rx7' are independently selected from among H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6_10 aryl, 5 to 7 membered heteroaryl, -OW, -0C(0)W, -0C(0)NR an, -0S(0)W, -0S(0)2W, -SW, -S(0)W, -S(0)2W, -S(0)NW R11, -S(0)2NR le, -0S(0)NW R11, -0S(0)2NW R11, -NRall, -NWC(0)Rs, -NWC(0)0Rs, -NWC(0)NRsRs', -NWS(0)Rs, -NWS(0)2Rs, -NWS(0)NRsRs', -NWS(0)2NRsRs, -C(0)W, -C(0)ORS or -C(0)NRIr ;
Rx7 and Rx7' are independently selected from among C1-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6_10 aryl, or 5 to 7 membered heteroaryl, and are additionally substituted by C1_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6_10 aryl, 5 to 7 membered heteroaryl, -OR% -0C(0)Rt, -0C(0)NRtRt', -0S(0)Rt, -0S(0)2Rt, -SRt, -S(0)Rt, -S(0)2Rt, -S(0)NRtRt', -S(0)2NRtRt', -0S(0)NleR t', -0S(0)2NRtRt', -NRtRt', -NRtC(0)Ru, -NRtC(0)01V,-NRtC(0)NRuR"', -FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 NRtS(0)1V, -NRtS(0)2Ru, -NRtS(0)NIVR', -NRtS(0)2NIV R', -C(0)Rt, -C(0)0Rt or -C(0)NRtRt', and;
The Rr, Rr', Rs, Rs', Rt, Rt', RU and R"' are independently selected from among H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, and to 7 membered heteroaryl.
Further, 01 and Rxr are independently selected from R", and;
WI' is selected from among C1-6 alkyl, C2_6 alkenyl, C5-7 aryl and C3_6 heteroaryl.
Further, 02, Rx2', Rx3, Rx3', Rx5 and Rx57 are independently selected from H
or OH.
Further, Rx4 and Rx4' are independently selected from R", and;
WI' is C1_6 alkoxy.
Further, the Rx4 and Rx4' are independently any one selected from a group comprised of methoxy, ethoxy and butoxy. .
Further, the Y and Y7 are 0.
Furtherõ the Rx6 is C3-12 alkylene, C3-12 alkenylene or C3-12 heteroalkylene, with the Rx6 substituted by -NH2, -NHR", -NHC(0)1r, -NHC(0)R", -NHC(0)CH2-[OCH2CH2]-R , or -[CH2CH2O]n-R ;
The Rxx is H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, C1_8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, C3_20 heteroaryl, C5_20 aryl or mono- or di-C1_8 alkyl amino, and;
n is an integer of 1 through 6.
Further, in one aspect of the present invention, the active agent is a pyrrolobenzodiazepine dimer denoted by General Formula XII or General Formula XIII;
[General Formula XII]
31 G WA.'Ab i 1 x. x Rot I Rx3* Rxs I Rxs H
, , -Rxe=Y si N H
, 4. N lb 0 Rx40 4 -- r., Rx2. Rx2 0 7.
1x7. 10 RAT
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 [General Formula XIII]
A
GI W "Ab G
* WI, itt Rx76 Xa' X8 4. 1 x 'I' z Ner Z 11.1_,_"'RX6_y , N Oil R _______________________________________________ N R x 8 Fem -= - ,, v., op RxT= . IN---* Rx2 0 Rx7 The Xa. and Xa' are independently selected from between a bond or C1_6 alkylene;
Zx' and Zx are independently selected from among hydrogen, C1-8 alkyl, halogen, cyano, 0 IVR C () 0 "RI" ' nitro, õ."."," , or -(C112).-0C113;
The respective R"' R9 and R1 are selected from among hydrogen, C1-8 alkyl, C2-6 alkenyl and C1_6 alkoxy, and;
m is an integer of 0 to 12.
The Zx' and Zx are independently any one selected from a group comprised of hydrogen, R Sal 0 0 0 ii y -Rioo 4106 and -(C112).-OCH3;
, The respective R80' R9 and R1 are selected from among hydrogen, C1_3 alkyl and C1-3 alkoxy;
m is an integer of 1 to 6 and;
the active agent is any one selected from a group comprised of:
N...õ0,-...
,h.Tisl OW , HO :.0 7 Ho:c70 iiim 6 H ...e..0 0 ,y =
HO I Z OH
I.J.L.r 400...."......"%õ0 40-11%
N ) 0 In Me FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 0 N .....õ.,,,, 0 ,fis1H :
H0.0 0 * a Tit 0.,t0 HO:07 ifit HO' -. OH 19.LIFI
0,-...,õ,,,,,,..,0 Me0 H
00:M e 0 HOC- oso H 0:C 0 e HO s= " OH . =. 4111 H 0 = ' OH
H 0 ....0,0 IH 0 0 OM e M e0 WI t:NS
O Or H H
0 N '-''NOMe 0 N..{.,.õ=-=,04NH2 H 0:C 0 vfl HO:C7 iiit 3 H 0 '. H .. OH 411 e 0 H 0 .' H '' OH 111111P0 , t_LZ.N iso ID ....."4""'N...,== 40.--5 N OM e Me )4 0 0 ,õ.^.. ow 0 H
HO:C 0 HOIC,4&.)0 . H :1114 HOILX:H 411 HO 'OH ktt0+"',-, 4--Am )4sf."."0--ki Hi I $ 14 0,4,0 0 = 0 HO 1 Y al FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H H
0 N ,.,,,,,,..ome 0 HO:C 7 . HOC 7.
0 ,0 H0 r 1 OH
* 0 H
OMe H H
0 N "0 Me 0 H 0:C 4V aiii HO:CV,,0 0 HO .. .. OH W HO' -OH
01 0,õ 0 H 0 i 1 OH
N -,Nb,,, H
W 0 Me hie0 H H .
0 N ,....õ-,..ome 0 N .-VO4-=,..õõ, N3 H 0:C 0 44f) .. * HOC 46,1Cf,,,,,r,P oir HOc,r, ". OH HO 's .'. OH
0 =,.."..,"N/1:) *
N 0 Me Nie0 N o=N =
0 N õ,..,õ",,, opvie 0 N ,,,..)---,/^==
HOC ,,1(.10)0P HOC 0 HO ' '' OH I. HO ' .. 0 OH
HO I I OH
* *
0 Me /4.1e0 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H H
0 N ''=-"-'0Me 0 HO:Cy0 yp Air HOC q 0 2 HO oy. OH 11111 HO OH
OH 0o OH 0...,.0 0 Me WO
H H =
O '`.,..*% OM e 0 N ,.... N3 HO . K 0:C 4,cr0 le s. ..
HO r 1 ,y. OH
LL,Z-N -N 00 0,...õ,,...,...õ,.."0 N
OM e M e0 N
0 =
H H =
0 N ."*.' OM e 0 H 0:C 0 HOC sci3O
HO y ... .' OH 41111) H
s 0 ,,0 HOOH.
.õ, HO Ie, OH 00 I OH
N
N
OM e M N e 0 11 I H
H H .
0 N ,_ ....., HO OH 1.1 H".044X1OH 111411 H 0 0 OH 0 ,,, 0 HO I I OH
,--=tI las 0 , ....
N 0 Me Me0 1 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H H - .
0 N õ,,NOM e 0 N..........."-No4NH:
HO H 02C *
'A'37 0 H . H 0 0 H
H 0 0 h 0 0 HO I I OH
0,,.,..õ,,,õ.._/0 N Ohl e M e0 0 Tyiti 0 t:,'"AN 'N(A1N H H
N
H 0 N ....,0 4... Hz 0., HO
00,,,,, 0 ,,,,. 0 H 0 1 i CH
0,,,,,,,,õõ,õ,..,,,,..,0 * N......1 , N OM.
H H
0 N ,_ ,o--.,, 0 N -.........,/N.0 +N H2 ' HO 2C y0 yP 0 HO 2C
110 ..0 H HO qc. H *
OH O,.0 OH 0 0 N N
H , iial 0 .õ...,.... 0 .
IA e M eo h4e0 0 M e H H H 0 , 0 N _ .0,-.
OM e 0 N
HO2C,7 H 02C 7) H 0 = 011 III H 0 - OH
OH 0 ,0 H 0 ,.õ 0 NI OH
IL:j.z.,:" NI I*1 0,,..,...,õ.0 401 ...... .., 41'r OM e M e0 N
0 or FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Hill H H H t=
0 N ,,...,0 me 0 N..õ..õ,,N,.,,N
HO.0 0 0 HOIC,*r:::13 * 0 O /
H07jc)70H * HO ' ''CoH
OH 0,,,.0 OH 0,,,, 0 N
H. 110c 110 LZtii 4: OM. r H , P
H H H ; 0 13 N'se''OMe 0 N
HO:CT:13,0 igki HO:C0 0 O /
0 ,0 H 0 ... 0 gli N 0 ..,..,...-õ,....õ."..õ 0 F.14.-44, Wi We Me 1" / let-1 H H .
O N --... OW 0 HO:p 470 la HOCI47 HO '. "..OH s'41111 HO . ,. oillt CH
HO I I CH
N tiot 0,,y,.."0 *
NH
N., ONie L Me) O r0 0 H H .
O N ."=.'" 0 IA e 0 N'%==="*.s%0M e HO 2C y.:õ.ip an HO 2C1A,(144) õI
HO.'0 H "lij HO . ...0 H
NH
..k N 0.1 IA e i M e0 O r'''.0 0 0 'O '%.s.%=)`).NH 2 Date Recue/Date Received 2021-08-09 0.KH:
0 , 0 me0---4 --HOC r" 0 yAOH 10 ,.0011 1104k:
H070.1 4 CO
lir v;
H = ,..,00 S 0 = CNI
Ali j-1 0,;0 011e VP
Heo 0 , ,,,ome 0, H 0:C 0 _,41 H 02C 7 air Ho"0õ
H
Tiro . 0 HO 4. .1:IH illij 0 *,.. 1 ('o III1 0 i OP) y.o oti õdo:
OM e 0 N....ome 0 v 3 H 0:C 0 Al HO:C 0 id*
H 0 ' "OH IP
H
4V) yo Ho. ..coity H 01,0 r"0 NN NH 0 ...pOM e IA e0 0 .õ,,,,,,.......0"....d. 0 iii ..... 0 O,:#i N4 H , and;
' OM e 0 HOC idii H 02C 0 idit,= 3 HOOH 1.*1 HO %OH !Illi 0 y0 H 0,1õ =
1 on N
N lir OM e IA e0 N
'= 0 Fl IBOSTON5259862.1 Date Recue/Date Received 2021-08-09 , N 7_1:N0"v Nr"."0"400.....0"XrNA N N
KikCilio 111* Hosccro 0 H 011;) OHUI
HO OH
In the present specification, "conjugates" refers to cell binding agents that are covalently linked to one or more molecules of a cytotoxic compound. Here, "cell binding agent" is a molecule having affinity for a biological target, for example, a ligand, protein, antibody, specifically a monoclonal antibody, protein or antibody fragment, and the binding agent serves to direct the biologically active compound to the biological target. In one aspect of the present invention, the conjugate may be designed to target tumor cells through cell surface antigens.
The antigen may be a cell surface antigen that is overexpressed or expressed in an abnormal cell type. Specifically, the target antigen may be expressed only on proliferative cells (e.g., tumor cells). Target antigens may be selected based on different expression, usually between proliferative and normal tissues. In the present invention, a ligand is bonded to a linker.
In the present specification, "antibody" refers to an immunoglobulin molecule which, through at least 1 antigen recognizing site located in the variable region of the immunoglobulin molecule, can bind with specificity to a target, for example a carbohydrate, polynucleotide, lipid or polypeptide, etc. The term "antibody" as used in the present specification encompasses not only complete monoclonal or polyclonal antibody, but also a given antigen-binding part (for example, "antigen-binding fragment") of a complete antibody having the capacity to bind with specificity to a certain antigen) or a single chain thereof, a fused protein comprising antibody, or any other modified arrangement of immunoglobulin molecule comprising an antigen recognizing site, non-limiting examples of which are: Fab; Fab'; F(ab')2Fd fragment; Fv fragment;
single domain antibody (dAb) fragment; isolated complementarity determining region (CDR);
single chain (scFv) and single domain antibody (e.g. shark and camel antibody), a maxibody, a minibody, an intrabody, a diabody, a triabody, a tetrabody, a v-NAR, or a bis-scFv (See e.g. the literature [Hollinger and Hudson, 2005, Nature Biotechnology 23(9): 1126-1136]".
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Antibodies include any category of antibody, for example IgG, IgA or IgM (or sub-categories thereof), and the antibody does not need to be of a specific type.
Depending on the amino acid sequence of the constant domain of the heavy chain of the antibody, an immunoglobulin may be assigned to different categories. There exist five major types of immunoglobulin: IgA, IgD, IgE, IgG and IgM, of which a number may be additionally categorized into sub-categories (isotypes), for example, IgGl, IgG2, IgG3, IgG4, IgAl and IgA2. The heavy chain (HC) constant domains corresponding to different categories are respectively referred to as, respectively, alpha, delta, epsilon, gamma and mu. The subunit structures and three-dimensional configuration of different categories of immunoglobulin are widely known to the art. The antibody of the present invention may be prepared using techniques widely known to related arts, for example, recombinant techniques, phage display techniques, synthesis techniques, combinations of the foregoing techniques, or other techniques readily known to related arts.
In the present specification, "isolated antibody" refers to an antibody which does not substantially comprise a different antibody having specificity to another antigen, which may substantially not comprise other cellular material and/or chemical substances.
In the present specification, "biological target" refers to an antigen located on the surface of a tumor, cancer cell or extracellular matrix.
In the present specification, "linker" refers to a compound which covalently bonds a cytotoxic compound to a ligand. In one aspect of the present invention, the linker disclosed in PCT/US2016/063564 and PCT/US2016/063595 may be used as the linker.
In the present specification, "therapeutic agent" refers to an agent that exerts cytotoxicity, cell proliferation inhibition and / or immunomodulatory effects on cancer cells or activated immune cells. Examples of therapeutic agents include cytotoxic agents, chemotherapeutic agents, cell proliferation inhibitors, and immunomodulators.
In the present specification, "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer.
In the present specification, "subject" is intended to include human and non-human animals, particularly mammals. Examples of subjects include human subjects, e.g., disorders, such as those described herein, e.g., human patients with cancer or normal subjects. "Non-human animal" is used in all vertebrate animals, such as non-mammals (e.g., Chickens, amphibians, reptiles) and mammals such as non-human primates, livestock and / or animals (e.g., sheep, dogs, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 cats, cows, pigs, etc.) and rodents (e.g., mice, rats, hamsters, guinea pigs, etc.). In certain embodiments, the subject is a human patient. In certain examples, the subject is a human patient.
In the present specification, "treating" or "treating" refers to both therapeutic treatment and prophylactic or preventative measures. A subject in need of treatment includes a subject already having a disorder, and a subject susceptible to a disorder or a subject to be prevented from disorder.
Thus, when used in reference to a subject in need of the disease or treatment, the term encompasses an inhibition or slowing of disease progression, remission of disease, prevention of symptoms, reduction of disease and / or symptom severity, but is not limited to these.
In the present specification, "administer" or "administering" refers to providing and / or contacting and / or delivering a compound or compounds by any suitable route to achieve the desired effect. Administration may be by oral, sublingual, parenteral (e.g.
intravenous, subcutaneous, intradermal, intramuscular, intraarticular, intraarterial, intrathecal, intrasternal, intraspinal, Rectal, nasal, buccal, rectal, vaginal, nasal, ophthalmic, inhaled and implanted.
In the present specification, "unsubstituted or substituted" refers to a parent group which may be unsubstituted or substituted, "substituted" refers to a parent group having at least 1 substituent group, and substituent group refers to a chemical part which is covalently bonded to a parent group or fused to a parent group.
In the present specification, "halo" refers to fluorine, chlorine, bromine or iodine, etc.
In the present specification, "alkyl" is a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an aliphatic or alicyclic, saturated or unsaturated (unsaturated, fully unsaturated) hydrocarbon compound. Examples of saturated alkyls include methyl, ethyl, Butyl, n-pentyl (amyl), n-hexyl, n-heptyl and the like, saturated cyclic alkyl groups such as methyl, ethyl, Isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and neopentyl, etc.
In the present invention, "alkoxy" refers to -OR where R is an alkyl group, and examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy, etc.
In the present invention, "aryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound having a ring atom.
In the present invention, "alkenyl" is an alkyl having at least one carbon-carbon double bond. Examples of unsaturated alkenyl groups are ethenyl (vinyl, -CH=CH2), 1-propenyl (-CH=CH-CH3), 2-propenyl, isopropenyl, butenyl, pentenyl and hexenyl, etc.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 In the present invention, "alkynyl" is an alkyl group having at least one carbon-carbon triple bond, and examples of unsaturated alkynyl group include ethynyl and 2-propynyl, etc.
In the present invention, "carboxy" refers to -C(=0)0H.
In the present invention, "formyl" refers to -C(=0)H.
In the present invention, "aryl" refers to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound. For example, "C5_7 aryl" is a moiety having from 5 to 7 ring atoms, which is a monovalent moiety obtained by removing a hydrogen atom from the aromatic ring atoms of an aromatic compound, and "C5_10 aryl" is a moiety having from 5 to 10 ring atoms, which is a monovalent moiety obtained by removing a hydrogen atom from the aromatic ring atoms of an aromatic compound. Here, the prefixes (C57, C5-10, etc.) refer to the number of ring atoms or a range for the number of ring atoms, regardless of whether they are carbon atoms or hetero atoms. For example, "C5_6 aryl" relates to an aryl group having 5 or 6 ring atoms. Here, the ring atoms may be all carbon atoms as in a "carboaryl group". Examples of a carboaryl group include, but are not limited to, those derived from benzene, naphthalene, azulene, anthracene, phenanthrene, naphthacene and pyrene. Examples of aryl groups that include a fused ring wherein at least one is an aromatic ring include, but are not limited to, groups derived from indane, indene, isoindene, tetralin, acenaphthene, fluorene, phenalene, acesphenanthrene and aseantrene. Alternatively, the ring atoms may contain one or more heteroatoms as in a "heteroaryl group".
In the present invention, " heteroaryl "refers to aryl containing one or more heteroatoms, such as pyridine, pyrimidine, benzothiophene, furyl, dioxolanyl, pyrrolyl, oxazolyl, pyridyl, pyridazinyl, More specifically benzofuran, isobenzofuran, indole, isoindole, indolizine, indolin, isoindoline, purine (adenine or guanine), benzimidazole, indazole, benzoxazole, benzisoxazole, benzodioxole, benzofuran, benzotriazole, benzothiofuran, benzothiazole, C9 having two fused rings derived from benzothiazole, chromene, iso-chromene, chroman, is-chroman, benzodioxane, quinoline, isoquinoline, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, Cio having two fused rings derived from pteridin, CH having two fused rings derived from benzodiazepine, carbazole, dibenzofuran, dibenzothiophene, carboline, pyrimidine, C13 having three fused rings derived from pyridoindole, acridine, xanthene, thioxanthene, phenoxathiine, phenazine, phenoxazine, phenothiazine, HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 thianthrene, phenanthridine, phenanthroline, and C14 having three fused rings derived from phenazine.
In the present invention, "cycloalkyl" refers to an alkyl group which is a cycloalkyl group, and relates to a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a cyclic hydrocarbon compound. Examples of cycloalkyl groups include, but are not limited to, those derived from:
Saturated single ring hydrocarbon compounds: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane and methylcyclohexane;
Unsaturated single ring hydrocarbon compounds: cyclopropene, cyclobutene, cyclopentene, cyclohexene, methylcyclopropene, dimethylcyclopropene, methylcyclobutene, dimethylcyclobutene, methylcyclopentene, dimethylcyclopentene and methylcyclohexene;
and saturated heterocyclic hydrocarbon compounds: norcaran, norphenen, and norbornene.
In the present invention, "heterocyclyl" refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound.
In the present invention, the prefixes (e.g., C1_12 , C 3 _8, etc.) refer to the number of ring atoms or a range for the number of ring atoms, regardless of whether they are carbon atoms or hetero atoms. For example, the term "C3-6 heterocyclyl" used in the present specification relates to a heterocyclyl group having 3 to 6 ring atoms.
Examples of single ring heterocyclyl groups include, but are not limited to, those derived from:
Ni: aziridine, azetidine, pyrrolidine, pyrroline, 2H- or 3H-pyrrole, piperidine, dihydropyridine, tetrahydropyridine, azepine;
N2: imidazolidine, pyrazolidine, imidazoline, pyrazoline, piperazine;
01: oxirane, oxetane, oxolane, oxol, oxane, dihydropyran, pyran, oxepine;
02: dioxolane, dioxane and dioxepane;
03: trioxane;
N101: tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole, morpholine, tetrahydrooxazine, dihydrooxazine, Si: thiiran, thiethan, thiolan, thian, tiepan;
Ni Si: thiazoline, thiazolidine, thiomorpholine;
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 N201: oxadiazine;
01Si: oxathiol, oxathian, and;
N101 Si : oxathiazine.
In the present invention, "prodrug" refers to compounds which, under in vivo physiological conditions (e.g. enzymatic oxidation, reduction and/or hydrolysis), may, by action of enzyme or gastric acid, be converted directly or indirectly into a pyrrolobenzodiazepine drug.
In the present invention, "pharmaceutically acceptable salt" may be an acid addition salt formed by pharmaceutically acceptable free acid, where the free acid is an organic acid or an inorganic acid.
The organic acids include, but are not limited to, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methane sulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutamic acid and aspartic acid. Also, the inorganic acids include, but are not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
For example, if the compound has a functional group which is an anion or may be an inion (e.g. -COOH may be -000-), a suitable cation may be used for forming a salt.
Examples of suitable inorganic cations include, but are not limited to, Na + and K ' alkaline earth cations such as Ca2+ and Mg2 ' and other cations such as A13 ' Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 ) and substituted ammonium ions (e.g. NH3R+, NH2R2+, NHR3+, NR4+).
Some examples of suitable substituted ammonium ions are derived from the following:
ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine , phenylbenzylamine, choline, meglumine and tromethamine, as well as amino acids such as lysine and arginine. An example of a typical quaternary ammonium ion is N(CH3)4 .
If the compound has a functional group which may be a cation or a cation (e.g., -NH2 may be -NH3), a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfuric acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 Examples of suitable organic anions include, but are not limited to, those derived from organic acids such as: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, But are not limited to, disulfonic acid, ethanesulfonic acid, fumaric acid, glutaronic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, But are not limited to, malic acid, methanesulfonic acid, mucilous acid, oleic acid, oxalic acid, palmitic acid, pamic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid and tartaric acid, etc. Examples of suitable multimeric organic anions include, but are not limited to, those derived from the following multimeric acids: tannic acid, carboxymethylcellulose, etc.
In the present invention, "solvate" refers to a molecular complex between a compound according to the present invention and solvent molecules, examples of which include but are not limited to water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, ethanolamine or the compound according to the present invention bonded to a mixed solvent thereof.
It may be convenient or desirable to prepare, purify and/or handle solvates corresponding to active compounds. In the present specification, the term "solvate" is used in its conventional sense to refer to solutes (e.g. active compounds and salts of active compounds) and complexes of solvents. When the solvent is water, the solvate may conveniently be referred to as a hydrate, such as monohydrate, dihydrate or trihydrate, etc.
The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carrier include large macromolecules that are slowly metabolized, such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, lipid aggregates, and the like.
Such pharmaceutically acceptable carriers may be appropriately selected and used by a person skilled in the art.
The composition comprising a pharmaceutically acceptable carrier may be of various oral or parenteral formulations. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrating agent, or a surfactant is usually used.
Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain at least one excipient such as starch, calcium carbonate, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 sucrose or lactose, gelatin, . In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used.
Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are commonly used simple diluents.
Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like.
The pharmaceutical composition may be in the form of tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze- It can have one formulation.
For intravenous, intradermal or hypodermic injection, the active ingredient may be in the form of an acceptable aqueous solution for parenteral administration, be pyrogen-free, and have the appropriate pH, isotonicity and stability. A person skilled in the art may prepare an appropriate solution using an isotonic vehicle such as sodium chloride solution, Ringer's solution or Ringer's lactate solution, and preservatives, stabilizers, buffers, anti-oxidants and other additives may be included as necessary. Solid forms suitable for injection may also be prepared as emulsions or in the form of polypeptide encapsulated in liposome.
As used herein, the phrase "effective amount" or "therapeutically effective amount" refers to the amount required to achieve the desired therapeutic result (for dose and duration and means of administration). An effective amount is at least the minimum amount of active agent required to confer a therapeutic benefit to a subject, and is less than the toxic amount. For example, the amount administered may be in a range of approximately 10Ong to approximately 100mg/kg per patient, more typically approximately lug/kg to approximately 10mg/kg. In a case where an active compound is a salt, ester, amide or prodrug, the dose is calculated based on the parent compound, and accordingly the actual weight used also increases proportionally. The pyrrolobenzodiazepine compound according to the present invention may be formulated to comprise 0.1mg to 3000mg, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 lmg to 2000mg, or 10mg to 1000mg of active ingredient per unit dosage form, but is not limited thereto. The active ingredient may be administered to give an active compound peak plasma concentration of approximately 0.05 pM to 100[M, 1 [tM to 50uM, or 5pM to 30pM. For example, optionally it may be administered by intravenous injection of a solution of 0.1 w/v% to 5 w/v%
active ingredient in saline solution.
In a pharmaceutical composition, the concentration of the active compound is determined by the absorption, inactivation and excretion rates of the drug, and other factors known not persons skilled in the art. The dose administered may vary depending on the severity of symptoms or the disease. Further, the dose and administration therapy for a specific patient may be adjusted according to the professional judgment of an administration supervisor, giving general consideration to the degree of the patient's symptoms and illness, need for the drug, age, and reactivity to the drug, etc. The range of concentrations stated in the present invention are only intended as an example, and the manner of carrying out the claimed composition is not limited hereto. Furtherõ the active ingredient may be administered once, or smaller doses may be administered across multiple administrations.
The prodrug compound, or prodrug-linker compound, or prodrug-linker-ligand conjugate compound may be used to treat proliferative diseases, in particular cancer.
The term "proliferative disease" refers to excessive, abnormal, undesired or unregulated cell growth either in vitro or in vivo, such as hyperplasia or cytogenesis. Non-limiting examples of proliferative disease include neoplasm, tumor, cancer, leukemia, psoriasis, bone disease, fibrous dysplasia and pharyngeal arteriosclerosis. Non-limiting examples of cancer are lung cancer, small cell lung carcinoma, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma and melanoma.
Benefits of the invention The antibody-drug conjugate according to the present invention, by comprising an anti-DLK1 antibody which binds with specificity to DLK1-expressing cells and is internalized into a cell exhibits the benefits of being able to deliver a drug effectively, selectively and with specificity, and allowing for a drug to bind stably to an antibody to exhibit the intended cytotoxicity while maintaining in vivo stability. In particular, by grafting technology for a linker including a self-immolative group, the present invention provides a drug-linker-ligand system which allows a drug HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 and/or toxin to stably reach a target cell and effectively exhibit a drug effect while having substantially reduced toxicity.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a diagram confirming the efficacy of the ADC according to the present invention in a patient-derived tumor animal model.
BEST MODE(S) FOR CARRYING OUT THE INVENTION
In the following, the present invention is described in further detail through embodiments and experimental examples.
The following embodiments and experimental examples are intended to aid in understanding the present invention, and are not intended to limit the scope of the present invention thereto.
<Example 1> Preparation of compounds 1, 2, 3 and 4 Ho C; 01,1 0 OA kik IAE
Ile Ih.."
z ;,31-1:, 0 0- ri ##%%#4#' 0.".'&P.Ct 'Ng. .T1FA
it #h.
I
r op 0 HO,L. A, 0: Olit 0 M PAE
HQ : 0, 1511 r 4 : A
:1LN MN +00",. 4 N 1-11 :2 HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 "QA 4 OA MMAE
0 N."-====,-"Ho % .
H H
.,",,....,k0 ,....,,X, 0 ,,,,..%)."...,,,ON,,,,-,..Ø14 H2 ' HO2C 00 4 H 0 .TFA
fivy e t.coH 4 01, NIMAE
4,410 H 0 õ eatt 0 * 0 AM MAE
H 0 i OH H H H
HO2Cy H ' H
0 N 0..."0,,,õ,,z-N +..".0+ NH2 H 0. 0 2C 0 0 .TPA
HO '' .. OH SI ".---M MAE
.y.,õ
Compounds 1, 2, 3 and 4 were prepared using the method stated in International Patent Publication W02017-089895.
In compounds 1, 2, 3 and 4, the structure of MMAE is as follows.
MIME
HO Pi ri I ,....4,,..: I .... 0 .....0 0 <Example 2> Preparation of compounds 5, 6, 7 and 8 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 0 it-,=*"OM e 0 H Ni0 .õ,..,... ..+NH2 .TFA
Fro 2Cy0 yD An HO2C7 iiii 6 HO *.Y.OH IIIF HO '. .. OH 'Pli OH = ,,,.0 H 0 ..... =
0,0 ilo Na OM e M e0 = 0 NIN
0 , 11. me 044+12 0, HD2C7 HO2C7 A . WA
HO " 'OH I* HD
H
HO a Y0 0 kr a OH
N N
ON, IA 00 = 0 0 1L ,OM, 0 --"*.- OM e HO2CV=00 41 14027 a HO ' ." OH HO ..0 H 41114IP
H 0 .....0 H 0 ..,o HO r 1 OH
0 õ,...õ.........õ..",.."0 N---S H
ome meo ir ,N --'-j=,' ,
7 Compounds 5, 6 and 7 were prepared using the method stated in Korean Laid-open Patent No. 10-2018-0110645.
o H o'-' -}'OH NH TFA
,-+- 2 '---f-0---2 0 , N,,,,,,ome LI 0 NN
HO2C73 is 0,1 iiii 0õr. oy.cop 1.
H 04 "'OH 0 ILI" H O.AyAbOH
0 õ,0,0 0..,0 OH
HO r o 41)1 o , 4 OH
N di N , "311'. ome M e0 lir P--,43,444.
6 . O
FHBOSTON5259862.1 Date Regue/Date Received 2021-08-09 Compound 8 was prepared using the method stated in Korean Patent Application No. 10-2019-0000514.
<Example 3> Preparation of ADC
ADC was prepared through the following two steps, and the LCB14-0511 and LCB14-0606 used commonly were prepared using the method stated in Korean Laid-open Patent No. 10-2014-0035393. The structural formulae of LCB14-0511 and LCB14-0606 are as follows:
I P
-o 3 (N1-14 ) _ _13_ 0 -3(N H4.) Step 1: Preparation of prenylated antibody A prenylation reaction mixture of an antibody (18A5) was prepared using the method stated in Korean Patent Application No. 10-2018-0107639 and reacted for 16 hours at 30 C. The reaction mixture was comprised of 2411M antibody (18A5), 200nM FTase (Calbiochem #344145) and a buffer solution (50 mM Tris-HC1 (pH 7.4), 5 mM MgCl2, 10 [tM ZnC12, 0.144 mM
DTT) containing 0.144 mM LCB14-0511 or LCB14-0606. After the reaction was completed, the prenylated antibody was desalted using a G25 Sepharose column (AKTA purifier, GE healthcare) equilibrated with PBS buffer solution.
Step 2: Method of drug-conjugation <Conjugation by oxime bond formation>
The mixture for oxime bond-forming reaction between prenylated antibody and linker-drug was prepared by mixing 100mM Na-acetate buffer solution pH 5.2, 10% DMSO, 2011M antibody and 20011M linker-drug (in house, compounds 1, 2, 3, 4, 5, 7 and 8 from Embodiments 1 and 2), and stirred lightly at 30 C. After reacting for 6 or 24 hours, an FLPC (AKTA
purifier, GE
healthcare) process was carried out to remove the surplus small compounds used. The protein fraction was collected and concentrated.
<Conjugation by click reaction>
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 The mixture for oxime bond-forming reaction between prenylated antibody and linker-drug was 10% DMSO, 20pM antibody and 200RM linker-drug (in house, compound 6 from Embodiment 2), 1mM copper (II) sulfate pentahydrate, 2mM (BimC4A)3 (Sigma-Aldrich 696854), 10mM sodium ascorbate and 10mM aminoguanidine hydrochloride, reacted for 3 hours at 25 C, then treated with 2.0mM EDTA and reacted for 30 minutes. After reacting, an FLPC (AKTA
purifier, GE healthcare) process was carried out to remove the surplus small compounds used. The protein fraction was collected and concentrated.
[Table 2] List of ADCs prepared ADCs Antibody Linker-toxin ADC1 Compound 1 ADC2 Compound 2 ADC3 Compound 3 ADC4 Compound 4 ADCS Compound 5 ADC6 Compound 6 ADC7 Compound 7 ADC8 Compound 8 Experimental Example 1: In vitro cytotoxicity assessment The cancer cell line cell proliferation inhibition activity of the drugs stated in Table 3 below and the ADCs prepared in <Embodiment 3> above was measured. For this purpose, commercially available human pancreatic cancer cell line MIA-PaCa2 (DLK1 negative or normal) and MIA-PaCa-2-DLK1 over-expressing cell line were used. As the drug, MMAF-0Me was used as the ADC, and the ADCs of Table 2 were used. In a 96-well plate, each well was seeded with 4,000 to 5,000 of the respective cancer cell lines for the 72-hour treatment group, 2,000 to 3,000 cells for the 96-hour treatment group, and 800 to 1,000 cells for the 168-hour treatment group. After culturing for 24 hours, they were treated with the drug and ADC at a concentration of 0.0015 to 10.0 nM (serially diluted threefold). 72, 96 and 168 hours later, respectively, the number of live cells was measured using SRB (Sulforhodamine B)dye.
[Table 3]
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 IC5D (tifv0 Test samples MA-PaCaZ-DLK1 negative MIA-PaCaZ-DLKI positive 7 thr 96h 166hr 7 Mr 96h _ 168h1 (AMA F- 01sile 0,41 01 11,1a 030 0.13 0.05 A DC1 >10 1.4,T >10 0$4 N,T 0,09 ADCZ >10 >10 >1 l 0,57 025 0,09 A .C3 > 1 0 2- 1 0 >10 0.19 , 0.11 0.03 A DC4 NIT > I 0 1\1,T N ,T 0,115 11,T
A DC5 > I 0 >1D Thre, 0,01 0,003 ADC 5 N.T N.T >111 N T N.T 11,Z1 7 A DC 7 >10 1,1,T >10 1 0.00B j N.T
0,004 A DC8 N ,T > I 0 NIT N,T 0,0DB NIT
*NT: not tested.
Most of the antibody-drug complexes were confirmed to have substantially improved cytotoxicity in pancreatic cancer cell lines with DLK1 over-expression than in pancreatic cancer cell lines without DLK1 expression. In pancreatic cancer cell lines over-expressing DLK1, pyrrolobenzodiazepine based antibody-drug complexes (ADCs 5, 7 and 8) were confirmed to exhibit stronger cytotoxicity than auristatin-based antibody-drug complexes (ADCs 1, 2, 3 and 4).
Furtherõ pyrrolobenzodiazepine based antibody-drug complexes was confirmed to exhibit stronger cytotoxicity compared to auristatin-based antibody-drug complexes with longer reaction time.
Experimental Example 2: In vivo efficacy assessment In a patient-derived tumor animal model, the efficacy of the ADCs prepared in <Embodiment 3> was assessed. Specifically, the patient-derived small cell lung cancer mouse model (PDX model) was provided by Champions Oncology. The control group of the PDX model was intravenously administered PBS in the tail, while the experimental groups were administered ADC4 at 6mpk/Q4D*4, 6 mpk/QW*4 and 9 mpk/QW*4, followed by measurement of tumor size.
In the results, as shown in Fig. 1, tumors disappeared from all 8 individual experimental animals in each of the 6 mpk/Q4D*4 group and the 9 mpk/QW*4 group (CR, complete remission), while tumors disappeared in 6 of the 8 experimental animals in the 6 mpk/QW*4 group.
INDUSTRIAL APPLICABILITY
The new antibody-drug conjugates (ADCs) targeting DLK1 and pharmaceutical compositions comprising the same may be used in production of drugs for treatment and/or prevention of diseases proliferative and/or angiogenetic diseases, for example, cancer.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09
o H o'-' -}'OH NH TFA
,-+- 2 '---f-0---2 0 , N,,,,,,ome LI 0 NN
HO2C73 is 0,1 iiii 0õr. oy.cop 1.
H 04 "'OH 0 ILI" H O.AyAbOH
0 õ,0,0 0..,0 OH
HO r o 41)1 o , 4 OH
N di N , "311'. ome M e0 lir P--,43,444.
6 . O
FHBOSTON5259862.1 Date Regue/Date Received 2021-08-09 Compound 8 was prepared using the method stated in Korean Patent Application No. 10-2019-0000514.
<Example 3> Preparation of ADC
ADC was prepared through the following two steps, and the LCB14-0511 and LCB14-0606 used commonly were prepared using the method stated in Korean Laid-open Patent No. 10-2014-0035393. The structural formulae of LCB14-0511 and LCB14-0606 are as follows:
I P
-o 3 (N1-14 ) _ _13_ 0 -3(N H4.) Step 1: Preparation of prenylated antibody A prenylation reaction mixture of an antibody (18A5) was prepared using the method stated in Korean Patent Application No. 10-2018-0107639 and reacted for 16 hours at 30 C. The reaction mixture was comprised of 2411M antibody (18A5), 200nM FTase (Calbiochem #344145) and a buffer solution (50 mM Tris-HC1 (pH 7.4), 5 mM MgCl2, 10 [tM ZnC12, 0.144 mM
DTT) containing 0.144 mM LCB14-0511 or LCB14-0606. After the reaction was completed, the prenylated antibody was desalted using a G25 Sepharose column (AKTA purifier, GE healthcare) equilibrated with PBS buffer solution.
Step 2: Method of drug-conjugation <Conjugation by oxime bond formation>
The mixture for oxime bond-forming reaction between prenylated antibody and linker-drug was prepared by mixing 100mM Na-acetate buffer solution pH 5.2, 10% DMSO, 2011M antibody and 20011M linker-drug (in house, compounds 1, 2, 3, 4, 5, 7 and 8 from Embodiments 1 and 2), and stirred lightly at 30 C. After reacting for 6 or 24 hours, an FLPC (AKTA
purifier, GE
healthcare) process was carried out to remove the surplus small compounds used. The protein fraction was collected and concentrated.
<Conjugation by click reaction>
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 The mixture for oxime bond-forming reaction between prenylated antibody and linker-drug was 10% DMSO, 20pM antibody and 200RM linker-drug (in house, compound 6 from Embodiment 2), 1mM copper (II) sulfate pentahydrate, 2mM (BimC4A)3 (Sigma-Aldrich 696854), 10mM sodium ascorbate and 10mM aminoguanidine hydrochloride, reacted for 3 hours at 25 C, then treated with 2.0mM EDTA and reacted for 30 minutes. After reacting, an FLPC (AKTA
purifier, GE healthcare) process was carried out to remove the surplus small compounds used. The protein fraction was collected and concentrated.
[Table 2] List of ADCs prepared ADCs Antibody Linker-toxin ADC1 Compound 1 ADC2 Compound 2 ADC3 Compound 3 ADC4 Compound 4 ADCS Compound 5 ADC6 Compound 6 ADC7 Compound 7 ADC8 Compound 8 Experimental Example 1: In vitro cytotoxicity assessment The cancer cell line cell proliferation inhibition activity of the drugs stated in Table 3 below and the ADCs prepared in <Embodiment 3> above was measured. For this purpose, commercially available human pancreatic cancer cell line MIA-PaCa2 (DLK1 negative or normal) and MIA-PaCa-2-DLK1 over-expressing cell line were used. As the drug, MMAF-0Me was used as the ADC, and the ADCs of Table 2 were used. In a 96-well plate, each well was seeded with 4,000 to 5,000 of the respective cancer cell lines for the 72-hour treatment group, 2,000 to 3,000 cells for the 96-hour treatment group, and 800 to 1,000 cells for the 168-hour treatment group. After culturing for 24 hours, they were treated with the drug and ADC at a concentration of 0.0015 to 10.0 nM (serially diluted threefold). 72, 96 and 168 hours later, respectively, the number of live cells was measured using SRB (Sulforhodamine B)dye.
[Table 3]
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 IC5D (tifv0 Test samples MA-PaCaZ-DLK1 negative MIA-PaCaZ-DLKI positive 7 thr 96h 166hr 7 Mr 96h _ 168h1 (AMA F- 01sile 0,41 01 11,1a 030 0.13 0.05 A DC1 >10 1.4,T >10 0$4 N,T 0,09 ADCZ >10 >10 >1 l 0,57 025 0,09 A .C3 > 1 0 2- 1 0 >10 0.19 , 0.11 0.03 A DC4 NIT > I 0 1\1,T N ,T 0,115 11,T
A DC5 > I 0 >1D Thre, 0,01 0,003 ADC 5 N.T N.T >111 N T N.T 11,Z1 7 A DC 7 >10 1,1,T >10 1 0.00B j N.T
0,004 A DC8 N ,T > I 0 NIT N,T 0,0DB NIT
*NT: not tested.
Most of the antibody-drug complexes were confirmed to have substantially improved cytotoxicity in pancreatic cancer cell lines with DLK1 over-expression than in pancreatic cancer cell lines without DLK1 expression. In pancreatic cancer cell lines over-expressing DLK1, pyrrolobenzodiazepine based antibody-drug complexes (ADCs 5, 7 and 8) were confirmed to exhibit stronger cytotoxicity than auristatin-based antibody-drug complexes (ADCs 1, 2, 3 and 4).
Furtherõ pyrrolobenzodiazepine based antibody-drug complexes was confirmed to exhibit stronger cytotoxicity compared to auristatin-based antibody-drug complexes with longer reaction time.
Experimental Example 2: In vivo efficacy assessment In a patient-derived tumor animal model, the efficacy of the ADCs prepared in <Embodiment 3> was assessed. Specifically, the patient-derived small cell lung cancer mouse model (PDX model) was provided by Champions Oncology. The control group of the PDX model was intravenously administered PBS in the tail, while the experimental groups were administered ADC4 at 6mpk/Q4D*4, 6 mpk/QW*4 and 9 mpk/QW*4, followed by measurement of tumor size.
In the results, as shown in Fig. 1, tumors disappeared from all 8 individual experimental animals in each of the 6 mpk/Q4D*4 group and the 9 mpk/QW*4 group (CR, complete remission), while tumors disappeared in 6 of the 8 experimental animals in the 6 mpk/QW*4 group.
INDUSTRIAL APPLICABILITY
The new antibody-drug conjugates (ADCs) targeting DLK1 and pharmaceutical compositions comprising the same may be used in production of drugs for treatment and/or prevention of diseases proliferative and/or angiogenetic diseases, for example, cancer.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09
Claims (62)
1. An antibody conjugate of General Formula I, or a pharmaceutically acceptable salt or solvate thereof:
[General Fomiula I] Ab - (X)y where, in the formula:
Ab is an antibody binding specifically to DLK1 (delta-like 1 homolog (Drosophila)) comprising a heavy chain variable region and a light chain variable region, or an antigen-binding fragment thereof; wherein the antibody which binds to DLK1 or antigen-binding fragment of the same comprises:
a heavy chain variable region comprising at least one heavy chain CDR1 selected from the group comprising SEQ ID NO. 2, 16, 30, 44, 58, 72 and 86, at least one heavy chain CDR2 selected from the group comprising SEQ ID NO.
4, 18, 32, 46, 60, 74 and 88, and at least one heavy chain CDR3 selected from the group comprising SEQ ID
NO. 6, 20, 34, 48, 62, 76 and 90; and a light chain variable region comprising at least one light chain CDR1 selected from the group comprising SEQ ID No. 9, 23, 37, 51, 65, 79, 93, 115 and 121, at least one light chain CDR2 selected from the group comprising SEQ ID No.
11, 25, 39, 53, 67, 81 and 95, and at least one light chain CDR3 selected from the group comprising SEQ ID
No. 13, 27, 41, 55, 69, 83, 97, 116 and 125;
X is independently a chemical residue comprising at least one active agent and a linker, wherein the linker links the antibody and the active agent, and y is an integer of 1 through 20.
[General Fomiula I] Ab - (X)y where, in the formula:
Ab is an antibody binding specifically to DLK1 (delta-like 1 homolog (Drosophila)) comprising a heavy chain variable region and a light chain variable region, or an antigen-binding fragment thereof; wherein the antibody which binds to DLK1 or antigen-binding fragment of the same comprises:
a heavy chain variable region comprising at least one heavy chain CDR1 selected from the group comprising SEQ ID NO. 2, 16, 30, 44, 58, 72 and 86, at least one heavy chain CDR2 selected from the group comprising SEQ ID NO.
4, 18, 32, 46, 60, 74 and 88, and at least one heavy chain CDR3 selected from the group comprising SEQ ID
NO. 6, 20, 34, 48, 62, 76 and 90; and a light chain variable region comprising at least one light chain CDR1 selected from the group comprising SEQ ID No. 9, 23, 37, 51, 65, 79, 93, 115 and 121, at least one light chain CDR2 selected from the group comprising SEQ ID No.
11, 25, 39, 53, 67, 81 and 95, and at least one light chain CDR3 selected from the group comprising SEQ ID
No. 13, 27, 41, 55, 69, 83, 97, 116 and 125;
X is independently a chemical residue comprising at least one active agent and a linker, wherein the linker links the antibody and the active agent, and y is an integer of 1 through 20.
2. The antibody which binds with specificity to DLK1 or an antigen-binding fragment thereof according to Claim 1, comprising:
at least one heavy chain FR1 selected from the group comprising SEQ ID No. 1, 15, 29, 43, 57, 71, 85 and 119;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 at least one heavy chain FR2 selected from the group comprising SEQ ID No. 3, 17, 31 , 45, 59, 73 and 87;
at least one heavy chain FR3 selected from the group comprising SEQ ID No. 5, 19, 33, 47, 61, 75 and 89;
at least one heavy chain FR4 selected from the group comprising SEQ ID No. 7, 21, 35, 49, 63, 77 and 91;
at least one light chain FR1 selected from the group comprising SEQ ID No. 8, 22, 36, 50, 64, 78, 92, 117 and 120;
at least one light chain FR2 selected from the group comprising SEQ ID No. 10, 24, 38, 52, 66, 80, 94 and 122;
at least one light chain FR3 selected from the group comprising SEQ ID No. 12, 26, 40, 54, 68, 82, 96, 118 and 123; and at least one light chain FR4 selected from the group comprising SEQ ID No. 14, 28, 42, 56, 70, 84, 98 and 125.
at least one heavy chain FR1 selected from the group comprising SEQ ID No. 1, 15, 29, 43, 57, 71, 85 and 119;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 at least one heavy chain FR2 selected from the group comprising SEQ ID No. 3, 17, 31 , 45, 59, 73 and 87;
at least one heavy chain FR3 selected from the group comprising SEQ ID No. 5, 19, 33, 47, 61, 75 and 89;
at least one heavy chain FR4 selected from the group comprising SEQ ID No. 7, 21, 35, 49, 63, 77 and 91;
at least one light chain FR1 selected from the group comprising SEQ ID No. 8, 22, 36, 50, 64, 78, 92, 117 and 120;
at least one light chain FR2 selected from the group comprising SEQ ID No. 10, 24, 38, 52, 66, 80, 94 and 122;
at least one light chain FR3 selected from the group comprising SEQ ID No. 12, 26, 40, 54, 68, 82, 96, 118 and 123; and at least one light chain FR4 selected from the group comprising SEQ ID No. 14, 28, 42, 56, 70, 84, 98 and 125.
3. The antibody which binds with specificity to DLK1 or an antigen-binding fragment thereof according to Claim 1, characterized in that it comprises a heavy chain variable region comprising a sequence that has at least 90% sequence homology with a sequence selected from the group comprising SEQ ID No. 99, 101, 103, 105, 107, 109, 111 and 127.
4. The antibody which binds with specificity to DLK1 or an antigen-binding fragment thereof according to Claim 1, characterized in that it comprises a light chain variable region comprising a sequence that has at least 90% sequence homology with a sequence selected from the group comprising SEQ ID No. 100, 102, 104, 106, 108, 110, 112, 126 and 128.
5. The antibody which binds with specificity to DLK1 according to Claim 1 or an antigen-binding fragment thereof, characterized in that the linker has the structure of General Formula II:
[General Formula II]
(Z), Ft1 Ab, W
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Where in the formula, the formula:
R4-(3 0 4.
)1/4*
R
G is a glucuronic acid moiety or R3 is a hydrogen or carboxyl protective group, and the respective R4 are independently hydrogen or hydroxyl protective groups;
Ab is an antibody binding with specificity to DLK1 or an antigen-binding fragment thereof:
B is an active agent;
Ri and R2 are, respectively and independently, hydrogen, (C 1-C8) alkyl or (C3-C8) cycloalkyl;
W is -C(0)-, -C(0)NR'-, -C(0)0-, -SO2NR'-, -P(0)R"NR'-, -SONR'- or -P02NR'-;
the C, S or P
directly bonds to a phenyl ring; the NR' bonds to L; and R' and R" are respectively and independently, hydrogen, (C 1 -C8) alkyl, (C3-C8) cycloalkyl, (C1 -C8) alkoxy, (C1 -C8) alkylthio, mono- or di-(C1-C8) alkylamino, (C3-C20) heteroaryl, or (C6-C20) aryl;
each Z is, independently, (Ci-C8) alkyl, halogen, cyano or nitro;
n is an integer of 1 through 3;
L is any one of the following:
A) Is a Ci-050 alkylene or a 1 to 50 atom heteroalkylene, and satisfies at least one of the following:
(i) L comprises at least one unsaturated bond (ii) 2 atoms within L are substituted with a divalent substituent the same as in a substituent, which completes heteroarylene;
(iii) L is a 1 to 50 atom heteroalkylene, and;
(iv) The alkylene is substituted by at least one C1-20 alkyl;
B) comprises at least one isoprenyl derivative unit of General Formula III
below, which can be recognized by isoprenoid transferase;
[General Formula III]
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 *ty'H#*.
[General Formula II]
(Z), Ft1 Ab, W
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Where in the formula, the formula:
R4-(3 0 4.
)1/4*
R
G is a glucuronic acid moiety or R3 is a hydrogen or carboxyl protective group, and the respective R4 are independently hydrogen or hydroxyl protective groups;
Ab is an antibody binding with specificity to DLK1 or an antigen-binding fragment thereof:
B is an active agent;
Ri and R2 are, respectively and independently, hydrogen, (C 1-C8) alkyl or (C3-C8) cycloalkyl;
W is -C(0)-, -C(0)NR'-, -C(0)0-, -SO2NR'-, -P(0)R"NR'-, -SONR'- or -P02NR'-;
the C, S or P
directly bonds to a phenyl ring; the NR' bonds to L; and R' and R" are respectively and independently, hydrogen, (C 1 -C8) alkyl, (C3-C8) cycloalkyl, (C1 -C8) alkoxy, (C1 -C8) alkylthio, mono- or di-(C1-C8) alkylamino, (C3-C20) heteroaryl, or (C6-C20) aryl;
each Z is, independently, (Ci-C8) alkyl, halogen, cyano or nitro;
n is an integer of 1 through 3;
L is any one of the following:
A) Is a Ci-050 alkylene or a 1 to 50 atom heteroalkylene, and satisfies at least one of the following:
(i) L comprises at least one unsaturated bond (ii) 2 atoms within L are substituted with a divalent substituent the same as in a substituent, which completes heteroarylene;
(iii) L is a 1 to 50 atom heteroalkylene, and;
(iv) The alkylene is substituted by at least one C1-20 alkyl;
B) comprises at least one isoprenyl derivative unit of General Formula III
below, which can be recognized by isoprenoid transferase;
[General Formula III]
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 *ty'H#*.
6. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in thatL is a nitrogen-containing 1 to 50 atom heteroalkylene , the linker comprising at least 2 atoms of a hydrophilic amino acid; and the nitrogen forms a peptide bond with a carbonyl of a hydrophilic amino acid selected from the group comprising arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine.
7. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that W is -C(0)NR'-, and the nitrogen of W is a nitrogen atom of a hydrophilic amino acid selected from the group comprising arginine, aspartate, asparagine, glutamate, glutamine, histidine, lysine, ornithine, proline, serine or threonine.
8. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 6 or Claim 7, characterized in that the amino acid covalently bonds an oxime of a linker to a polyethylene glycol unit of the linker.
9. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 6 or Claim 7, characterized in that the hydrophilic amino acid is an amino acid selected from the group consisting of aspartate, glutamate, ornithine, lysine, and arginine comprising a side chain having a moiety representing a charge at neutral pH in an aqueous solution.
10. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that the linker comprises a peptide, the peptide comprising 2 to 20 amino acids and comprising at least one hydrophilic amino acid selected from the group comprising alanine, aspartate, asparagine, glutamate, glutamine, glycine, lysine, ornithine, proline, serine and threonine, and comprising at least one hydrophilic amino acid selected from FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 the group consisting of aspartate, glutamate, ornithine, lysine and arginine comprising a side chain having a moiety that exhibits charge at neutral pH in an aqueous solution.
11. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 10, characterized in that W is -C(0)NR'-, and the nitrogen of W is a nitrogen atom of an N-terminal amino acid of the peptide.
12. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that the peptide covalently bonds an oxime of a linker to a polyethylene glycol unit of the linker.
13. The antibody conjugate according or a pharmaceutically acceptable salt or solvate thereof to Claim 5, characterized in that the L is covalently bonded to an antibody by a thioether bond, and the thioether bond comprises a sulfur atom of the cysteine of the antibody.
14. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 13, characterized in that the antibody comprises an amino acid which can be recognized by isoprenoid transferase at the C-terminal of the antibody, and the thioether bond comprises a sulfur atom of the cysteine of the antibody.
15. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 14, characterized in that the amino acid motif is a CYYX sequence;
C is cysteine;
Y is an aliphatic amino acid selected from the group consisting of alanine, isoleucine, leucine, methionine and valine;
X is any one selected from the group consisting of glutamine, glutamate, serine, cysteine, methionine, alanine and leucine; and the thioether bond comprises a sulfur atom of cysteine of the amino acid motif.
C is cysteine;
Y is an aliphatic amino acid selected from the group consisting of alanine, isoleucine, leucine, methionine and valine;
X is any one selected from the group consisting of glutamine, glutamate, serine, cysteine, methionine, alanine and leucine; and the thioether bond comprises a sulfur atom of cysteine of the amino acid motif.
16. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 15, characterized in that the amino acid motif is a CVIM or CVLL
sequence.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
sequence.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
17. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of Claim 14 through Claim 16, characterized in that at least one of the 1 to 10 amino acids preceding the amino acid motif is selected from among glycine, proline, aspartic acid, arginine and serine.
18. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 17, characterized in that the 1 to 10 amino acids preceding the amino acid motif are respectively glycine.
19. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that the L comprises the amino sequence GGGGGGGCVIM at the C-terminal.
20. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that L comprises at least one isoprenyl derivative unit of General Formula III below, which can be recognized by isoprenoid transferase:
[General Formula III]
tirt
[General Formula III]
tirt
21. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that L is a 3 to 50 heteroalkylene comprising an 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 to Ab, or; 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.
22. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 20 or Claim 21, characterized in that L comprises an oxime, and in that at least one isoprenyl unit covalently links the oxime to Ab.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09
23.
The antibody conjugate or a phannace ., solvate thereof according 4- - in that L comprises Or N
The antibody conjugate or a phannace ., solvate thereof according 4- - in that L comprises Or N
24. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that L further comprises a connecting unit represented by General Formula VIII or General Fomiula IX:
[General Formula VIII]
-(C112),(V(C112)p)q-[General Formula IX]
-(CH2C112X)-where: V is a single bond, -0-, -S-, -NR21-, -C(0)NR22-, NR23C(0)-, NR24S02-, or -S02NR25-;
X is -0-, C1-C8 alkylene or -NR21-;
R21 tO R25 are, independently and respectively hydrogen, (Ci-C6) alkyl, (Ci-C6) alkyl (C6-C20) aryl, or (Ci-C6) alkyl (C3-C2o) heteroaryl;
r is an integer of 0 to 10;
p is an integer of 0 to 10;
q is an integer of 1 to 20; and w is an integer of 1 to 20.
[General Formula VIII]
-(C112),(V(C112)p)q-[General Formula IX]
-(CH2C112X)-where: V is a single bond, -0-, -S-, -NR21-, -C(0)NR22-, NR23C(0)-, NR24S02-, or -S02NR25-;
X is -0-, C1-C8 alkylene or -NR21-;
R21 tO R25 are, independently and respectively hydrogen, (Ci-C6) alkyl, (Ci-C6) alkyl (C6-C20) aryl, or (Ci-C6) alkyl (C3-C2o) heteroaryl;
r is an integer of 0 to 10;
p is an integer of 0 to 10;
q is an integer of 1 to 20; and w is an integer of 1 to 20.
25. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 24, characterized in that L comprises 1 to 20 polyethylene glycol units represented by or
26. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 25, characterized in that L comprises 1 to 12 -OCH2C112- units.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09
27. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 25, characterized in that L comprises an oxime; and 1 to 20 polyethylene glycol units covalently bond the oxime to the active agent.
28. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that L further comprises a binding unit formed by a 1,3-dipolar cycloaddition reaction, hetero-diels reaction, nucleophilic substitution reaction, non-aldol type carbonyl reaction, addition to carbon-carbon multiple bond, oxidation reaction or click reaction.
29. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 28, characterized in that the binding unit is formed by a reaction between acetylene and azide, or a reaction between aldehyde or a ketone group and hydrazine or alkoxyamine.
30. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that L further comprises binding units represented by General Formulae IV, V, VI or VII below:
[General Formula IV]
.t.<1 N
N'N
[General Formula V]
L/IN\
[General Formula VI]
yr [General Formula VII]
R11-"N-Li -where, in the formula, HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 the L1 is a single bond or a C1-C30 alkylene; and R" is hydrogen or a Ci-Cio alkyl.
[General Formula IV]
.t.<1 N
N'N
[General Formula V]
L/IN\
[General Formula VI]
yr [General Formula VII]
R11-"N-Li -where, in the formula, HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 the L1 is a single bond or a C1-C30 alkylene; and R" is hydrogen or a Ci-Cio alkyl.
31. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 30, L1 is a single bond or a C11 or C12 alkylene.
32. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according \õ, s --(C112),(V(CH2)p)q to Claim 30, characterized in that L comprises N Or 1--(CH2)r(V(CH2)0(N"-k).--1 V is a single bond, -0-, -S-, -NR21-, -C(0)NR22-, NR23C(0)-, NR24S02-, or -S02NR25-;
R21 to R25 are, independently, hydrogen, (C1_6) alkyl, (C1_6) alkyl (C6_20) aryl, or (C1_6) alkyl (C3-20) heteroaryl;
r is an integer of 0 to 10;
p is an integer of 0 to 10;
q is an integer of 1 to 20; and L1 is a single bond.
R21 to R25 are, independently, hydrogen, (C1_6) alkyl, (C1_6) alkyl (C6_20) aryl, or (C1_6) alkyl (C3-20) heteroaryl;
r is an integer of 0 to 10;
p is an integer of 0 to 10;
q is an integer of 1 to 20; and L1 is a single bond.
33. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 32, characterized in that the L comprises any one selected from the group comprising oriu¨ 8 No.. o Hod OH 4) n LB
HO--t Ab 5 FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 HOAIO
HO
6H Ce`N"--and;
co,H
OH
the Ab is an antibody which bonds with specificity to DLK1 or an antigen-binding fragment thereof;
B is an active agent; and n is an integer of 0 to 20.
HO--t Ab 5 FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 HOAIO
HO
6H Ce`N"--and;
co,H
OH
the Ab is an antibody which bonds with specificity to DLK1 or an antigen-binding fragment thereof;
B is an active agent; and n is an integer of 0 to 20.
34. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that the isoprenoid transferase is a farnesyl protein transferase (FTase) or a geranylgeranyl transferase (GGTase).
35. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that L comprises at least one branch linker covalently bonded to Ab, i) the respective branch linkers comprise a branched unit (BR) covalently bonded to Ab by a primary linker (PL);
ii) the respective branch linkers bind a first active agent to a branched unit, and comprise a first branch (B1) comprising a second linker (SL) and a cleaving group (CG);
and iii) the respective branch linkers comprise a) a second branch (B2) wherein a second active agent is covalently bonded to a branched unit by a second linker (SL) and a cleaving group (CG), or b) a second branch wherein a polyethylene glycol moiety is covalently bonded to a branched unit;
iv) and the respective cleaving groups are hydrolyzed to release an active agent from an antibody conjugate.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
ii) the respective branch linkers bind a first active agent to a branched unit, and comprise a first branch (B1) comprising a second linker (SL) and a cleaving group (CG);
and iii) the respective branch linkers comprise a) a second branch (B2) wherein a second active agent is covalently bonded to a branched unit by a second linker (SL) and a cleaving group (CG), or b) a second branch wherein a polyethylene glycol moiety is covalently bonded to a branched unit;
iv) and the respective cleaving groups are hydrolyzed to release an active agent from an antibody conjugate.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
36. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according le.G2 L31' L4'G3,"
to Claim 35, characterized in that the branch linker is -"-rtr'-' , cs-2LN rs'ss'N--A)5 R4o t,<-30 Or the L2, L3 and L4 are, respectively and independently, direct bonds or -Cn}12n-; n is an integer of 1 to 30;
o 0 R4 `ssLN)L)'s -"Hr. NH 'sss' the G1' G2 and G3 are, independently, a direct bond R30 R3 0 N
Or ; and the R3 is hydrogen or C1-30 alkyl.
to Claim 35, characterized in that the branch linker is -"-rtr'-' , cs-2LN rs'ss'N--A)5 R4o t,<-30 Or the L2, L3 and L4 are, respectively and independently, direct bonds or -Cn}12n-; n is an integer of 1 to 30;
o 0 R4 `ssLN)L)'s -"Hr. NH 'sss' the G1' G2 and G3 are, independently, a direct bond R30 R3 0 N
Or ; and the R3 is hydrogen or C1-30 alkyl.
37. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 36, characterized in that it comprises 1-10.211 o 0 B
HOyODj HO' i OH 0 IrBe wherein the B and B' indicate active agents which may be different or identical;
n indicates, respectively and independently, an integer of 0 to 30;
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 f indicates, respectively and independently, an integer of 0 to 30; and L indicates a bond to Ab.
HOyODj HO' i OH 0 IrBe wherein the B and B' indicate active agents which may be different or identical;
n indicates, respectively and independently, an integer of 0 to 30;
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 f indicates, respectively and independently, an integer of 0 to 30; and L indicates a bond to Ab.
38. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 37, characterized in that L comprises an oxime and 1 to 20 polyethylene glycol unit(s) which covalently binds the oxime to the active agent.
39. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 35, characterized in that the cleavage group may be cleaved within a target cell, and the cleavage group may release one or more active agents.
40. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that L comprises 1 to 6 branched linkers covalently bonded to Ab;
and 2 to 6 identical or different active agents covalently bonded to the branched linkers.
and 2 to 6 identical or different active agents covalently bonded to the branched linkers.
41. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 40, characterized in that the respective active agents are bonded to the branched linker by a cleavable bond.
42. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 40, characterized in that the respective branched linkers comprise a branched unit, the respective active agents are bonded to the branched unit through a second linker, and the branched units are bonded to Ab by a first linker.
43. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 42, characterized in that the branched unit is a nitrogen unit or a lysine unit.
44. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 42, characterized in that the branched unit is an amide, and the first linker or the second linker comprises a carbonyl of the amide.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
45. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that the active agent is a chemotherapeutic agent or a toxin.
46. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that the active agent is an immunoregulatory compound, anti-cancer agent, antiviral, antibacterial, antifungal, antiparasitic or a combination thereof.
47. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 5, characterized in that the active agent is selected from the following:
(a) erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787/ZK 222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, teimethylolomelamine, bullatacin, bullataciionone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocannycin, KW-2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotoxin, fotemustine, lomustine, nimustine, ranimustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, esperamicin, neocarzinostatin chromophore, aclacinomysins, actinomycin, antrymycin, azaserine, bleomycins, catcinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubucin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tudercidin, ubenimex, zinostatin, zorubicin, 5-fluoDLKacil, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thiguianine, ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone, propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide,mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatrexate, defofamine, democolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k, razoxane, rhizoxin, sizofiran, spirogennanium, tenuazonic acid, triaqizuone, 2,2', 2"-trichlorotriethylamine, T-2 toxin, verracurin A, DLKidin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, docetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS
2000, difluoromethylornithine, retinoic acid, capecitabine, or pharmaceutically acceptable salts, solvates or acids thereof;
(b) monokine, lympokine, traditional polypeptide homione, parathyroid homione, thyroxine, relaxin, pDLKelaxin, glycoprotein homione, follicle stimulating homione, thyroid stimulating hormone, luteinizing hormone, hepatic growth factor fibroblast growth factor, prolactin, placental lactogen, tumor necrosis factor, tumor necrosis factor-a, tumor necrosis factor-I3, Mullerian inhibiting substance, mouse gonadotropin associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, osteoinductive factor, interferon, interferon-a, interferon-I3, interferon-y, colony stimulating factor (CSF), macrophage-CSF, granulocyte-macrophage-CSF), granulocyte-macrophage-CSF, granulocyte-CSF, interleukin (IL), IL-1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, I L-12, tumor necrosis factor, TNF-a, TNF-I3, polypeptide factor, LIF, kit ligand, or mixtures thereof;
(c) diphtheria toxin, botulinum toxin, tetanus toxin, dysentery toxin, cholera toxin, amanitin, a-amatinin, pyrrolobenzodiazepine, pyrrolobenzodiazepine derivative, indolinobenzodiazepine, pyridobenzodiazepine, tetrodotoxin, brevetoxin, ciguatoxin, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 ricin, AM toxin, auristatin, tubulysin, geldanamycin, maytansinoid, calicheamicin, daunomycin, doxorubicin, methotrexate, vindesine, SG2285, dolastatin, dolastatin analog, auristatin, cryptophycin, camptothecin, rhizoxin, rhizoxin derivatives, CC-1065, CC-1065 analogs or derivatives, duocannycin, enediyne antibiotic, esperamicin, epothilone, toxoid, or mixtures thereof;
(d) affinity ligand, where the affinity ligand is a substrate, inhibitor, active agent, neurotransmitter, radioactive isotope, or mixtures thereof;
(e) radioactive label, 32P, 35S, fluorescent dye, electron dense reagent, enzyme, biotin, streptavidin, dioxigenin, hapten, immunogenic protein, nucleic acid molecule with a sequence complementary to a target, or mixtures thereof;
(f) immunomodulatory compound, anti-cancer agent, anti-viral agent, anti-bacterial agent, anti-fungal agent, anti-parasitic agent, or mixtures thereof;
(g) tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone or toremifene;
(h) 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole or anastrozole (i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine;
(j) aromatase inhibitor;
(k) protein kinase inhibitor;
(1) lipid kinase inhibitor;
(m) antisense oligonucleotide;
(n) ribozyme;
(o) vaccine; and (p) anti-angiogenic agent.
(a) erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787/ZK 222584, oxaliplatin, 5-fluorouracil, leucovorin, rapamycin, lapatinib, lonafarnib, sorafenib, gefitinib, AG1478, AG1571, thiotepa, cyclophosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, ethylenimine, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, teimethylolomelamine, bullatacin, bullataciionone, camptothecin, topotecan, bryostatin, callystatin, CC-1065, adozelesin, carzelesin, bizelesin, cryptophycin 1, cryptophycin 8, dolastatin, duocannycin, KW-2189, CB1-TM1, eleutherobin, pancratistatin, sarcodictyin, spongistatin, chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotoxin, fotemustine, lomustine, nimustine, ranimustine, calicheamicin, calicheamicin gamma 1, calicheamicin omega 1, dynemicin, dynemicin A, clodronate, esperamicin, neocarzinostatin chromophore, aclacinomysins, actinomycin, antrymycin, azaserine, bleomycins, catcinomycin, carabicin, carninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubucin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubucin, liposomal doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomigrin, streptozocin, tudercidin, ubenimex, zinostatin, zorubicin, 5-fluoDLKacil, denopterin, methotrexate, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thiguianine, ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone, propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide,mitotane, trilostane, folinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatrexate, defofamine, democolcine, diaziquone, elfornithine, elliptinium acetate, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, 2-ethylhydrazide, procarbazine, polysaccharide-k, razoxane, rhizoxin, sizofiran, spirogennanium, tenuazonic acid, triaqizuone, 2,2', 2"-trichlorotriethylamine, T-2 toxin, verracurin A, DLKidin A, anguidine, urethane, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, albumin-engineered nanoparticle formulation of paclitaxel, docetaxel, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, platinum, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, CPT-11, topoisomerase inhibitor RFS
2000, difluoromethylornithine, retinoic acid, capecitabine, or pharmaceutically acceptable salts, solvates or acids thereof;
(b) monokine, lympokine, traditional polypeptide homione, parathyroid homione, thyroxine, relaxin, pDLKelaxin, glycoprotein homione, follicle stimulating homione, thyroid stimulating hormone, luteinizing hormone, hepatic growth factor fibroblast growth factor, prolactin, placental lactogen, tumor necrosis factor, tumor necrosis factor-a, tumor necrosis factor-I3, Mullerian inhibiting substance, mouse gonadotropin associated peptide, inhibin, activin, vascular endothelial growth factor, thrombopoietin, erythropoietin, osteoinductive factor, interferon, interferon-a, interferon-I3, interferon-y, colony stimulating factor (CSF), macrophage-CSF, granulocyte-macrophage-CSF), granulocyte-macrophage-CSF, granulocyte-CSF, interleukin (IL), IL-1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, I L-12, tumor necrosis factor, TNF-a, TNF-I3, polypeptide factor, LIF, kit ligand, or mixtures thereof;
(c) diphtheria toxin, botulinum toxin, tetanus toxin, dysentery toxin, cholera toxin, amanitin, a-amatinin, pyrrolobenzodiazepine, pyrrolobenzodiazepine derivative, indolinobenzodiazepine, pyridobenzodiazepine, tetrodotoxin, brevetoxin, ciguatoxin, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 ricin, AM toxin, auristatin, tubulysin, geldanamycin, maytansinoid, calicheamicin, daunomycin, doxorubicin, methotrexate, vindesine, SG2285, dolastatin, dolastatin analog, auristatin, cryptophycin, camptothecin, rhizoxin, rhizoxin derivatives, CC-1065, CC-1065 analogs or derivatives, duocannycin, enediyne antibiotic, esperamicin, epothilone, toxoid, or mixtures thereof;
(d) affinity ligand, where the affinity ligand is a substrate, inhibitor, active agent, neurotransmitter, radioactive isotope, or mixtures thereof;
(e) radioactive label, 32P, 35S, fluorescent dye, electron dense reagent, enzyme, biotin, streptavidin, dioxigenin, hapten, immunogenic protein, nucleic acid molecule with a sequence complementary to a target, or mixtures thereof;
(f) immunomodulatory compound, anti-cancer agent, anti-viral agent, anti-bacterial agent, anti-fungal agent, anti-parasitic agent, or mixtures thereof;
(g) tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone or toremifene;
(h) 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, letrozole or anastrozole (i) flutamide, nilutamide, bicalutamide, leuprolide, goserelin, or troxacitabine;
(j) aromatase inhibitor;
(k) protein kinase inhibitor;
(1) lipid kinase inhibitor;
(m) antisense oligonucleotide;
(n) ribozyme;
(o) vaccine; and (p) anti-angiogenic agent.
48. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 1, characterized in that the the active agent is a pyrrolobenzodiazepine dimer, wherein the linker links Ab to the N10 or N'10 position of the pyrrolobenzodiazepine dimer.
49. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 48, characterized in that the activator is a pyrrolobenzodiazepine dimer;
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 the pyrrolobenzodiazepine dimer is substituted by X at the N10 position or by X' at the N'10 position, where X or X' links the pyrrolobenzodiazepine dimer to the linker;
X and X' are, respectively and independently, -C(0)0*, -S(0)0-*, -C(0)-*, -C(0)NRx-*, -S(0)2NRx-*, -P(0)R'NRx-*, -S(0)NRx-*, or -P02NRx-*;
Rx is C1_8 alkyl, C3_8 cycloalkyl, C3_20 heteroaryl or C5-20 aryl;
Rx'+ is OH, N3, CN, SH, C1-8 alkyl, C3-8 cycloalkyl, C1_8 alkoxy, C1_8 alkylthio, C3_20 heteroaryl, C5-20 aryl or amino; and * is a binding site between the pyrrolobenzodiazepine dimer and the linker.
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 the pyrrolobenzodiazepine dimer is substituted by X at the N10 position or by X' at the N'10 position, where X or X' links the pyrrolobenzodiazepine dimer to the linker;
X and X' are, respectively and independently, -C(0)0*, -S(0)0-*, -C(0)-*, -C(0)NRx-*, -S(0)2NRx-*, -P(0)R'NRx-*, -S(0)NRx-*, or -P02NRx-*;
Rx is C1_8 alkyl, C3_8 cycloalkyl, C3_20 heteroaryl or C5-20 aryl;
Rx'+ is OH, N3, CN, SH, C1-8 alkyl, C3-8 cycloalkyl, C1_8 alkoxy, C1_8 alkylthio, C3_20 heteroaryl, C5-20 aryl or amino; and * is a binding site between the pyrrolobenzodiazepine dimer and the linker.
50. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 49, characterized in that the pyrrolobenzodiazepine dimer is represented by General Fomiula X or General Formula XI below:
[General Fomiula X]
R" ). 05 Rx51 )tic RX31 N Y-Rx6-YN
H H
, I
t_ N Rxi=
0* Rx4'==1--.----NirN/ , , - - -- -Rxi Rx2, Rx2 r, RX7I s# = R47 [General Fomiula XI]
Z r b X' Rx3' ' za' NRx" r_Rxa_y , , 11 N - 1 -,,õR
, ' X4r RX3 i NR÷
Rx4 RV. 0 Rx2' Rx2 0 RXT
where, in the formula:
the dotted lines denote the selective existence of double bonds between Cl and C2, between C2 and C3, between C'l and C'2, or between C'2 and C'3;
Rxl and Rxl' are independently selected from H, OH, =0, =CH2 CN, Rm ORm, =CH-Rm', =C(Rm')2, 0-502-Rm, CO2Rm, CORm, halo and dihalo;
Rm' is selected from among Rm, CO2Rm, CORm, CHO, CO2H and halo;
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 each Rm is independently selected from a group comprised of C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5_20 aryl, C5-20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl and 5 to 7 membered heteroaryl;
RX2, RX2', RX3, RX3', RX5 and RX5' are independently selected from among H, Rm, OH, OR", SH, SRm, NH2, NHRm, NRm2, NO2, Me3Sn and halo;
Rx4 and Rx4' are independently selected from among H, R", OH, ORm, SH, SRm, NH2, NHRm, NRm2, NO2, Me3Sn, halo, C1-6 alkyl, C1_6 alkenyl, C2-6 alkynyl, C2-6 aryl, C3-6 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl, 5 to 7 membered heteroaryl, -CN, -NCO, -ORn, -0C(0)Rn, -0C(0)NRnRn', -0S(0)Rn, -0S(0)2Rn, -SRn, -S(0)Rn, -S(0)2Rn, -S(0)NRnRn', -S(0)2NRnRn', -0S(0)NRnRn', -0S(0)2NRnRn', -NRnRn', -NR"C(0)R , -NR"C(0)0R , -NR"C(0)NR R ', -NR"S(0)R , -NR"S(0)2R , -NRnS(0)NR R ', -NRnS(0)2NR R ', -C(0)Rn, -C(0)0Rn and -C(0)NRnir;
Rx and Rx are independently selected from among H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, C1_8 alkyl, C3-8 cycloalkyl, C1_8 alkoxy, C1-8 alkylthio, C3_20 heteroaryl, C5_20 aryl or mono- or di-C1_8 alkylamino;
Y and Y' are independently selected from 0, S and N(H);
Rx6 is independently selected from C3_12 alkylene, C3_12 alkenylene, or C3_12 heteroalkylene;
RX7 and RXT are independently selected from among H, C1-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6-10 aryl, 5 to 7- membered heteroaryl, -OW, -0C(0)W, -0C(0)NWR", -0S(0)W, -0S(0)2W, -SW, -S(0)W, -S(0)2W, -S(0)NWR", -S(0)2NR a", -0S(0)NW R", -0S(0)2NW R", -NWR", -NWC(0)W, -NWC(0)0W, -NWC(0)NWR5', -NWS(0)W, -NWS(0)2W, -NWS(0)NWR5', -NRrs(0)2NRsRs, -C(0)W, -C(0)0R5 or -C(0)NWR";
each R" R', Rs and W' is independently selected from H, C1-7 alkyl, C2_7 alkenyl, C2_7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-10 aryl and 5 to 7 membered heteroaryl;
each RX8 and RX8' is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 heteroalkyl, 3 to 7 membered heterocycloalkyl, C5-10 aryl, 5 to 7 membered heteroaryl, -S(0)Rm, -S(0)2Rm, -S(0)NRmRnn, -S(0)2NRmRn", -NRmRm', -NRmC(0)Rm, -NRmC(0)0Rn, -NRmC(0)NRnR", -NRmS(0)Rn, -NRmS(0)2Rn, -NRmS(0)NRnir, -NRmS(0)2NRnir, -C(0)Rm, -C(0)0Rm and -C(0)NRmR";
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Za is selected from among ORx12", NRx12aRX12a, or SRxl2a;
Zb is selected from among 0013a, NRX13aRX13a, or SR)(13a;
Za.' is selected from among 0012a, NRx12aRX12a, or SRxl2a;
Zb' is selected from among ORxl3a', NRX13a'RX13a', or SRxl3"';
each Rxl2a, RX12a', RX13a' and Rx13a' is independently selected from H, Cl_6 alkyl, C2-6alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, 5 to 7 membered heteroaryl, -C(0)015a+, -C(0)0015a and -C(0)NRx15aRX15a'; and each Rx15a and Rx15"' is independently selected from C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5-20 aryl, C5_20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, and 5 to 7 membered heteroaryl; and the Rxl3a and Rxl4a optionally join 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 the R)(13a' and WULia' optionally join the atoms to which they are attached to form 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, or 3 to 7 membered heteroaryl; and each of the R", R"', R , R ', RP and RP' is independently selected from among H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, and to 7 membered heteroaryl.
[General Fomiula X]
R" ). 05 Rx51 )tic RX31 N Y-Rx6-YN
H H
, I
t_ N Rxi=
0* Rx4'==1--.----NirN/ , , - - -- -Rxi Rx2, Rx2 r, RX7I s# = R47 [General Fomiula XI]
Z r b X' Rx3' ' za' NRx" r_Rxa_y , , 11 N - 1 -,,õR
, ' X4r RX3 i NR÷
Rx4 RV. 0 Rx2' Rx2 0 RXT
where, in the formula:
the dotted lines denote the selective existence of double bonds between Cl and C2, between C2 and C3, between C'l and C'2, or between C'2 and C'3;
Rxl and Rxl' are independently selected from H, OH, =0, =CH2 CN, Rm ORm, =CH-Rm', =C(Rm')2, 0-502-Rm, CO2Rm, CORm, halo and dihalo;
Rm' is selected from among Rm, CO2Rm, CORm, CHO, CO2H and halo;
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09 each Rm is independently selected from a group comprised of C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5_20 aryl, C5-20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl and 5 to 7 membered heteroaryl;
RX2, RX2', RX3, RX3', RX5 and RX5' are independently selected from among H, Rm, OH, OR", SH, SRm, NH2, NHRm, NRm2, NO2, Me3Sn and halo;
Rx4 and Rx4' are independently selected from among H, R", OH, ORm, SH, SRm, NH2, NHRm, NRm2, NO2, Me3Sn, halo, C1-6 alkyl, C1_6 alkenyl, C2-6 alkynyl, C2-6 aryl, C3-6 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl, 5 to 7 membered heteroaryl, -CN, -NCO, -ORn, -0C(0)Rn, -0C(0)NRnRn', -0S(0)Rn, -0S(0)2Rn, -SRn, -S(0)Rn, -S(0)2Rn, -S(0)NRnRn', -S(0)2NRnRn', -0S(0)NRnRn', -0S(0)2NRnRn', -NRnRn', -NR"C(0)R , -NR"C(0)0R , -NR"C(0)NR R ', -NR"S(0)R , -NR"S(0)2R , -NRnS(0)NR R ', -NRnS(0)2NR R ', -C(0)Rn, -C(0)0Rn and -C(0)NRnir;
Rx and Rx are independently selected from among H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, C1_8 alkyl, C3-8 cycloalkyl, C1_8 alkoxy, C1-8 alkylthio, C3_20 heteroaryl, C5_20 aryl or mono- or di-C1_8 alkylamino;
Y and Y' are independently selected from 0, S and N(H);
Rx6 is independently selected from C3_12 alkylene, C3_12 alkenylene, or C3_12 heteroalkylene;
RX7 and RXT are independently selected from among H, C1-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6-10 aryl, 5 to 7- membered heteroaryl, -OW, -0C(0)W, -0C(0)NWR", -0S(0)W, -0S(0)2W, -SW, -S(0)W, -S(0)2W, -S(0)NWR", -S(0)2NR a", -0S(0)NW R", -0S(0)2NW R", -NWR", -NWC(0)W, -NWC(0)0W, -NWC(0)NWR5', -NWS(0)W, -NWS(0)2W, -NWS(0)NWR5', -NRrs(0)2NRsRs, -C(0)W, -C(0)0R5 or -C(0)NWR";
each R" R', Rs and W' is independently selected from H, C1-7 alkyl, C2_7 alkenyl, C2_7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-10 aryl and 5 to 7 membered heteroaryl;
each RX8 and RX8' is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 heteroalkyl, 3 to 7 membered heterocycloalkyl, C5-10 aryl, 5 to 7 membered heteroaryl, -S(0)Rm, -S(0)2Rm, -S(0)NRmRnn, -S(0)2NRmRn", -NRmRm', -NRmC(0)Rm, -NRmC(0)0Rn, -NRmC(0)NRnR", -NRmS(0)Rn, -NRmS(0)2Rn, -NRmS(0)NRnir, -NRmS(0)2NRnir, -C(0)Rm, -C(0)0Rm and -C(0)NRmR";
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 Za is selected from among ORx12", NRx12aRX12a, or SRxl2a;
Zb is selected from among 0013a, NRX13aRX13a, or SR)(13a;
Za.' is selected from among 0012a, NRx12aRX12a, or SRxl2a;
Zb' is selected from among ORxl3a', NRX13a'RX13a', or SRxl3"';
each Rxl2a, RX12a', RX13a' and Rx13a' is independently selected from H, Cl_6 alkyl, C2-6alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, 5 to 7 membered heteroaryl, -C(0)015a+, -C(0)0015a and -C(0)NRx15aRX15a'; and each Rx15a and Rx15"' is independently selected from C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5-20 aryl, C5_20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, and 5 to 7 membered heteroaryl; and the Rxl3a and Rxl4a optionally join 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 the R)(13a' and WULia' optionally join the atoms to which they are attached to form 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl, or 3 to 7 membered heteroaryl; and each of the R", R"', R , R ', RP and RP' is independently selected from among H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_10 aryl, and to 7 membered heteroaryl.
51. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 50, characterized in that the Rm is independently selected from a group comprised of 12 alkyl, C2-12 alkenyl, C2_12 alkynyl, C5_20 aryl, C5-20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl and 5 to 7 membered heteroaryl;
and the Rm is additionally substituted with of C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5_20 aryl, C5-20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl or 5 to 7 membered heteroaryl.
and the Rm is additionally substituted with of C1_12 alkyl, C2_12 alkenyl, C2_12 alkynyl, C5_20 aryl, C5-20 heteroaryl, C3-6 cycloalkyl, 3 to 7 membered heterocyclyl, 3 to 7 membered heterocycloalkyl or 5 to 7 membered heteroaryl.
52. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 50, characterized in that the Rx4 and Rx4' are independently selected from among H, Rm, OH, OR'', SH, SR'', NH2, NHRm, NRmRm NO2, Me3Sn, halo, C1_6 alkyl C1-6 alkoxy, alkenyl, C2_6 alkynyl, C3_6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5_12 aryl, 5 to 7 FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 membered heteroaryl, -CN, -NCO, -ORn, -0C(0)Rn, -0C(0)NRnir, -0S(0)Rn, -0S(0)2Rn, -SRn, -S(0)Rn, -S(0)2Rn, -S(0)NRnir, -S(0)2NRW, -0S(0)NRnir, -0S(0)2NRnR", -NRnir, -NRnC(0)R , -NRnC(0)0R", -NRnC(0)NR R ', -NRnS(0)R , -NRnS(0)2R", -NRnS(0)NR
R6',-NRnS(0)2NR R ', -C(0)Rn, -C(0)0Rn and -C(0)NRnR"; and the 04 or 04' is C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl or 5 to 7 membered heteroaryl, and additionally is substituted with at least one C1_6 alkyl, C1_6 alkoxy, C2-6 alkenyl, C2-6alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-10 aryl, to 7 membered heteroaryl, -ORP, -0C(0)RP, -C(0)NRPRP', -0S(0)RP, -0S(0)2RP, -SRP,-S(0)RP, -S(0)2RP, -S(0)NRPRP', -S(0)2NRPRP', -0S(0)NRPRP', -0S(0)2NRPRP', -NRPRP',-NRPC(0)Rq, -NRPC(0)0Rq, -NRPC(0)NRqRq', -NRPS(0)Rq, -NRPS(0)2Rq, -NRPS(0)NRW, -NRPS(0)2NRW', -C(0)RP, -C(0)ORP or -C(0)NRPRP.
R6',-NRnS(0)2NR R ', -C(0)Rn, -C(0)0Rn and -C(0)NRnR"; and the 04 or 04' is C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-12 aryl or 5 to 7 membered heteroaryl, and additionally is substituted with at least one C1_6 alkyl, C1_6 alkoxy, C2-6 alkenyl, C2-6alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-10 aryl, to 7 membered heteroaryl, -ORP, -0C(0)RP, -C(0)NRPRP', -0S(0)RP, -0S(0)2RP, -SRP,-S(0)RP, -S(0)2RP, -S(0)NRPRP', -S(0)2NRPRP', -0S(0)NRPRP', -0S(0)2NRPRP', -NRPRP',-NRPC(0)Rq, -NRPC(0)0Rq, -NRPC(0)NRqRq', -NRPS(0)Rq, -NRPS(0)2Rq, -NRPS(0)NRW, -NRPS(0)2NRW', -C(0)RP, -C(0)ORP or -C(0)NRPRP.
53. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 50, characterized in that Rx7and RxT are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6-10 aryl, 5 to 7 membered heteroaryl, -OW, -0C(0)W, -0C(0)NW R", -0S(0)W, -0S(0)2W, -SW, -S(0)W, -S(0)2W, -S(0)NWR", -S(0)2NW R", -0S(0)NW R", -0S(0),NW R", -NWR", -NWC(0)Rs, -NWC(0)0Rs, -NWC(0)NRsRs', -NWS(0)Rs, -NWS(0)2Rs, - NWS(0)NRsRs', -NWS(0)2NRsRs, -C(0)W, -C(0)0Rs or -C(0)NWR"; Rx7 and RxT are independently selected from among H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6-10 aryl, or 5 to 7 membered heteroaryl, and are additionally substituted by C1_6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3 to 7 membered heterocycloalkyl, C6-10 aryl, 5 to 7 membered heteroaryl, -01e, -0C(0)Rt, -0C(0)NRtie, -0S(0)Rt, -0S(0)2Rt, -Sle, -S(0)Rt, -S(0)21e, -S(0)NRtR", -S(0),NRtie, -0S(0)NRtR", -0S(0),NRtR", -NieR", -NRtC(0)Ru, -NleC(0)0R",-NleC(0)NIVR', -NRtS(0)Ru, -NRtS(0)21V, -NRtS(0)NR" R', -NRtS(0)2NIVR', -C(0)Rt, -C(0)0Rt or -C(0)NR tR"; and the Rr, RI', Rs, Rs', Rt, Re, R`T and R'" are independently selected from among H, C1-7 alkyl, C2_7 alkenyl, C2_7 alkynyl, C3-13 cycloalkyl, 3 to 7 membered heterocycloalkyl, C5-10 aryl, and 5 to 7 membered heteroaryl.
54. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 50, characterized in that the Rx6 is C3-12 alkylene, C3-12 alkenylene or C3-12 FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 heteroalkylene, with the RX6 substituted by -NH2, -NHRm, -NHC(0)Rm, -NHC(0)CH2, [OCH2CH2].-Rxx, or ¨[CH2CH20].-Rxx;the Rxx is H, OH, N3, CN, NO2, SH, NH2, ONH2, NHNH2, halo, C1-8 alkyl, C3-8 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio, C3_20 heteroaryl, C5_20 aryl or mono- or di-C1_8 alkyl amino; and n is an integer of 1 through 6.
55. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 50, characterized in that the active agent is a pyrrolobenzodiazepine dimer denoted by General Formula XII or General Formula XIII;
[General Formula XII]
-G' G W1.
Nikb I. (nys x, x. x Rxs, 1 tem. Rxs 1 R"
N
..-9.
& N 1161 RX. Rx41.1 Rx1. ," le au, Rx2 0 Rx7. R"
[General Formula XIII]
I-G' (Z G
Illit 11 lit qx, x.. x.
)i. 1 x zw . N,/,..R". õR._ Rx3 L 8 215 Za , N
R ZIP Y
, , -RX7 okx2. R. 0 Rx7 Xa and Xa' are independently selected from a bond or C1_6 alkylene;
Zx' and Zx are independently selected from among hydrogen, C1-8 alkyl, halogen, cyano, nitro, 0 14 R' Q,. - R t 30 I ' VVIA0 or ¨(CH2)m-OCH3;
, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 the respective R80' R9 and R1 are selected from among hydrogen, C1-8 alkyl, C2_6 alkenyl and C1-6 alkoxy; and m is an integer of 0 to 12.
[General Formula XII]
-G' G W1.
Nikb I. (nys x, x. x Rxs, 1 tem. Rxs 1 R"
N
..-9.
& N 1161 RX. Rx41.1 Rx1. ," le au, Rx2 0 Rx7. R"
[General Formula XIII]
I-G' (Z G
Illit 11 lit qx, x.. x.
)i. 1 x zw . N,/,..R". õR._ Rx3 L 8 215 Za , N
R ZIP Y
, , -RX7 okx2. R. 0 Rx7 Xa and Xa' are independently selected from a bond or C1_6 alkylene;
Zx' and Zx are independently selected from among hydrogen, C1-8 alkyl, halogen, cyano, nitro, 0 14 R' Q,. - R t 30 I ' VVIA0 or ¨(CH2)m-OCH3;
, FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 the respective R80' R9 and R1 are selected from among hydrogen, C1-8 alkyl, C2_6 alkenyl and C1-6 alkoxy; and m is an integer of 0 to 12.
56. The antibody conjugate or a pharmaceutically acceptable salt or solvate thereof according to Claim 1, characterized in that the active agent is selected from among the group comprising:
H H
0 t 4 '-'"" 0 Mt 0 HO ylr 1 OH
J N
0,....,............-..õ.0 OMe WO 1111 --41411141 H
HO:C f At IHO:C 0 4 õ 0111 HO I i OH
Nih--bs 0 .,...,..-N......,=-=,...,0 meo 110 H
N M*
N O
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 CO2Me 0 ,, TI HoiC 0 At,- HIV 0 , 8 IMO " 'OH '''tI91F
' N TO
= õ,,e,0 KO ' OH
ft 0%0, =
Lat.
Neo lir d, N
0 i 43 ''. IN. 140Me 0 ,, HOiC 0 it sisl!
HO
= No 0 HO2C
RPJ H 'OH 0' , MO I T ON
:1106..Npoõ...õ.N0,,,N.,,,Ort40)5146, OMe Me0 =:=, *
NO.0 7 ,, .07 A
HO iii kitot,,..eto0 .4weNotwis ,= 0 0 = 0 064 . 1-PI OM' WO
H
0 ,,, 0 NN/0.0401.
HOCyOyO HOIC70 iii HO'? .04 Milli` He ... OH
= sop 046õ,0 HO r 1 OH
Mk Pidle0 41Ir , N
Date Recue/Date Received 2021-08-09 H H
0 N.,õ.., tome HO:CV=0 HO.Cscy is HO' "OH IV HO" **OH
OH 0 o ci ,.õ, 0 HO f 1 OH
N -:(/e_,,3,,,, ,H
:... 4.d--N a 0,...õ..........õ,....õ..0 .
N "WI OMe Me H H
0 N '''''' OM e 0 N .,......."...04-.N.,,, N 3 H O:C 0 0 HOI,C crp 40 HO .' " OH
4.(if OH 0 ,..0 OH 0 ...,. 0 2d. '44 410 0 "=,"'''N= $0 N 0 Meeo , N ".4N
H 0p 7) HOC 0 HO ' ' OH HO:' .. 0 OH
OH 0 .,..0 H/eN IN * N-.1,4-Sis.,4 H H .
0 N''OMe HO:CV0C. , a Ho:ccip imi, HO .* "OH "P. HO*. .'' OH "Ilij OH 0 ,..,40 OH 0...,0 N -..,.N.
O.../"./"N.., *I
FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H H , CI --,-""'` OM e 0 N ,,,,..N., N 3 H 0:C y 0 yp,O so H OS 4i(Or0 at HO y. OH HO''' OH 0 ,0 OH 0 0 y N
0 .õ,..,....õ.õ...õ,., 0 0111 (00 01/le M e0 H
%
H H .
0 N NN,'"N-OM e 0 N.,,,,.,,,,.N
H 0:C c)D git H 0:C 7.
H 0 ' ." 0 H lit*P H 0 e *. 0 H
H 0 õ,,C) HO I I OH
0 ,,,.....",.....õ..-...õ...0 : =,,4,.',. :4 , uso am OM e M e0 H H , O N -.., ¨ 0 Me 0 H 0 N...VO4NH.
HO
H:Xj.Q0H = H1714XCIOH 4111 0...,0 HO I OH
ioid! 0 ...../..õ.õ...,,,O is i, N 0 Me Me0 .
H H
O s., N ,..., 0 OM e .
H 0 :CTO 040 HOV 0H 411 HO 's4T:11 *.' OH
H 0 0 OH 0 ,,,õ 0 HO I p.1 OH
N OM e M e0 o 6 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 , 0 Xirki 0 MIC's'N'eN0'^N''AINI N/A N H H
H .i 0 N ,,...0 +N H:
0 = 3 110 H 0:C H ,r,, oz. 0 0 ' 'CH
HO 1.,,, 1 OH
:;,.t. N
N OMe H H
0 N ====1".() ii e 0 N ./....0 4.¨N H2 .
a HO 2C itrO ,p y, * HO 2C 7 HO '' .10 H HO '''.(0 H *
0 H 0 ,õ.e,0 0 H 0 .õ() HO f 1 0 H
N N
., N OMe Me N ,,, M e0 0 M e H H H 0 .
0 N . ,,,-,õ
¨ OM e 0 N ..,..,,,,-....õN y.."...
1...
HO:C 73 H 0:C c,=,5:1 411 0 HO 'OH 4111 HO . ' OH
0 * N -- iSaii N OM e M e0 N
H:N,õ _ , 0 N .õ,,..0 ma 0, HO,C 0 0 HC10,r,..:()TO At 0 HOTJOH 411:1 HO' *.OH ..'*÷.
OH 0 ,C:) OH 0 HO 1 2, OH
........
, FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H , H H H : P 0 0 I'L =,...
-,- OM e 0 N
HOST:Ai!) 0 H 0.0 0 0 An 0 HO OH H O'VOH IIN"Pj H 0,..,0 H 0 ,y0 ai N --Sri.
OM e M 450 111=9 /
H H .
s'==00,eis, 0 N
HO...0 :ziO H 014 (...r.:2=2 . Sik HO ''.0H * H 0".. = CH
..,,e,0 HO I I CH
FL,ZA 401 .,,y=.,- . N'''*<4 N NH
OW L WO
0 ra 0 0,,,,....Ø.........,.Ø...........,,, H H , 0 NN"-%.0 M e 0 HO 2O sr.,:rr HOZC iisci. iit HO ** '0 H IF HO = ..*0 H IIIPP
0 H O õs0 0 H O õ,.,0 HO i I 0 H
N N
0 M e NH
1 L Me0 0 r0 0 ----~.0'^--- -NH2 0 -N H:
H H , 0 N , ,....
¨. 01,4 e C\ me) =",/N O
HO:C.õcrM o < Ali 0, ICI ,CO,H
HO
4"JHO")*N.%0H
' 'O
N
HO .YO 0 y = _ N wall 0,,,,,,0ts&
0 Me Me0 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 0 ''' 11.0,1110 0 ,. 114 4Ø1No4:2".õ1112 ' H 0:C 0 ,. HO:C 0 = MI, HO OH HO
H
47.0 = a 00 H 0 1- ro a _. 0A ii 0)04 0 N iii-µ Om. , -,- me0 . 0 0 õ,.....0õ.
HO:C 0 H 0 ' ."OH Mil) ' H
Ts?õ
oyo HO' soli H ovo rµo Niti thi of%1 dp0 14),00 0 Cl ir OU 0 M 00 111" i N4 N
H and 0 , N N..", Om e 0 ,,, HO:C4,,;,. ..0,190 )) 4 3 HO .. OH 11111P) NO
H 01020 0,u, 0 N N
...- 0,/,.....õ"õ4,0 16 .11,Lei4.
N lir OM e moo 1PF5 N
i .$ 0 o o o OW
(1)4411NooNsellrOv^e=Nr0.0"06NAli",v=AN
1'7 147 ND "ON* NO ON
IN =O
04 Ho t h, 1 0H
:01671giXI
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
H H
0 t 4 '-'"" 0 Mt 0 HO ylr 1 OH
J N
0,....,............-..õ.0 OMe WO 1111 --41411141 H
HO:C f At IHO:C 0 4 õ 0111 HO I i OH
Nih--bs 0 .,...,..-N......,=-=,...,0 meo 110 H
N M*
N O
FIMOSTON5259862.1 Date Recue/Date Received 2021-08-09 CO2Me 0 ,, TI HoiC 0 At,- HIV 0 , 8 IMO " 'OH '''tI91F
' N TO
= õ,,e,0 KO ' OH
ft 0%0, =
Lat.
Neo lir d, N
0 i 43 ''. IN. 140Me 0 ,, HOiC 0 it sisl!
HO
= No 0 HO2C
RPJ H 'OH 0' , MO I T ON
:1106..Npoõ...õ.N0,,,N.,,,Ort40)5146, OMe Me0 =:=, *
NO.0 7 ,, .07 A
HO iii kitot,,..eto0 .4weNotwis ,= 0 0 = 0 064 . 1-PI OM' WO
H
0 ,,, 0 NN/0.0401.
HOCyOyO HOIC70 iii HO'? .04 Milli` He ... OH
= sop 046õ,0 HO r 1 OH
Mk Pidle0 41Ir , N
Date Recue/Date Received 2021-08-09 H H
0 N.,õ.., tome HO:CV=0 HO.Cscy is HO' "OH IV HO" **OH
OH 0 o ci ,.õ, 0 HO f 1 OH
N -:(/e_,,3,,,, ,H
:... 4.d--N a 0,...õ..........õ,....õ..0 .
N "WI OMe Me H H
0 N '''''' OM e 0 N .,......."...04-.N.,,, N 3 H O:C 0 0 HOI,C crp 40 HO .' " OH
4.(if OH 0 ,..0 OH 0 ...,. 0 2d. '44 410 0 "=,"'''N= $0 N 0 Meeo , N ".4N
H 0p 7) HOC 0 HO ' ' OH HO:' .. 0 OH
OH 0 .,..0 H/eN IN * N-.1,4-Sis.,4 H H .
0 N''OMe HO:CV0C. , a Ho:ccip imi, HO .* "OH "P. HO*. .'' OH "Ilij OH 0 ,..,40 OH 0...,0 N -..,.N.
O.../"./"N.., *I
FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H H , CI --,-""'` OM e 0 N ,,,,..N., N 3 H 0:C y 0 yp,O so H OS 4i(Or0 at HO y. OH HO''' OH 0 ,0 OH 0 0 y N
0 .õ,..,....õ.õ...õ,., 0 0111 (00 01/le M e0 H
%
H H .
0 N NN,'"N-OM e 0 N.,,,,.,,,,.N
H 0:C c)D git H 0:C 7.
H 0 ' ." 0 H lit*P H 0 e *. 0 H
H 0 õ,,C) HO I I OH
0 ,,,.....",.....õ..-...õ...0 : =,,4,.',. :4 , uso am OM e M e0 H H , O N -.., ¨ 0 Me 0 H 0 N...VO4NH.
HO
H:Xj.Q0H = H1714XCIOH 4111 0...,0 HO I OH
ioid! 0 ...../..õ.õ...,,,O is i, N 0 Me Me0 .
H H
O s., N ,..., 0 OM e .
H 0 :CTO 040 HOV 0H 411 HO 's4T:11 *.' OH
H 0 0 OH 0 ,,,õ 0 HO I p.1 OH
N OM e M e0 o 6 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 , 0 Xirki 0 MIC's'N'eN0'^N''AINI N/A N H H
H .i 0 N ,,...0 +N H:
0 = 3 110 H 0:C H ,r,, oz. 0 0 ' 'CH
HO 1.,,, 1 OH
:;,.t. N
N OMe H H
0 N ====1".() ii e 0 N ./....0 4.¨N H2 .
a HO 2C itrO ,p y, * HO 2C 7 HO '' .10 H HO '''.(0 H *
0 H 0 ,õ.e,0 0 H 0 .õ() HO f 1 0 H
N N
., N OMe Me N ,,, M e0 0 M e H H H 0 .
0 N . ,,,-,õ
¨ OM e 0 N ..,..,,,,-....õN y.."...
1...
HO:C 73 H 0:C c,=,5:1 411 0 HO 'OH 4111 HO . ' OH
0 * N -- iSaii N OM e M e0 N
H:N,õ _ , 0 N .õ,,..0 ma 0, HO,C 0 0 HC10,r,..:()TO At 0 HOTJOH 411:1 HO' *.OH ..'*÷.
OH 0 ,C:) OH 0 HO 1 2, OH
........
, FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 H , H H H : P 0 0 I'L =,...
-,- OM e 0 N
HOST:Ai!) 0 H 0.0 0 0 An 0 HO OH H O'VOH IIN"Pj H 0,..,0 H 0 ,y0 ai N --Sri.
OM e M 450 111=9 /
H H .
s'==00,eis, 0 N
HO...0 :ziO H 014 (...r.:2=2 . Sik HO ''.0H * H 0".. = CH
..,,e,0 HO I I CH
FL,ZA 401 .,,y=.,- . N'''*<4 N NH
OW L WO
0 ra 0 0,,,,....Ø.........,.Ø...........,,, H H , 0 NN"-%.0 M e 0 HO 2O sr.,:rr HOZC iisci. iit HO ** '0 H IF HO = ..*0 H IIIPP
0 H O õs0 0 H O õ,.,0 HO i I 0 H
N N
0 M e NH
1 L Me0 0 r0 0 ----~.0'^--- -NH2 0 -N H:
H H , 0 N , ,....
¨. 01,4 e C\ me) =",/N O
HO:C.õcrM o < Ali 0, ICI ,CO,H
HO
4"JHO")*N.%0H
' 'O
N
HO .YO 0 y = _ N wall 0,,,,,,0ts&
0 Me Me0 FHBOSTON5259862.1 Date Recue/Date Received 2021-08-09 0 ''' 11.0,1110 0 ,. 114 4Ø1No4:2".õ1112 ' H 0:C 0 ,. HO:C 0 = MI, HO OH HO
H
47.0 = a 00 H 0 1- ro a _. 0A ii 0)04 0 N iii-µ Om. , -,- me0 . 0 0 õ,.....0õ.
HO:C 0 H 0 ' ."OH Mil) ' H
Ts?õ
oyo HO' soli H ovo rµo Niti thi of%1 dp0 14),00 0 Cl ir OU 0 M 00 111" i N4 N
H and 0 , N N..", Om e 0 ,,, HO:C4,,;,. ..0,190 )) 4 3 HO .. OH 11111P) NO
H 01020 0,u, 0 N N
...- 0,/,.....õ"õ4,0 16 .11,Lei4.
N lir OM e moo 1PF5 N
i .$ 0 o o o OW
(1)4411NooNsellrOv^e=Nr0.0"06NAli",v=AN
1'7 147 ND "ON* NO ON
IN =O
04 Ho t h, 1 0H
:01671giXI
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
57. A pharmaceutical composition for prevention or treatment of proliferative, cancer or angiogenetic disease, the composition comprising the antibody conjugate of Claim 1.
58. The pharmaceutical composition of Claim 57, further comprising a pharmaceutically efficacious amount of chemotherapeutic agent.
59. The pharmaceutical composition of Claim 57, characterized in that the cancer is selected from the group comprising lung cancer, small cell lung carcinoma, gastrointestinal cancer, colon cancer, intestinal cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma and melanoma.
60. A method for prevention of proliferative, cancer or angiogenetic disease, the method comprising a step of administering an individual with a pharmaceutically efficacious amount of the conjugate of Claim 1.
61. A method for treatment of proliferative, cancer or angiogenetic disease, the method comprising a step of administering an individual with a pharmaceutically efficacious amount of the conjugate of Claim 1.
62. A use for the conjugate of Claim 1 as a pharmaceutical composition for prevention or treatment of proliferative, cancer or angiogenetic disease.
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
HIBOSTON5259862.1 Date Recue/Date Received 2021-08-09
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20190025987 | 2019-03-06 | ||
KR10-2019-0025987 | 2019-03-06 | ||
KR1020200027373A KR102503143B1 (en) | 2019-03-06 | 2020-03-04 | Antibody-drug conjugate comprising antibody against human DLK1 and its use |
KR10-2020-0027373 | 2020-03-04 | ||
PCT/KR2020/003100 WO2020180121A1 (en) | 2019-03-06 | 2020-03-05 | Antibody-drug conjugates including antibody against human dlk1, and use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CA3129581A1 true CA3129581A1 (en) | 2020-09-10 |
Family
ID=72669539
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3129581A Pending CA3129581A1 (en) | 2019-03-06 | 2020-03-05 | Antibody-drug conjugates including antibody against human dlk1, and use thereof |
Country Status (6)
Country | Link |
---|---|
KR (1) | KR102503143B1 (en) |
CN (1) | CN112135638A (en) |
AU (1) | AU2020233532A1 (en) |
CA (1) | CA3129581A1 (en) |
IL (1) | IL285953A (en) |
SG (1) | SG11202108550PA (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111278860B (en) * | 2017-09-08 | 2024-03-29 | Y生物股份有限公司 | Antibodies against human DLK1 and uses thereof |
AU2019276833A1 (en) | 2018-05-29 | 2020-11-26 | Intocell, Inc. | Novel benzodiazepine derivatives and uses thereof |
WO2023107560A1 (en) * | 2021-12-07 | 2023-06-15 | The Regents Of The University Of California | Dlk1 antibodies and methods of treating cancer |
US20230190939A1 (en) * | 2021-12-21 | 2023-06-22 | Intocell, Inc. | Antibody drug conjugates comprising toxins with polar groups and uses thereof |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101573384B (en) * | 2006-10-27 | 2013-02-20 | 健泰科生物技术公司 | Antibodies and immunoconjugates and uses therefor |
MX2010003718A (en) * | 2007-10-19 | 2010-04-21 | Genentech Inc | Cysteine engineered anti-tenb2 antibodies and antibody drug conjugates. |
ES2527521T3 (en) * | 2008-03-17 | 2015-01-26 | Livtech Inc. | Anti-human antibodies against Dlk-1 that have antitumor activity |
WO2012138102A2 (en) * | 2011-04-04 | 2012-10-11 | 한국생명공학연구원 | Dlk1-specific human antibodies and pharmaceutical composition containing same |
CN113599533A (en) * | 2015-11-25 | 2021-11-05 | 乐高化学生物科学股份有限公司 | Antibody-drug conjugates comprising branched linkers and methods related thereto |
TWI822055B (en) * | 2016-11-21 | 2023-11-11 | 台灣浩鼎生技股份有限公司 | Conjugated biological molecules, pharmaceutical compositions and methods |
HUE056289T2 (en) * | 2017-02-08 | 2022-02-28 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
WO2018182341A1 (en) * | 2017-03-29 | 2018-10-04 | 주식회사 레고켐 바이오사이언스 | Pyrrolobenzodiazepine dimer precursor and ligand-linker conjugate compound thereof |
KR20190018400A (en) * | 2017-08-14 | 2019-02-22 | 주식회사 레고켐 바이오사이언스 | Antibody-drug conjugate comprising antibody binding to epidermal growth factor receptor variant III |
CN111278860B (en) * | 2017-09-08 | 2024-03-29 | Y生物股份有限公司 | Antibodies against human DLK1 and uses thereof |
-
2020
- 2020-03-04 KR KR1020200027373A patent/KR102503143B1/en active IP Right Grant
- 2020-03-05 CA CA3129581A patent/CA3129581A1/en active Pending
- 2020-03-05 SG SG11202108550PA patent/SG11202108550PA/en unknown
- 2020-03-05 CN CN202080001611.1A patent/CN112135638A/en active Pending
- 2020-03-05 AU AU2020233532A patent/AU2020233532A1/en active Pending
-
2021
- 2021-08-30 IL IL285953A patent/IL285953A/en unknown
Also Published As
Publication number | Publication date |
---|---|
SG11202108550PA (en) | 2021-09-29 |
KR102503143B1 (en) | 2023-02-24 |
AU2020233532A1 (en) | 2021-09-16 |
KR20200107837A (en) | 2020-09-16 |
CN112135638A (en) | 2020-12-25 |
IL285953A (en) | 2021-10-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3936150A1 (en) | Antibody-drug conjugates including antibody against human dlk1, and use thereof | |
US11707533B2 (en) | Antibody-drug conjugate comprising antibody against human ROR1 and use for the same | |
TWI727958B (en) | Anti-cd123 antibodies and conjugates and derivatives thereof | |
JP6671555B2 (en) | Pyrrolobenzodiazepine antibody conjugate | |
EP3342785B1 (en) | Linkers for antibody-drug conjugates | |
CN107148285B (en) | Pyrrolobenzodiazepine-antibody conjugates | |
CA3129581A1 (en) | Antibody-drug conjugates including antibody against human dlk1, and use thereof | |
BR112019028295A2 (en) | compounds comprising cleavable ligand and uses thereof | |
CA3202759A1 (en) | Mcl-1 inhibitor antibody-drug conjugates and methods of use | |
KR20210099658A (en) | Compounds comprising cleavable linkers and uses thereof | |
KR20210099660A (en) | Compounds comprising cleavable linkers and uses thereof | |
EP4257606A1 (en) | Preparation and use of anti-fshr antibody and antibody-drug conjugate thereof | |
JP2016511257A (en) | Administration of anti-GCC antibody-drug conjugates and DNA damaging agents in the treatment of cancer | |
RU2801630C2 (en) | Antibody-drug conjugates including antibody against human dlk1 and their use | |
TW202135864A (en) | Antibody-drug conjugate including antibodies to human dlk1 and uses thereof | |
KR20220158181A (en) | ROR1 and B7-H3 binding antibody-drug conjugate and use thereof | |
US20240058465A1 (en) | Anti-ror1 antibody conjugates, compositions comprising anti ror1 antibody conjugates, and methods of making and using anti-ror1 antibody conjugates | |
KR20210028556A (en) | Antibody-drug conjugate comprising antibody binding to antibody against human ROR1 and its use | |
KR20210063070A (en) | Antibody-drug conjugate comprising anti-B7-H3 antibody and its use | |
WO2023194800A1 (en) | Antibody-drug conjugate comprising antibody against human trop2 and use thereof | |
TW202400266A (en) | Ligand-drug conjugate and use thereof | |
TW202348252A (en) | Combination therapies for treatment of cancer with therapeutic binding molecules | |
TW202408589A (en) | Anti-ror1 antibodies and antibody conjugates, compositions comprising anti‑ror1 antibodies or antibody conjugates, and methods of making and using anti-ror1 antibodies and antibody conjugates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |
Effective date: 20210809 |
|
EEER | Examination request |
Effective date: 20210809 |
|
EEER | Examination request |
Effective date: 20210809 |
|
EEER | Examination request |
Effective date: 20210809 |
|
EEER | Examination request |
Effective date: 20210809 |
|
EEER | Examination request |
Effective date: 20210809 |
|
EEER | Examination request |
Effective date: 20210809 |
|
EEER | Examination request |
Effective date: 20210809 |
|
EEER | Examination request |
Effective date: 20210809 |
|
EEER | Examination request |
Effective date: 20210809 |