CN107849090A - 抗体药物偶联物 - Google Patents
抗体药物偶联物 Download PDFInfo
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- CN107849090A CN107849090A CN201680018919.0A CN201680018919A CN107849090A CN 107849090 A CN107849090 A CN 107849090A CN 201680018919 A CN201680018919 A CN 201680018919A CN 107849090 A CN107849090 A CN 107849090A
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- 239000000611 antibody drug conjugate Substances 0.000 title claims abstract description 22
- 229940049595 antibody-drug conjugate Drugs 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 125000005647 linker group Chemical group 0.000 claims abstract description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- VEGGTWZUZGZKHY-GJZGRUSLSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)-n-[4-(hydroxymethyl)phenyl]pentanamide Chemical compound NC(=O)NCCC[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)NC1=CC=C(CO)C=C1 VEGGTWZUZGZKHY-GJZGRUSLSA-N 0.000 claims 1
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 239000000562 conjugate Substances 0.000 abstract description 17
- RHJPBGWFGOAEID-BEDNPZBZSA-N chembl1256416 Chemical class C1([C@H](CC[C@H](C)[C@@H]2[C@H]([C@@H]3C[C@@]4(O[C@@](O)(CC(=O)O[C@H](CC(=O)O3)[C@@H](C)O)[C@H](C)CC4(C)C)O2)C)OC)=CC(O)=CC=C1Br RHJPBGWFGOAEID-BEDNPZBZSA-N 0.000 abstract description 7
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
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- 150000001412 amines Chemical class 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
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- -1 (dimethylamino) phosphine hexafluorophosphate Chemical compound 0.000 description 5
- 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 5
- 239000000047 product Substances 0.000 description 5
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- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 4
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 4
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- 238000000034 method Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 4
- 150000003053 piperidines Chemical class 0.000 description 4
- 229960001612 trastuzumab emtansine Drugs 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
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- 238000007920 subcutaneous administration Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
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- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 2
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 0 CC*C[C@@](CC**)C=*N Chemical compound CC*C[C@@](CC**)C=*N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
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- 230000010261 cell growth Effects 0.000 description 2
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
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- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
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- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- AGGWFDNPHKLBBV-YUMQZZPRSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=O AGGWFDNPHKLBBV-YUMQZZPRSA-N 0.000 description 1
- NNWYWNRCBPYLML-GWCFXTLKSA-N (2s)-2-amino-n-[(2s)-1-[4-(hydroxymethyl)anilino]-1-oxopropan-2-yl]-3-methylbutanamide Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)NC1=CC=C(CO)C=C1 NNWYWNRCBPYLML-GWCFXTLKSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-N 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 108010044540 auristatin Proteins 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
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- 201000011510 cancer Diseases 0.000 description 1
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical compound NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical class CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
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- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000006611 pharmacological activation Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
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- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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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
- A61K47/6889—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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Abstract
本发明公开了与抗体偶联的海兔毒素衍生物,其包含如式IV的海兔毒素衍生物部分。本发明提供了化合物和偶联物,如ADC(抗体药物偶联物),其中,基于肽的连接基团部分在其C末端具有以受控的方式与抗体上的Cys或Lys反应的连接点。
Description
技术领域
本发明提供一种抗体药物偶联物(式I),其包含如式II的海兔毒素衍生部分作为药物成分。
背景技术
海兔毒素,如天然产物海兔毒素10,及其合成衍生物一甲基澳瑞他汀E(Monomethyl Auristatin,MMAE)和一甲基澳瑞他汀F(MMAF),是显示强效抗肿瘤及抑制微管蛋白的产品。由于其具有高毒性,直接使用海兔毒素作为治疗剂没有效果。相反,将其与用于靶向递送的抗体偶联以便杀伤癌细胞。
概要
本发明提供了一种化合物,其包含如式IV的海兔毒素衍生部分。
式中,Y为OH或NH2,
R4为OH,NH2,F,Cl,Br,I,OR5,其中R5为C1-C4烷基。
本发明进一步提供一种具有式I结构的抗体药物偶联物或其药学上可接受的盐:
式中:
Ab为单克隆抗体
L1为连结物
L2为连接基团
D为具有式II结构的活性剂
式中Y为O或NH,波浪线表示连接点,
X为–CH2N3或式中R为C1-C8烷基,C3-C6环烷基,芳基或杂芳基。
n为1-8的整数。
优选地,L2选自:氨基酸,肽,-(CH2)n-,-(CH2CH2O)n-,对氨基苄基(PAB),Val-Cit(瓜氨酸)-PAB,Val-Ala-PAB,Ala-Ala-Asn-PAB或其组合。
优选地,-L1-L2选自下组:
优选地,Ab-L1-L2选自下组:
本发明进一步提供了用于合成具有式I结构的抗体药物偶联物或其药学上可接受的盐的合成方法。
式中:
Ab为单克隆抗体
L1为连结物
L2为连接基团
D为具有式II结构的活性剂
式中Y为O或NH,波浪线表示连接点,
X为–CH2N3或式中R为C1-C8烷基,C3-C6环烷基,芳基或杂芳基。
n为1-8的整数,包括
使式III化合物与Ab上的Lys反应
式中,G选自:-F,-Cl,-Br,-I,-N3,-OR,SR,-ONRR,RC(=O)O-和RSO2-O-;且
R为任意取代的烷基或任意取代的芳基,
m=0或1。
附图简要说明
图1显示通过静脉内给药,将单一剂量的偶联物16给予BALB/c裸鼠(n=8)。
图2显示通过静脉内给药,将单一剂量的偶联物16给予BALB/c裸鼠(n=8)。
图3显示了治疗后35天的小鼠的照片。
图4A显示ADC-23(抗Her2抗体)在一组肿瘤细胞系中的体外活性。
图4B显示ADC-16(抗Her2抗体)在一组肿瘤细胞系中的体外活性。
图5显示ADC-65,ADC-23和ADC-19在多种异种移植肿瘤模型中的体内功效。
图6A和6B显示通过静脉内给药,将单一剂量的偶联物16和19给予BALB/c裸鼠(n=8)。
详细说明
本发明提供了化合物和偶联物,如ADC(抗体药物偶联物),其中,基于肽的连接基团部分,在其C末端具有以受控的方式与抗体上的Cys或Lys反应的连接点。例如,对于Lys偶联,DAR(药物抗体比)为2。当在Cys上发生偶联时,大多数偶联物的DAR(药物抗体比)为4。
表1.用于Lys偶联到抗体上的药物-连接基团部分的结构的例子
表2.用于偶联到IgG类抗体的铰链区上的药物-连接基团化合物的结构(用于Cys缀合)的例子
表3.抗体(Ab)-药物偶联物的结构的例子
定义
缩略语定义如下:
Ac 乙酰基
aq. 水性
BOC或Boc 叔丁氧基羰基
BrOP 溴代三(二甲基氨基)膦鎓六氟磷酸盐
Bu 正丁基
℃ 摄氏度
Cit 瓜氨酸
DCM 二氯甲烷
DEPC 氰基膦酸二乙酯
DIC 二异丙基碳二亚胺
DIEA 二异丙基乙胺
DMA N,N'-二甲基乙酰胺
DMF N,N'-二甲基甲酰胺
EDC 1-乙基-3-(3-二甲氨基丙基)碳二亚胺
Et 乙基
EtOAc 乙酸乙酯
Eq 化学当量
Fmoc 9-芴甲氧羰基
g 克
h 小时
HATU 2-(1H-7-氮杂苯并***-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐
HOBT N-羟基苯并***
HOSu N-羟基琥珀酰亚胺
HPLC 高效液相色谱法
LC/MS 液相色谱-质谱联用
Me 甲基
MeOH 甲醇
MeCN 乙腈
mL 毫升
MS 质谱
PAB 对氨基苯
RP-HPLC 反相高效液相色潽法
rt 室温
t-Bu 叔丁基
TEA 三乙胺
Tert,t 叔
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
μL 微升
一般合成程序-从酸形成活化酯(如NHS)
将酸溶于DCM(二氯甲烷)中,如果需要,加入DMF(N,N'-二甲基甲酰胺)以帮助溶解。加入N-羟基琥珀酰亚胺(1.5化学当量),然后加入EDC·HCl(1-乙基-3-(3-二甲氨基丙基)碳二亚胺)(1.5化学当量)。将反应混合物在室温下搅拌1小时,直到大部分酸被消耗。通过RP-HPLC监测反应进程。然后将混合物用DCM稀释并依次用柠檬酸(10%水溶液)和盐水洗涤。将有机层干燥并浓缩至干。粗产物任选地通过RP-HPLC或硅胶柱色谱纯化。
实施例1
制备化合物1
将含有哌啶4-羧酸(60mg)的NaHCO3(1mL)的饱和盐溶液,加入到含有化合物47(0.1mmol)在THF(3mL)的粗溶液中。将混合物在室温下搅拌30分钟,然后用1N的HCl水溶液酸化pH=4-5。将反应混合物浓缩,残余物通过反相HPLC纯化,得到冻干后的白色粉末状化合物1(68mg)。MS m/z 1020.7(M+H)。
实施例2
制备化合物2
将化合物52(185mg,0.2mmol)溶于DCM/DMF(5/1,v/v,5mL)中。加入EDC.HCl(0.5mmol)、HOSu(0.3mmol)。将混合物在室温下搅拌30分钟。HPLC分析证实化合物52全部被消耗。用DCM(50mL)稀释反应体系并用盐水洗涤。将有机层浓缩至1mL,用乙腈/水(6/4,v/v,3mL)稀释。加入饱和水性NaHCO3(1mL)配制的吡咯烷3-羧酸(60mg)溶液。将混合物在室温下搅拌10分钟。反应物用HOAc酸化并浓缩。粗产物用RP-HPLC纯化,得到化合物2(138mg,68%)。MS m/z 1020.6(M+H)。
实施例3
制备化合物4
制备化合物38:
将HATU(217mg,0.57mmol)、DIEA(362μL,2.08mmol)、胺36(213mg,0.52mmol)加入化合物37(261mg,0.52mmol)的6mL DMF溶液中。将混合物搅拌30分钟后,加入400μL哌啶并搅拌10分钟。将混合物蒸发并通过HPLC纯化,得到化合物38(171mg,60%)。MS m/z 548.3(M+H)。
制备化合物40:
将HATU(59mg,0.15mmol)、DIEA(108μL,0.6mmol)、胺38(102mg,0.15mmol)加入化合物39(37mg,0.15mmol)的4mL DMF溶液中。将混合物搅拌30分钟后,蒸发至干。残余物溶于2mL DCM中后,加入1mL TFA并搅拌10分钟。将混合物蒸发并通过HPLC纯化,得到化合物40(94mg,78%)。MS m/z 673.4(M+H)。
制备化合物4:
将HATU(48mg,0.12mmol)、DIEA(83μL,0.48mmol)、胺40(94mg,0.12mmol)加入化合物41(85mg,0.12mmol)的2mL DMF溶液中。将混合物搅拌30分钟后,加入1mL的90mg NaOH水溶液并搅拌30分钟。通过HPLC纯化混合物,得到化合物4(86mg,58%)。MS m/z 1239.7(M+H)。
实施例4
制备化合物6
制备化合物46:
将HATU(640mg,1.68mmol)、DIEA(870μL,5.00mmol)、胺45(535mg,1.67mmol)加入化合物41(1000mg,1.67mmol)的20mL DMF溶液中。将混合物搅拌30分钟后,蒸发并通过HPLC纯化,得到化合物46(1140mg,70%)。MS m/z 865.5(M+H)。
制备化合物47:
将二(对硝基苯)碳酸酯(210mg,0.69mmol)、DIEA(35μL,0.2mmol)加入化合物46(500mg,0.57mmol)的10mL DMA溶液中。将混合物搅拌18小时后,加入100mL***,过滤收集沉淀物,得到化合物47(500mg,85%)。MS m/z 1030.6(M+H)。
制备化合物49:
将HOBt(7mg,0.05mmol)、DIEA(21μL,0.12mmol)、胺48(40mg,0.12mmol)加入化合物47(125mg,0.12mmol)的4mL DMF溶液中。将混合物搅拌16小时后,加入200μL哌啶并搅拌10分钟。将混合物蒸发并通过HPLC纯化,得到化合物49(72mg,60%)。MS m/z 1005.6(M+H)。
制备化合物6:
将DIEA(15μL,0.086mmol)、DIEA(50μL,0.288mmol)、酸酐50(19mg,0.027mmol)加入化合物49(30mg,0.027mmol)的2mL DCM溶液中。将混合物搅拌30分钟后,蒸发并通过HPLC纯化,得到化合物6(32mg,88%)。MS m/z 1347.5(M+H)。
实施例5
制备化合物7
如化合物6的合成所述,由化合物49(0.1mmol)和酐63(0.1mmol)合成化合物7。产率:79%。MS m/z 1296.8(M+H)。
实施例6
制备化合物8
将化合物64(0.15mmol,67mg)的乙腈/水(1/1,v/v,1mL)溶液加入化合物47(0.1mmol)的THF(3mL)溶液中,然后加入DIEA(50μL)。30分钟后,将反应物酸化并浓缩。残余物通过反相HPLC纯化,得到白色固体化合物8(87mg)。MS m/z 1243.6[M+H]+。
实施例7
制备化合物9
制备化合物52:
将K2CO3(118mg,0.85mmol)、溴乙酸酯51(35mg,0.18mmol)加入化合物46(120mg,0.12mmol)的3mL DMF溶液中。混合物搅拌16小时,然后蒸发。残余物溶于2mL DCM中,过滤,并加入2mL TFA。20分钟后,蒸发并HPLC纯化,得到化合物52(92mg,83%),MS m/z 923.5(M+H)。
制备化合物53:
将HATU(38mg,0.1mmol)、DIEA(70μL,0.4mmol)、肼羧酸叔丁酯(15mg,0.12mmol)加入化合物52(92mg,0.1mmol)的2mL DMF溶液中。混合物搅拌30小时,蒸发至干。将残余物溶于2mL DCM中,然后加入1mL TFA并搅拌10分钟。混合物蒸发并HPLC纯化,得到化合物53(82mg,78%),MS m/z 937.5(M+H)。
制备化合物9:
将DIC(10mg,0.078mmol)加入化合物54(53mg,0.156mmol)的2mL DCM溶液中,搅拌10分钟。然后加入DIEA(54μL,0.312mmol)、胺53(82mg,0.078mmol),混合物搅拌15分钟。混合物蒸发并经HPLC纯化,得到化合物9(62mg,63%),MS m/z 1260.5(M+H)。
实施例8
制备化合物13
将HATU(110mg,0.29mmol)、DIEA(175μL,1mmol)、胺36(110mg,0.27mmol)加入化合物37(130mg,0.26mmol)的3mL DMF溶液中。将混合物搅拌30分钟,然后浓缩至干。将残余物用TFA/DCM(1/4,v/v,5mL)处理30分钟。将混合物蒸发并通过HPLC纯化,得到化合物66(108mg,65%)。MS m/z 670.5(M+H)。
将HATU(48mg,0.12mmol)、DIEA(83μL,0.48mmol)、胺66(94mg,0.12mmol)加入化合物41(85mg,0.12mmol)的2mL DMF溶液中。将混合物搅拌30分钟后,加入哌啶(0.2mL)并搅拌30分钟。将混合物浓缩并通过HPLC纯化,得到化合物67(87mg,63%)。MS m/z 1028.7(M+H)。
将PyBrOP(0.055mmol)、DIEA(35μL)加入化合物67(57mg,0.05mmol)和酸68(22mg)的DCM/DMF(3/1,v/v,4mL)溶液中。将混合物在室温下搅拌30分钟后,浓缩至约2mL。残余物通过反相HPLC纯化,得到化合物13(41mg)。MS m/z 1425.7(M+H)。
实施例9.
该实施例提供了在特定细胞中,体外测定指定药物偶联抗体的EC50测定的结果。所使用的抗体是抗HER2IgG类抗体。
实施例10
该实施例显示ADC16(抗Her2抗体偶联物)在皮下N87异种移植模型中的体内功效。图1显示通过静脉内给药,将单一剂量的偶联物16给予BALB/c裸鼠。每组8只小鼠,共6组小鼠进行了研究:3组以不同剂量注射T-DM1(曲妥珠单抗-DM1偶联物);2组以不同剂量注射ADC16;和一运载体对照组。所有药物以相同的方式施用(单次剂量)。以1mg/kg或3mg/kg静脉内给予单剂量的ADC-16的效果分别优于3mg/kg或10mg/kg的T-DM1。并且3mg/kg的ADC-16完全抑制肿瘤生长达100天。
实施例11
该实施例显示在皮下N87异种移植模型中ADC16(抗Her2抗体偶联物)的体内安全性。图2显示通过静脉内给药,将单一剂量的偶联物16给予BALB/c裸鼠。每组8只小鼠,共7组小鼠进行了研究:3组以不同剂量注射T-DM1(曲妥珠单抗-DM1偶联物);3组以不同剂量注射ADC16;一运载体对照组。所有药物以相同的方式施用(单次剂量)。以1mg/kg、3mg/kg或10mg/kg静脉内给予单剂量的ADC-16不妨碍小鼠体重增加。T-DM1和ADC-16组之间的体重差异是由肿瘤重量的差异引起的。图3显示了治疗后35天的小鼠的照片。
实施例12
该实施例(图4A)显示在乳腺癌细胞系中,与MMAE偶联物相比,ADC-23诱导相当或更强的抗增殖活性。在这些研究中,细胞均用ADC-23或MMAE偶联物处理3天。IC50测定为显示50%细胞生长抑制的浓度。
实施例13
该实施例(图4B)显示在乳腺癌细胞系中,与MMAE偶联物相比,ADC-16诱导相当或更强的抗增殖活性。在上述研究中,细胞均用ADC-16或MMAE偶联物处理3天。IC50测定为显示50%细胞生长抑制的浓度。
实施例14
该实施例(图5)显示了在LoVo(结肠),MDA-MB-468(乳腺),BxPC-3(胰腺),PA-1(卵巢)以及H1975NSCLC异种移植裸鼠中,ADC-65,ADC-23和ADC-19的体内功效。所有ADC均在指定浓度下通过静脉内单剂量给药。在大多数情况下,ADC的测试效果表现优于MMAF,并且单剂量完全抑制肿瘤生长。
实施例15
该实施例显示在皮下N87异种移植模型中,ADC19(抗Her2抗体偶联物)的体内安全性和功效。图6A和6B显示通过静脉内给药,将单一剂量偶联物19给予BALB/c裸鼠。每组8只小鼠,共3组小鼠进行研究:1组小鼠注射ADC16;1组小鼠注射ADC19;和一运载体对照组。所有药物以相同的方式施用(单次剂量)。以2mg/kg静脉内给予单剂量的ADC-19的效果与相同剂量的ADC-16相当,并且完全抑制肿瘤生长达49天,与ADC-16相比不妨碍小鼠体重增加。
实施例16
该实施例显示了用于合成抗体药物偶联物16,17,19和64的通用偶联方法。以部分或连续流动的方式向在含0-30%有机溶剂的pH6.0-9.0的缓冲液中的0.5-50mg/mL抗体加入0.1-10当量的活化药物连接基团偶联物(1,或2,或3,或4,或5,或62)。在轻微搅拌或摇动下,在0-40℃下反应0.5-50小时,用HIC-HPLC监测。所得到的粗ADC产物经历了必要的下游步骤,其中使用现有技术方法进行脱盐,缓冲液更换/配制,以及任选的纯化。ADC产物通过HIC-HPLC,SEC,RP-HPLC和任选的LC-MS表征。
实施例17
该实施例显示了用于合成抗体药物偶联物21,22,23,24,28和65的通用偶联方法。在pH 5.0-9.0的某些缓冲溶液(例如PBS)中向0.5-50mg/mL的抗体溶液中加入0.5-100当量的还原剂,例如TCEP和DTT。在轻微搅拌或摇动下,在0-40℃下还原0.5-40小时,然后通过柱或超滤除去还原剂。向含有0-30%的有机共溶剂,如DMA的pH 5.0-9.0的某些缓冲溶液(例如PBS)配制的还原抗体(0.5-50mg/mL)中加入0.5-10当量的药物-连接基团反应物(选自化合物6-15或63)。反应在0-40℃下进行0.5-40小时,同时温和搅拌或摇动,通过HIC-HPLC监测。所得到的粗ADC产物经历了必要的下游步骤,其中使用现有技术方法进行脱盐,缓冲液更换/配制,以及任选的纯化。最终的ADC产品通过HIC-HPLC,SEC,RP-HPLC和任选的LC-MS表征。
Claims (5)
1.一种具有式IV的化合物,
其中,Y为OH或NH2,
R4为OH,NH2,F,Cl,Br,I,OR5,其中R5为C1-C4烷基。
2.一种具有式I结构的抗体药物偶联物(ADC),
或其药学上可接受的盐,
式中:
Ab为单克隆抗体
L1为连结物
L2为连接基团,其选自:氨基酸,肽,-(CH2)n-,-(CH2CH2O)n-,PAB,Val-Cit-PAB,Val-Ala-PAB,Ala-Ala-Asn-PAB及其组合;
其中-L1-L2选自下组:
其中Ab-L1-L2为
D为具有式II结构的活性剂
式中Y为O或NH,
X为CH2N3或式中R为C1-C8烷基,C3-C6环烷基,芳基或杂芳基。
3.如权利要求2所述的ADC,其中X为–CH2N3。
4.如权利要求2所述的ADC,其中X为式中R为C1-C8烷基,C3-C6环烷基,芳基或杂芳基。
5.如权利要求2所述的ADC,其中式I的结构具有选自下组的结构:
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112341521A (zh) * | 2019-08-09 | 2021-02-09 | 上海翰森生物医药科技有限公司 | 一种小分子活性化合物及其抗体偶联物、其制备方法和医药用途 |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6239598B2 (ja) | 2012-05-15 | 2017-11-29 | ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. | 薬物複合体、複合体形成方法、およびその使用 |
CA2934030A1 (en) | 2013-10-15 | 2015-04-23 | Sorrento Therapeutics Inc. | Drug-conjugates with a targeting molecule and two different drugs |
PL3086815T3 (pl) | 2013-12-27 | 2022-06-13 | Zymeworks Inc. | Układy łącznikowe dla koniugatów leków zawierające ugrupowanie sulfonamidowe |
WO2016041082A1 (en) | 2014-09-17 | 2016-03-24 | CDRD Ventures, Inc. | Cytotoxic and anti-mitotic compounds, and methods of using the same |
CN107849090A (zh) | 2015-01-28 | 2018-03-27 | 索伦托医疗有限公司 | 抗体药物偶联物 |
CN106729743B (zh) * | 2015-11-23 | 2021-09-21 | 四川科伦博泰生物医药股份有限公司 | 抗ErbB2抗体-药物偶联物及其组合物、制备方法和应用 |
CN107029244B (zh) * | 2016-02-04 | 2021-04-27 | 浙江昭华生物医药有限公司 | 抗her2抗体-药物偶联物及其应用 |
US10517958B2 (en) | 2016-10-04 | 2019-12-31 | Zymeworks Inc. | Compositions and methods for the treatment of platinum-drug resistant cancer |
WO2018069851A2 (en) * | 2016-10-11 | 2018-04-19 | Sorrento Therapeutics, Inc. | C-met antibody drug conjugate |
CN108285487B (zh) * | 2017-01-08 | 2021-02-19 | 浙江昭华生物医药有限公司 | 抗5t4抗体-药物偶联物及其应用 |
EP3617221A4 (en) | 2017-04-19 | 2021-04-14 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | CYTOTOXIN AND CONJUGATE, USES THEREOF AND MANUFACTURING PROCESSES THEREFORE |
EP3641831A1 (en) * | 2017-06-20 | 2020-04-29 | Sorrento Therapeutics, Inc. | Cd38 antibody drug conjugate |
CN107744592B (zh) * | 2017-09-15 | 2020-04-28 | 四川大学 | 抗cd56抗体与海兔毒素偶联复合物及其制备方法和用途 |
FR3112547B1 (fr) * | 2020-07-20 | 2023-01-20 | Mc Saf | Composés capables de se lier à des protéines et conjugués obtenus à partir de ces composés |
JP2024509169A (ja) | 2021-03-03 | 2024-02-29 | ソレント・セラピューティクス・インコーポレイテッド | 抗bcma抗体を含む抗体-薬物コンジュゲート |
WO2023173026A1 (en) | 2022-03-10 | 2023-09-14 | Sorrento Therapeutics, Inc. | Antibody-drug conjugates and uses thereof |
TW202400247A (zh) * | 2022-05-10 | 2024-01-01 | 美商索倫多醫療公司 | 包含抗folr1抗體之抗體藥物結合物 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013173391A1 (en) * | 2012-05-15 | 2013-11-21 | Concortis Biosystems, Corp | Drug-conjugates, conjugation methods, and uses thereof |
Family Cites Families (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6569834B1 (en) | 1992-12-03 | 2003-05-27 | George R. Pettit | Elucidation and synthesis of antineoplastic tetrapeptide w-aminoalkyl-amides |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
AU689131B2 (en) | 1993-10-01 | 1998-03-26 | Teikoku Hormone Mfg. Co., Ltd. | Novel peptide derivative |
EP1334114A2 (en) * | 2000-10-25 | 2003-08-13 | Mayo Foundation For Medical Education And Research | Transcobalamin binding conjugates useful for treating abnormal cellular proliferation |
US20090068178A1 (en) | 2002-05-08 | 2009-03-12 | Genentech, Inc. | Compositions and Methods for the Treatment of Tumor of Hematopoietic Origin |
DK1545613T3 (da) * | 2002-07-31 | 2011-11-14 | Seattle Genetics Inc | Auristatinkonjugater og deres anvendelse til behandling af cancer, en autoimmun sygdom eller en infektiøs sygdom |
DE10254439A1 (de) | 2002-11-21 | 2004-06-03 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Tubulysine, Herstellungsverfahren und Tubulysin-Mittel |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
KR101520209B1 (ko) | 2003-11-06 | 2015-05-13 | 시애틀 지네틱스, 인크. | 리간드에 접합될 수 있는 모노메틸발린 화합물 |
US20070134243A1 (en) | 2004-12-01 | 2007-06-14 | Gazzard Lewis J | Antibody drug conjugates and methods |
CA2594636A1 (en) | 2005-01-31 | 2006-08-10 | Genentech, Inc. | Anti-ephb2 antibodies and methods using same |
AR059900A1 (es) | 2006-03-17 | 2008-05-07 | Genentech Inc | Anticuerpos anti-tat226 e inmunoconjugados |
US20110263650A1 (en) | 2007-07-20 | 2011-10-27 | Helmholtz-Zentrum Für Infektions-Forschung Gmbh | Tubulysin D Analogues |
AU2009270988A1 (en) | 2008-07-15 | 2010-01-21 | Genentech, Inc. | Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds |
EP2174947A1 (en) | 2008-09-25 | 2010-04-14 | Universität des Saarlandes | Bioactive pre-tubulysins and use thereof |
CA2749115C (en) | 2009-01-09 | 2022-06-21 | Seattle Genetics, Inc. | Weekly dosing regimens for anti-cd30 vc-pab-mmae antibody drug-conjugates |
EA201201120A1 (ru) | 2010-02-08 | 2013-03-29 | Эдженсис, Инк. | Конъюгаты антитело-лекарственное средство (adc), которые связываются с белками 161p2f10b |
EP2579897A1 (en) | 2010-06-08 | 2013-04-17 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
EP2409983A1 (en) | 2010-07-19 | 2012-01-25 | Leibniz-Institut für Pflanzenbiochemie (IPB) | Tubulysin analogues |
EP2621508B1 (de) | 2010-09-29 | 2015-08-26 | Seattle Genetics, Inc. | N-carboxyalkyl-auristatine und ihre verwendung |
CA2818713C (en) | 2010-12-02 | 2019-03-26 | Nerviano Medical Sciences S.R.L. | Process for the preparation of morpholinyl anthracycline derivatives |
KR20200128601A (ko) | 2011-05-27 | 2020-11-13 | 암브룩스, 인코포레이티드 | 비-천연 아미노산 연결된 돌라스타틴 유도체를 함유하는 조성물, 이를 수반하는 방법, 및 용도 |
MX371526B (es) | 2011-05-27 | 2020-01-31 | Ambrx Inc | Composiciones que contienen, metodos que incluyen, y usos de derivados de dolastatina enlazados a aminoacidos no naturales. |
US8815226B2 (en) | 2011-06-10 | 2014-08-26 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
CN103648532A (zh) | 2011-06-21 | 2014-03-19 | 伊缪诺金公司 | 具有肽连接子的新型美登木素生物碱衍生物及其偶联物 |
JP2015500287A (ja) | 2011-12-05 | 2015-01-05 | アイジェニカ・バイオセラピューティクス・インコーポレイテッドIgenica Biotherapeutics,Inc. | 抗体−薬物のコンジュゲート、ならびに関連する化合物、組成物および方法 |
AU2013270686B2 (en) | 2012-06-07 | 2016-11-10 | Ambrx, Inc. | Prostate-specific membrane antigen antibody drug conjugates |
CN111499684A (zh) | 2012-06-19 | 2020-08-07 | Ambrx公司 | 抗cd70抗体药物结合物 |
MX2015000314A (es) | 2012-07-09 | 2015-04-10 | Genentech Inc | Anticuerpos anti-cd79b e inmunoconjugados. |
WO2014107024A1 (ko) * | 2013-01-03 | 2014-07-10 | 셀트리온 | 항체-링커-약물 결합체, 그의 제조방법 및 그를 포함하는 항암제 조성물 |
CA2934030A1 (en) | 2013-10-15 | 2015-04-23 | Sorrento Therapeutics Inc. | Drug-conjugates with a targeting molecule and two different drugs |
JP2018502149A (ja) | 2014-12-08 | 2018-01-25 | ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. | c−Met抗体薬物コンジュゲート |
CN107849090A (zh) | 2015-01-28 | 2018-03-27 | 索伦托医疗有限公司 | 抗体药物偶联物 |
CN107635405A (zh) | 2015-02-06 | 2018-01-26 | 索伦托医疗有限公司 | 抗体药物缀合物 |
-
2016
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- 2016-01-28 EP EP22175524.2A patent/EP4137159A1/en active Pending
- 2016-01-28 US US15/009,775 patent/US10590165B2/en active Active
- 2016-01-28 WO PCT/US2016/015482 patent/WO2016123412A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013173391A1 (en) * | 2012-05-15 | 2013-11-21 | Concortis Biosystems, Corp | Drug-conjugates, conjugation methods, and uses thereof |
WO2013173392A1 (en) * | 2012-05-15 | 2013-11-21 | Concortis Biosystems, Corp | Drug-conjugates, conjugation methods, and uses thereof |
WO2013173393A1 (en) * | 2012-05-15 | 2013-11-21 | Concortis Biosystems, Corp | Drug-conjugates, conjugation methods, and uses thereof |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112341521A (zh) * | 2019-08-09 | 2021-02-09 | 上海翰森生物医药科技有限公司 | 一种小分子活性化合物及其抗体偶联物、其制备方法和医药用途 |
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