CN111001012A - 一种亲水碳酸酯型抗体偶联药物 - Google Patents
一种亲水碳酸酯型抗体偶联药物 Download PDFInfo
- Publication number
- CN111001012A CN111001012A CN201910915742.XA CN201910915742A CN111001012A CN 111001012 A CN111001012 A CN 111001012A CN 201910915742 A CN201910915742 A CN 201910915742A CN 111001012 A CN111001012 A CN 111001012A
- Authority
- CN
- China
- Prior art keywords
- hydrophilic
- compound
- unit
- drug
- carbonate
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 87
- 229940079593 drug Drugs 0.000 title claims abstract description 80
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 title claims abstract description 20
- 230000008878 coupling Effects 0.000 title description 10
- 238000010168 coupling process Methods 0.000 title description 10
- 238000005859 coupling reaction Methods 0.000 title description 10
- 229940049595 antibody-drug conjugate Drugs 0.000 claims abstract description 59
- 239000000611 antibody drug conjugate Substances 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 150000001413 amino acids Chemical class 0.000 claims description 12
- 235000001014 amino acid Nutrition 0.000 claims description 11
- 229940024606 amino acid Drugs 0.000 claims description 11
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 claims description 10
- 239000003446 ligand Substances 0.000 claims description 8
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 6
- 239000004472 Lysine Substances 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 6
- 235000018417 cysteine Nutrition 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 5
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 5
- 235000013922 glutamic acid Nutrition 0.000 claims description 5
- 239000004220 glutamic acid Substances 0.000 claims description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- 125000006850 spacer group Chemical group 0.000 claims description 5
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 4
- 102000004243 Tubulin Human genes 0.000 claims description 4
- 108090000704 Tubulin Proteins 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000004474 valine Substances 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 3
- 208000035473 Communicable disease Diseases 0.000 claims description 3
- 239000012624 DNA alkylating agent Substances 0.000 claims description 3
- 229940126161 DNA alkylating agent Drugs 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-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
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 3
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims description 3
- 239000004473 Threonine Substances 0.000 claims description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 3
- 235000004279 alanine Nutrition 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 235000009697 arginine Nutrition 0.000 claims description 3
- 235000009582 asparagine Nutrition 0.000 claims description 3
- 229960001230 asparagine Drugs 0.000 claims description 3
- 235000003704 aspartic acid Nutrition 0.000 claims description 3
- 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 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 229940125532 enzyme inhibitor Drugs 0.000 claims description 3
- 239000002532 enzyme inhibitor Substances 0.000 claims description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 3
- 235000004554 glutamine Nutrition 0.000 claims description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000002955 immunomodulating agent Substances 0.000 claims description 3
- 230000002584 immunomodulator Effects 0.000 claims description 3
- 229940121354 immunomodulator Drugs 0.000 claims description 3
- 208000015181 infectious disease Diseases 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
- 229960000310 isoleucine Drugs 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 2
- 108010038807 Oligopeptides Proteins 0.000 claims description 2
- 102000015636 Oligopeptides Human genes 0.000 claims description 2
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 claims description 2
- 230000002924 anti-infective effect Effects 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 208000026278 immune system disease Diseases 0.000 claims description 2
- 239000000138 intercalating agent Substances 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 claims description 2
- 125000003729 nucleotide group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 36
- 238000001727 in vivo Methods 0.000 abstract description 11
- 239000002253 acid Substances 0.000 abstract description 8
- 230000000857 drug effect Effects 0.000 abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 162
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- 238000006243 chemical reaction Methods 0.000 description 64
- 150000001875 compounds Chemical class 0.000 description 48
- 230000015572 biosynthetic process Effects 0.000 description 38
- 238000003786 synthesis reaction Methods 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 238000004809 thin layer chromatography Methods 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 25
- 125000005647 linker group Chemical group 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 229910052757 nitrogen Inorganic materials 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
- 239000000203 mixture Substances 0.000 description 18
- 239000000427 antigen Substances 0.000 description 17
- 108091007433 antigens Proteins 0.000 description 17
- 102000036639 antigens Human genes 0.000 description 17
- 238000001035 drying Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- 239000007858 starting material Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000005406 washing Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 11
- 238000011068 loading method Methods 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000007821 HATU Substances 0.000 description 9
- 239000000562 conjugate Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- -1 aminomethoxy Chemical group 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000000178 monomer Substances 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 5
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 239000000084 colloidal system Substances 0.000 description 4
- 229940125833 compound 23 Drugs 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical class C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 description 3
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 3
- AXKGIPZJYUNAIW-UHFFFAOYSA-N (4-aminophenyl)methanol Chemical compound NC1=CC=C(CO)C=C1 AXKGIPZJYUNAIW-UHFFFAOYSA-N 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- 206010010144 Completed suicide Diseases 0.000 description 3
- 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 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940125878 compound 36 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229960004275 glycolic acid Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229960004768 irinotecan Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 238000002741 site-directed mutagenesis Methods 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 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
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Inorganic materials Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[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@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N anhydrous diethylene glycol Natural products OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 108091092356 cellular DNA Proteins 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 229960005215 dichloroacetic acid Drugs 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 210000003712 lysosome Anatomy 0.000 description 2
- 230000001868 lysosomic effect Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 2
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 229960001860 salicylate Drugs 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 1
- FLDNDAMSCINJDX-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-trimethylsilylethyl carbonate Chemical compound C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O FLDNDAMSCINJDX-UHFFFAOYSA-N 0.000 description 1
- CTYHQVFFQRDJSN-LHEWISCISA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[[(4-methoxyphenyl)-diphenylmethyl]amino]hexanoic acid Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)NCCCC[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 CTYHQVFFQRDJSN-LHEWISCISA-N 0.000 description 1
- AJDUMMXHVCMISJ-ZDUSSCGKSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-5-phenylmethoxypentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCC(=O)OCC1=CC=CC=C1 AJDUMMXHVCMISJ-ZDUSSCGKSA-N 0.000 description 1
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 1
- 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 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- 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 1
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 1
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- DJQYYYCQOZMCRC-UHFFFAOYSA-N 2-aminopropane-1,3-dithiol Chemical group SCC(N)CS DJQYYYCQOZMCRC-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 description 1
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000006306 Antigen Receptors Human genes 0.000 description 1
- 108010083359 Antigen Receptors Proteins 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 230000007118 DNA alkylation Effects 0.000 description 1
- 239000012623 DNA damaging agent Substances 0.000 description 1
- 239000012625 DNA intercalator Substances 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- SBJKKFFYIZUCET-JLAZNSOCSA-N Dehydro-L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(=O)C1=O SBJKKFFYIZUCET-JLAZNSOCSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHAHEQEKNJCSD-UHFFFAOYSA-N Dihydroasparagusic acid Natural products OC(=O)C(CS)CS KRHAHEQEKNJCSD-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical group SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 108091005461 Nucleic proteins Chemical group 0.000 description 1
- 102000016979 Other receptors Human genes 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 230000004099 anaerobic respiration Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000003452 antibody preparation method Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 108010044540 auristatin Proteins 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- VPYJBEIOKFRWQZ-UHFFFAOYSA-N benzyl 2-hydroxyacetate Chemical compound OCC(=O)OCC1=CC=CC=C1 VPYJBEIOKFRWQZ-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- JYGAZEJXUVDYHI-UHFFFAOYSA-N dihydroartemisininic acid Natural products C1CC(C)=CC2C(C(C)C(O)=O)CCC(C)C21 JYGAZEJXUVDYHI-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 231100000782 microtubule inhibitor Toxicity 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- ULRUOUDIQPERIJ-PQURJYPBSA-N sacituzumab govitecan Chemical compound N([C@@H](CCCCN)C(=O)NC1=CC=C(C=C1)COC(=O)O[C@]1(CC)C(=O)OCC2=C1C=C1N(C2=O)CC2=C(C3=CC(O)=CC=C3N=C21)CC)C(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN(N=N1)C=C1CNC(=O)C(CC1)CCC1CN1C(=O)CC(SC[C@H](N)C(O)=O)C1=O ULRUOUDIQPERIJ-PQURJYPBSA-N 0.000 description 1
- 229950000143 sacituzumab govitecan Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000008467 tissue growth 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
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
本发明提供一种亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐。本发明提供的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，可在肿瘤弱酸性微环境中有效释放药物，获得对肿瘤更好的体内药效，可在高DAR下获得很好的体内PK。
Description
技术领域
本发明公开一种亲水碳酸酯型抗体药物偶联物。更具体而言，本发明中连接子以碳酸酯键与药物连接，在连接子中通过亲水氨基酸改善ADC药物PK特征。
背景技术
抗体偶联药物(ADC)作为新型的靶向药物，一般由三部分组成：抗体或抗体类配体，小分子药物以及将配体和药物偶联起来的连接子。抗体偶联药物利用抗体对抗原的特异性识别，将药物分子运输至靶细胞附近并有效释放药物分子，达到治疗目的。2011年8月，美国食品药品监督管理局(FDA)批准西雅图基因公司研制的用于治疗霍奇金淋巴瘤以及复发性变性大细胞淋巴瘤(ALCL)的ADC新药AdecteisTM上市，临床应用证明了此类药物的安全性和有效性。
ADC药物抗体主要作用为靶向传递功能，最终发挥药效为所偶联的药物分子。目前应用于ADC领域的药物分子根据作用机制不同分为：微管抑制剂、DNA损伤剂、拓扑异构酶抑制剂、RNA聚合酶抑制剂、蛋白翻译抑制剂等。
在ADC药物中，抗体将药物分子靶向携带至肿瘤细胞附近，与肿瘤细胞表面抗原靶点结合，通过内化作用进入细胞内释放药物分子。由于抗体与靶点结合的特异性，药物只能进入特定靶点表达的肿瘤细胞，而对异质性明显的肿瘤来说，其他无特定抗原表达的肿瘤细胞无法被有效杀灭。碳酸酯型抗体偶联药物可有效解决该问题，肿瘤在快速生长过程中由于氧气供应减少，无氧呼吸增加，导致肿瘤微环境中PH呈现弱酸性。碳酸酯在肿瘤弱酸性环境中释放药物，后利用药物的跨膜作用，非选择性的杀灭抗原表达及非表达肿瘤细胞。
抗体-药物偶联物设计中的另一项重要因素是，每个靶向剂能够递送的药物的量(即，连接至各靶向剂(例如，抗体)的细胞毒剂的数量，称为药物载量(drug load)或载药量(drug loading)或DAR)。曾经有假设认为，较高的药物载量将优于较低的药物载量(例如，8-单位载量对比4-单位载量)。该理论是，载药量更高的偶联物将向靶细胞递送更多的药物(细胞毒剂)。该理论由如下观察结果支持：具有较高载药量的偶联物在体外对于细胞系具有较高的活性。然而，后续某些研究揭示，该假设在动物模型中并没有得到证实。观察到，具有某种奥瑞他汀的4或8单位药物载量的偶联物在小鼠模型中具有相似活性。参见例如，Hamblett等，Clinical Cancer Res.10:7063-70(2004).Hamblett等进一步报道了更高载体的ADC在动物模型中将被更快的清除出循环。该更快的清除表明，较高载量的物质相比较低载量的物质的PK更加不稳定的倾向，参见Hamblett等。另外，较高载量的偶联物在小鼠中有较低的MTD，并且因此具有较窄的报告治疗指数。相反，报告单克隆抗体中工程改造的位点处载药量为2的ADC具有与某些4-单位载量ADC相比相同或更好的PK性质和治疗指数。例如，参见Junutula等，Clinical Cancer Res.16:4769(2010).因此，近期的趋势是开发具有低载药量的ADC。
专利CN104755494描述了一类依喜替康ADC，其核心为以四肽为酶切片段，搭配氨甲氧基为自我消除结构，采用非定点偶联技术实现DAR＝8。然而，其缺陷显而易见，在高DAR下，分子亲水性不足，导致依喜替康ADC体内药效降低。
IMMUNOGEN公司开发的IMMU132通过长链PEG改善亲水性，但众所周知，在分子主链中引入长链PEG对亲水性改善的效果有限并且将导致分子流动性降低。
发明内容
本发明的目的在于公开一种亲水碳酸酯型抗体药物偶联物。更具体而言，本发明中连接子以碳酸酯键与药物连接，在连接子中通过亲水氨基酸改善ADC药物PK特征。
为了实现以上目的，本发明采用的技术方案为：如结构式(I)的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，
其中，A为能与靶点结合的配体部分；
D为含羟基的药物单元；
La为任意的连接单元；
Lb为由2-3个亲水氨基酸组成的亲水单元；
Lc为间隔单元，间隔单元Lc与药物单元D之间通过碳酸酯键连接，药物单元D与碳酸酯共用氧原子；
n选自2-20的整数。
具体的，所述连接单元La连接单元La包含结构：
其中，L2为
或单键；
n1-n5分别选自1～8的整数。
优选的，药物单元D为微管蛋白结合剂、DNA烷化剂、DNA嵌入剂、酶抑制剂、免疫调控剂、肽、核苷酸中的至少一种。
优选的，组成亲水单元Lb的亲水氨基酸为(D/L)丙氨酸、(D/L)精氨酸、(D/L)天冬酰胺、(D/L)天冬氨酸、(D/L)半胱氨酸、(D/L)谷氨酰胺、(D/L)谷氨酸、(D/L)甘氨酸、(D/L)组氨酸、(D/L)异亮氨酸、(D/L)亮氨酸、(D/L)赖氨酸、(D/L)甲硫氨酸、(D/L)苯丙氨酸、(D/L)脯氨酸、(D/L)丝氨酸、(D/L)苏氨酸、(D/L)色氨酸、(D/L)酪氨酸、(D/L)缬氨酸、(R/S)2、3-二氨基丙酸中的至少一种。
优选的，接单元Lc包含以下结构，
其中，R为任选的取代基团。
优选的，R为H、卤素、C1-4的烷基、OR1、SR1、NR1R2、SO2R1、CONHR1、CN、COOR1中的至少一种，其中，R1和R2可独立的选自于H、C1-4的烃基、苯基或者取代苯基。
更加优选的，亲水单元Lb为由(D/L)谷氨酸，(D/L)赖氨酸，(R/S)2、3-二氨基丙酸中的至少一种组成的寡肽。
更加优选的，亲水单元Lb选自以下结构或其药学上可接受的盐：
本发明还提供上述亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐的药物组合物。所述药物组合物为抗肿瘤药物、抗免疫疾病药物、抗感染性疾病药物，其中，抗肿瘤药物中包括抗癌药物。
本发明人在对抗体偶联药物构效关系综合理解的基础上，设计出一种具有亲水单元的碳酸酯型ADC，并通过实验惊奇的发现，该类ADC药物很好的利用了肿瘤微环境释放药物，并通过亲水氨基酸有效提高其载药量，同时降低上述聚集现象发生，改善药物PK，在体内模型中获得理想的药效。
发明提供的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐用于治疗有此需要的患者时，向患者给予上述亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐或包含其的药物组合物，患者患有肿瘤、自身免疫疾病或感染性疾病，并且所述的药物-配体偶联物的抗体特异性结合至所述癌症、自身免疫疾病的靶细胞。
发明人经过广泛而深入的研究，惊奇的发现具有亲水结构的碳酸酯型抗体药物偶联物具有很好的的体内外药效。
缩写和定义
除非另有说明，否则如本文所用的以下术语和短语旨在具有以下含义。当本文中使用商标名称时，除非上下文中另有指明，否则商标名称包括所述商标名称产品的产品配方、通用药物和活性药物成分。
除非本文中另有说明，文中所用的化合物的“衍生物”是指具有与化合物相似的化学结构但还含有至少一个化合物中不存在的化学基团和/或缺少至少一个化合物中存在的化学基团的物质。衍生物所比较的化合物被称为“母体”化合物。通常，“衍生物”可在一个或多个化学反应步骤中由母体化合物产生。
如本文所用“亲水”是指在水中有较高溶解性，与亲酯性相对。
本文中所述“碳酸酯”是指化学单元
该化学结构在一定条件下可通过释放二氧化碳断裂。
本文中所述“亲水氨基酸”是指具有高水溶性的氨基酸，包括丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸、2、3-二氨基丙酸及其衍生物。
本文中所述“微管蛋白结合剂”是指通过与细胞内微管蛋白结合，影响细胞微管聚合/解聚的药物，例如包括但不限于MMAE、MMAF及其衍生物等。
本文中所述“DNA烷化剂”是指通过与细胞DNA作用，导致DNA烷基化而杀灭细胞的药物，例如包括但不限于PBD、CBI等。
本文中所述“DNA嵌入剂”是指通过与细胞DNA作用，嵌入DNA双链结构，而杀灭细胞的药物。
本文中所述“酶抑制剂”是指与特定酶发生可逆/不可逆结合，影响细胞正常功能而杀灭细胞的药物。例如包括但不限于喜树碱类化合物：喜树碱，羟基喜树碱，SN-38，依喜替康，伊立替康等。
本文中所述“免疫调节剂”是指通过调节免疫功能而发挥药效的药物。
本文所述的各种亲水氨基酸均包括天然或非天然构型。
本文中所述“间隔单元”是指在两个相隔的化学单元之间的间隔连接单元，包括但不限于有烷基、亚烷基、氧醚键、酰胺键、二硫键、聚PEG单元等组成。
本文所述的“烃基”是指结构中包含碳、氢的饱和或不饱和结构单元。
本文所述的“取代基”是指各种给电子/吸电子基团，例如包括但不限于羟基、烷基、取代烷基、硝基、氰基、醛基、羧基、卤素氟、氯、溴、碘等。
术语“payload”是指linker+药物单元，可与抗体等生物大分子连接，最终释放毒素发挥作用。
如本文所用，“抗体”或“抗体单元”在其所属的范围内，包括抗体结构的任何部分。这一单元可以结合，反应性关联，或者络合一个受体，抗原，或者靶向细胞群体具有的其它受体单元。抗体可以是任何蛋白或蛋白类分子，它可以结合，络合，或者与待治疗或生物改造的细胞群体的一部分发生反应。在一些实施方式中，连接子共价连接至抗体的硫原子。在一些方面中，硫原子是半胱氨酸残基的硫原子，其形成抗体的链间二硫键。在另一方面中，硫原子是已经导入配体单元的半胱氨酸残基的硫原子，其形成抗体的链间二硫键。在另一方面中，硫原子是已经导入配体单元的半胱氨酸残基的硫原子(例如，通过定点诱变或化学反应)。在其他方面中，连接子结合的硫原子选自形成抗体的链间二硫键的半胱氨酸残基或已经引入配体单元的额半胱氨酸残基(例如，通过定点诱变或化学反应)。在一些实施方式中，按照Kabat(Kabat E.A等，(1991))《免疫学感兴趣的蛋白质序列》(Sequences ofproteins of Immunological Interest),第五版，NIH出版物91-3242)中的EU索引编号系统。
本发明中组成抗体药物偶联物的抗体最好保持其原有野生状态时的抗原结合能力。因此，本发明中的抗体能够，最好专一性的与抗原结合。涉及的抗原包括，例如，肿瘤相关抗原(TAA)，细胞表面受体蛋白和其他细胞表面分子，细胞存活调节因子，细胞增殖调节因子，与组织生长与分化相关的分子(如已知或预知的具有功能性的)，淋巴因子，细胞因子，参与细胞循环调节的分子，参与血管生成的分子，以及与血管生成有关的分子(如已知或预知的具有功能性的)。肿瘤相关因子可以是簇分化因子(如CD蛋白)。
本文所述应用在抗体药物偶联物中的抗体包括，但不局限于，针对细胞表面受体和肿瘤相关抗原的抗体。这样的肿瘤相关抗原是业内所熟知的，可以通过业内熟知的抗体制备方法和信息来制备。为了开发可用于癌症诊断与治疗的有效的细胞水平目标物，研究人员力图找寻跨膜或其他肿瘤相关多肽。这些目标物能够特异性的表达在一种或多种癌细胞表面，而在一种或多种非癌细胞表面表达很少或不表达。通常，相对于非癌细胞表面而言，这样的肿瘤相关多肽在癌细胞表面更加过度表达。确认这样的肿瘤相关因子，可大大提高基于抗体治疗癌症的专一靶向特性。
肿瘤相关抗原包括但不局限于业内所熟知的肿瘤相关抗原。与肿瘤相关抗原对应的核酸和蛋白序列可参见公开数据库，例如Genbank。抗体靶向对应的肿瘤相关抗原包括所有的氨基酸序列变种和同种，与参考文献中确认的序列具有至少70％，80％，85％，90％，或者95％的同源性，或者具备与引用文献中的肿瘤相关抗原序列具有完全一致的生物性质和特征。
术语“抑制”指，减少了可检测的量，或完全阻止。
术语“癌症”指的是以失调的细胞生长为特征的生理病症或疾病。“肿瘤”包括癌细胞。
术语“自身免疫疾病”是源自针对个体自身的组织或蛋白质的疾病或紊乱。
本文中所用“定点偶联”优选为定点突变抗体原有氨基酸至半胱氨酸或在抗体中插入一个半胱氨酸或一段含半胱氨酸的多肽，通过以上方法引入的半胱氨酸巯基与连接子中的丁二酰亚胺相偶联。“非定点偶联”方式为通过利用抗体原有的链间二硫键与连接子-毒素相偶联。
本文中所用的短语“药学上可接受的盐”指的是，化合物(例如，药物，药物-接头或配体-接头-药物偶联物)的药学上可接收到有机或无机盐。该化合物可含有至少一个氨基或羧基，并且因此可与相应的酸或碱形成加成盐。示例性的盐包括但不限于：硫酸盐、三氟乙酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸性磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、水杨酸盐、甲酸盐、本甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐，钾盐、钠盐等。另外，药学上可接受的盐在结构中具有超过一个的带点原子。其中多个带电原子是药学上可接受的盐的一部分的示例能有多个抗衡例子。例如，药学上可接受的盐具有一个或多个带电原子和/或一个或多个抗衡原子。
另一方面，药物并不仅仅局限于上述提到的类别，还包括所有可用于抗体药物偶联物的药物。
按照在细胞内药物释放的机制，如本文所用，“连接单元”或“抗体药物偶联物的连接单元”可被分为两类：不可断裂连接单元和可断裂连接单元。
对于含有不可断裂连接单元的抗体药物偶联物，其药物释放机制为：偶联物与抗原结合并被细胞内吞后，抗体在溶酶体中被酶解，释放出由小分子药物，连接子，和抗体氨基酸残基共同组成的活性分子。由此带来的药物分子结构改变并不减弱其细胞毒性，但由于活性分子是带电荷的(氨基酸残基)，从而导致其不能渗入邻近细胞。因此，此类活性药物不能杀死邻近不表达靶向抗原(抗原阴性细胞)的肿瘤细胞(旁观者效应，bystandereffect)(Ducry等，2010，Bioconjugate Chem.21:5-13)。
对pH值敏感的连接子，通常又称为酸断裂连接子。这样的连接子在血液的中性环境下相对稳定(pH7.3-7.5)，但是在弱酸性的内涵体(pH5.0-6.5)和溶酶体(pH4.5-5.0)内将会被水解。第一代的抗体药物偶联物大多应用这类连接子，例如腙，碳酸酯，缩醛，缩酮类。由于酸断裂连接子有限的血浆稳定性，基于此类连接子的抗体药物偶联物通常具有较短的半衰期(2-3天)。这种较短的半衰期在一定程度上限制了pH敏感连接子在新一代抗体药物偶联物中的应用。
自杀式连接子一般嵌合在可断裂连接子与活性药物之间，或者本身就是可断裂连接子的一部分。自杀式连接子的作用机制是：当可断裂连接子在合宜的条件下断裂后，自杀式连接子能够自发的进行结构重排，进而释放与之连接的活性药物。常见的自杀式连接子包括对氨基苄醇类(PAB)和β-葡萄糖醛酸苷类(β-Glucuronide)等。
本专利可以使用以下缩写并具有指定的定义：
缩写和符号：
Boc：叔丁氧羰基；
PyBOP：1H-苯并三唑-1-基氧三吡咯烷基鏻六氟磷酸盐；
Cit：瓜氨酸；
CO2：二氧化碳；
DCM：二氯甲烷；
DIPEA：二异丙基乙胺；
DMF：二甲基甲酰胺；
DMSO：二甲基亚砜；
DPBS：杜氏磷酸盐缓冲液；
DTPA：二乙基三胺五乙酸；
DTT：二硫苏糖醇；
EA：乙酸乙酯；
EDTA：乙二胺四乙酸；
FBS：胎牛血清；
HATU：O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯；
H2O：水；
HOBt：1-羟基苯并三唑；
mAb：单克隆抗体；
MEM：最低基础培养基；
MTS：3-(4,5-二甲基噻唑-2-基)-5-(3-羧甲酯基)-2-(4-磺苯基)-2H-四唑，内盐；
MTT：3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐；
PAB：对氨基苯甲氧基；
PBS：磷酸盐缓冲液；
Sodium Pyruvate：丙酮酸钠；
THF：四氢呋喃；
TLC：薄层色谱法；
Tris：三羟甲基氨基甲烷；
Val：缬氨酸；
Trt-Cl：三苯基氯甲烷；
TBTU：O-(1H-苯并三唑-1-基)-N,N,N’,N’-四甲基异脲四氟化硼；
HOBT：1-羟基苯并三唑；
TFA：三氟醋酸；
TBS-Cl：叔丁基二甲基氯硅烷；
HOSu：N-羟基丁二酰亚胺；
Na2CO3：碳酸钠；
EDCI：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
药学上可接受的赋形剂包括任何载体，稀释剂，佐剂或赋形剂，如防腐剂和抗氧剂，填充剂，崩解剂，湿润剂，乳化剂，悬浮剂，溶剂，分散介质，包衣剂，抗细菌剂和抗真菌剂和吸收延迟剂等。这样的介质和药剂用于药物活性物质的使用在本领域时公知的。除了任何常规的介质或试剂与活性成分不相容以外，其在治疗组合物中的用途也被考虑到。作为合适的治疗组合，还可以将补充的活性成分掺入组合物中。
本发明的主要优点在于：
1、本发明提供的一种碳酸酯型抗体偶联药物，可在肿瘤弱酸性微环境中有效释放药物，获得对肿瘤更好的体内药效。
2、本发明提供的亲水碳酸酯型抗体偶联药物，可在高DAR下获得很好的体内PK。
附图说明
图1为带亲水碳酸酯型抗体药物偶联物在A431模型中的体内药效；
图2为接受带亲水碳酸酯型抗体药物偶联物小鼠体重变化情况。
具体实施方式
下面结合具体实施例，进一步阐述本发明，应理解，这些实施例只用于说明本发明，而不用于限制本发明的范围。下列实施例中未注明具体条件的试验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比例、比率、或份数按重量计。
除非另行定义，文中所使用的所有专业和科学用于与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
本发明下列实施例中采用的通用步骤是：
通用步骤A
偶联制备ADC
将通过初步的纯化后单体率大于95％的抗体分子，使用超滤离心管换液至含有EDTA的磷酸盐缓冲液中，浓度10mg/ml。加入10倍于抗体摩尔分子数的TCEP，室温下反应2h。使用超滤离心管换液至pH6.5的磷酸缓冲液中，再加入10倍于抗体摩尔分子数的DHAA，室温下反应2h。加入10倍于抗体摩尔分子数的TCEP，室温下反应8h。打开抗体链间二硫键，并用Ellman方法测定游离巯基数，判断二硫键是否全部打开。然后加入10倍于抗体摩尔分子数的payload，室温下反应8h。反应结束后，使用截留分子量为30KDa的超滤离心管换液至PBS中，并去除未偶联的payload。
实施例1-6
实施例1化合物1的合成
单口瓶中加入Fmoc-Lys(MMT)-OH(2g，3.2mmol，1eq)，PABOH(788.16mg，6.4mmol，2eq)，HATU(1.34g，3.52mmol，1.1eq)，DIEA(1.24g，9.6mmol，3eq)及20mlDMF，搅拌溶解后氮气保护，25℃反应；点板检测，赖氨酸反应完全。向反应液中加入200ml水，有大量固体析出，EA(60ml)萃取3次，有机相用盐水洗涤三次，无水硫酸钠干燥，旋干得黄色油状物2.85g。将上步中间体用20ml二乙胺溶解，氮气保护，25℃反应；点板检测，原料反应完全。将溶剂旋干并加入100ml EA溶解，盐水洗涤三次，无水硫酸钠干燥，旋干得产品浅棕色油状物2.58g。柱层析纯化条件：以DCM：MeOH＝100:1至50:1为流动相剂进行梯度洗脱，得产品白色泡状固体750mg。
H1NMR(400MHz,CDCl3):8.01(s,1H),7.63-7.65(m,2H),7.32-7.40(m,6H),7.29-7.31(m,8H),6.87-6.89(m,2H),4.62(s,2H),3.84(s,3H),3.37(t,1H),2.55(m,2H),1.89(m,2H),1.40(m,2H),1.24(m,2H).
实施例2化合物2的合成
单口瓶中加入化合物1(300mg，0.574mmol，1eq)，N3(PEG)8COOH(350mg，0.631mmol，1.1eq)，HOBT(85mg，0.631mmol，1.1eq)，DIEA(149mg，1.15mmol，2.0eq)及4ml干燥DMF，氮气保护，冰水浴降温搅拌溶清；加入HATU(240mg，0.631mmol，1.1eq)，25℃反应；点板检测，至化合物1反应完全。
后处理：向反应液中加入50ml水，EA(50mlx3)萃取，有机相用盐水洗涤三次，无水硫酸钠干燥，旋干得浅黄色油状物920mg。薄层板制备纯化：用DCM：MeOH＝15:1为展开剂展开一次，纯化得产品淡黄色油状物500mg。
实施例3化合物3的合成
单口瓶中加入化合物TBS-SN38 250mg，0.5mmol，1.5eq)、DMAP(183mg，1.5mmol，4.5eq)及重蒸的10ml DCM，溶清后氮气保护，加入三光气(52mg，0.175mmol，0.52eq)，室温反应，反应液变浑浊，搅拌30s后澄清；点板检测，化合物TBS-SN38反应完全，加入化合物2(353mg，0.333mmol，1.0eq)；点板检测，化合物2反应完全，加入3ml甲醇淬灭反应，旋干得黄色固体900mg。薄层板制备纯化：用DCM：MeOH＝10:1为展开剂展开一次，纯化得产品微黄色固体化合物3 350mg。
实施例4化合物4的合成
单口瓶中加入化合物3(350mg，0.215mmol，1.0eq)及DCM，溶解后氮气保护；加入1MTBAF溶液(0.537ml，2.5eq)，反应液变为橙黄色，加入冰醋酸(1.07mmol)，颜色变为金黄色，25℃反应；点板检测，化合物3反应完全，后处理。反应液加入100ml DCM稀释，盐水洗涤三次，无水硫酸钠干燥，旋干得产品化合物4 410mg。
实施例5化合物5的合成
单口瓶中加入化合物4(400mg，0.273mmol，1eq)、SMCC-氨基乙炔(186mg，0.682mmol，2.5eq)及10mlDMSO，搅拌溶解后氮气保护，加入CuBr(78mg，0.546mmol，2eq)及2.5ml水，25℃搅拌反应；
反应液中有胶体生成，附于瓶底；取胶体及反应液，DCM溶解，水洗后点板，化合物4反应完全，后处理。
反应液倒入100ml水中，有大量固体析出，DCM(60mlx3)萃取，有机相用盐水洗涤三次，无水硫酸钠干燥旋干得黄色固体化合物5 550mg。
实施例6化合物6的合成
单口瓶中加入550mg化合物5、1ml苯甲醚及10mlDCM，氮气保护，溶清，冰水浴降温；加入2ml二氯乙酸，保持冰水浴，反应液变为黄色；升至25℃反应；点板检测，化合物5反应完全。30℃旋去大部分溶剂，加入20ml甲叔醚析晶，有大量黄色固体析出，冰水浴降温固化1h，过滤，油泵干燥，得粗品黄色粉末350mg。
HPLC制备纯化：C18制备液相柱，以乙腈-水(0.9％TFA)为流动相进行梯度洗脱，冻干后共得产品黄色粉末化合物6 130mg，LC-MS：[M+H]+＝1480.69。
实施例7化合物7的合成
将化合物起始物料(CAS:162558-25-0,100g,0.235mol)溶于DCM/DMF(400ml/100ml)的混合溶液中，再加入碳酸铯(152.8g，0.47mol)、碘化钾5g。室温下滴加苄溴(100.2g，0.586mol)，滴完室温搅拌反应过夜。TLC监测(PE:EA＝3:1)至原料反应完。加入纯化水搅拌分液，有机层再用NaCl水洗一次，加入无水硫酸钠干燥，40℃减压浓缩掉大部分DCM，加入PE析晶，过滤，得白色固体。再用石油醚搅洗一次，得产品化合物7 60g。
实施例8化合物8的合成
将60g化合物7溶于200ml DCM中，未完全溶清，加入TFA 80ml，溶清，室温下搅拌发应2-3小时。TLC监测(PE:EA＝3:1)至原料反应完。40℃减压旋干，再加入甲苯带两次，得黄色油状物化合物8，直接投下一步。
实施例9化合物9的合成
将上步所得化合物8(0.116mol)溶于300ml二氯甲烷中，水浴下缓慢加入三乙胺(48.5ml，0.35mol)。滴完水浴下继续滴加Cbz-Cl(27.8g，0.163mol)，滴完室温搅拌反应过夜。TLC监测(DCM:MeOH＝5:1)至原料反应完全。加入纯化水，萃取，收集DCM层再用0.1M/L的稀盐酸水溶液、NaCl水溶液各洗一次。无水硫酸钠干燥，过滤，40℃减压浓缩干得浅黄色油状物化合物9 56g。(可用DCM/异丙醚重结晶纯化)
实施例10化合物10的合成
将50g化合物9溶于400mlDCM中，再加入80ml哌啶，室温下搅拌反应2-3小时，TLC监测(PE:EA＝3:1)至原料反应完。40℃减压旋干，得白色固体化合物10。不纯化直接投下一步。
实施例11化合物11的合成
将上步所得化合物10(0.091mol)溶于400mlDMF中，再加入TBTU(87.6g,0.273mol)、HOBT(36.9g,0.273mol)、Boc-Glu(OBzl)-OH(30.7g,0.091mol)、DIEA(45ml,0.273mol)搅拌溶清，室温搅拌下反应5小时，TLC监测(DCM:MeOH＝10:1)至原料反应完全。加入纯化水、EA萃取，EA层再用NaCl水溶液洗一次。无水硫酸钠干燥，过滤，40℃减压浓缩干得浅黄色油状物粗品80g。经柱层析纯化(PE:EA＝8:1→5:1→3:1→2:1)得产品化合物1138g,LC-MS：[M+H]+＝648.3。
实施例12化合物12的合成
将38g化合物11溶于200mlDCM中，溶清，加入80mlTFA，室温下搅拌发应2-3小时。TLC监测(PE:EA＝3:2)至原料反应完。40℃减压旋干，再加入甲苯带两次，得油状物，直接投下一步。
实施例13化合物13的合成
将上步所得化合物12(0.0587mol)溶于300mlDCM中，冰水浴下缓慢加入DIEA(29ml，0.176mol)，加完再加入二甘醇酐(6.8g，0.0587mol)，撤去冰水浴室温下搅拌反应1小时，TLC监测(DCM:MeOH＝10:1)至原料反应完全。40℃减压旋干，得油状物80g。经柱层析纯化(DCM:MeOH＝40:1→20:1→10:1)得产品化合物13 35g,LC-MS：[M+H]+＝664.2。
实施例14化合物14的合成
将13(35g，0.0528mol)溶于200mlDMF中，再加入HATU(24g，0.063mol)、HOBT(8.5g，0.063mol)、DIEA(21ml，0.063mol)、对氨基苄醇(7.76g，0.063mol)搅拌溶清，室温下搅拌反应。TLC监测(DCM:MeOH＝6:1)至原料反应完全。加入纯化水、EA萃取，EA层再用NaCl水溶液洗一次。无水硫酸钠干燥，过滤，40℃减压浓缩干得油状物。经柱层析纯化(DCM:MeOH＝50:1→25:1→10:1)得产品化合物14 30g,LC-MS：[M+H]+＝769.1。
TBS-羟基乙酸苄酯的合成
将羟基乙酸苄酯(10g，0.06mol)溶于100mlDCM，再加入咪唑(4.9g，0.072mol)，搅拌溶清，冰水浴。缓慢滴加TBS-Cl(10.8g，0.072mol)，滴完室温搅拌反应。TLC监测(PE:EA＝3:1)至原料反应完。加入纯化水萃取，DCM层再用NaCl水溶液洗一次。无水硫酸钠干燥，过滤，40℃减压浓缩干得油状物。
TBS-羟基乙酸的合成
将TBS-羟基乙酸苄酯(14g)溶于甲醇，再加入5％Pd/C(4.2g)，氢气置换两次，室温搅拌下反应2-3小时。TLC监测(PE:EA＝3:1)至原料反应完。过滤，40℃减压旋干，得油状物。经柱层析纯化(PE:EA＝3:1→DCM:MeOH＝50:1→25:1→10:1)得油状物TBS-羟基乙酸5g。
实施例15化合物15的合成
将依喜替康(300mg，0.565mmol)、PyBOP(600mg，1.13mmol)溶于DMF，未溶清。加入DIEA(0.56ml，3.39mmol)很快溶清，加入TBS-羟基乙酸(322mg，1.7mmol)，室温下搅拌反应。TLC监测(DCM:MeOH＝8:1)至原料反应完全。加入纯化水、EA萃取，EA层再用NaCl水溶液洗一次。无水硫酸钠干燥，过滤，40℃减压浓缩干得油状物。刮板纯化：DCM:MeOH＝15:1，得产品白色固体化合物15 250mg，LC-MS：[M+H]+＝608.2。
实施例16化合物16的合成
将化合物15(250mg，0.411mmol)、DMAP(500mg，4.11mmol)溶于20ml
重蒸DCM中，氮气保护下加入三光气(122mg，0.411mmol)。室温下搅拌反应15min。TLC监测(DCM:MeOH＝12:1)至原料反应完全。水泵减压抽5min，边抽边通入氮气。再加入化合物14(475mg，0.616mmol)反应15min。TLC监测(DCM:MeOH＝12:1)至酰氯反应完全。室温下减压旋干。刮板纯化：DCM:MeOH＝10:1，得产品化合物16 380mg，LC-MS：[M+H]+＝1402.1。
实施例17化合物17的合成
将化合物16(380mg，0.271mmol)溶于40mLDCM中，再加入65μL冰乙酸，1M TBAF/THF溶液(0.81mL，0.814mmol)，加完继续搅拌反应2-3小时。TLC监测(EA:MeOH＝15:1)至原料反应完全。室温下减压旋干。刮板纯化：EA:MeOH＝12:1，得产品化合物17 270mg，LC-MS：[M+H]+＝1288.5。
实施例18化合物18的合成
将化合物17(270mg，0.21mmol)溶于150ml甲醇中，基本溶清。加入5％Pd/Ba SO4(108mg)，氢气置换两次，室温下搅拌反应6小时。HPLC监测反应。反应结束后，过滤，40℃减压浓缩干，直接投下一步。
实施例19化合物19的合成
将上步所得化合物18溶于5mL超干DMF，再加入MC-OSu(97mg，0.315mmol)、DIEA(104μL，0.63mmol)室温下搅拌反应1小时。HPLC监测反应。反应结束后，室温下油泵减压旋干，制备纯化得产物化合物19 50mg，LC-MS：[M+H]+＝1168.1。
实施例20化合物20的合成
将SN38-OTBS(396mg，0.78mmol)、DMAP(286mg，2.34mmol)溶于重蒸的10mlDCM中，氮气保护下加入三光气(81mg，0.273mmol)，有固体生成，后变澄清。室温下搅拌反应15min。TLC监测(DCM:MeOH＝12:1)至原料反应完全。再加入化合物14(300mg，0.39mmol)反应15min。TLC监测(DCM:MeOH＝12:1)至酰氯反应完全。室温下减压旋干。刮板纯化：DCM:MeOH＝10:1，得产品化合物20 300mg。
实施例21化合物21的合成
将化合物20(300mg，0.23mmol)溶于100ml甲醇中，基本溶清。加入120mg 5％Pd/BaSO4，氢气置换两次，室温下搅拌反应6小时。HPLC监测反应至大部分为产品。反应结束后，过滤，40℃减压浓缩干，直接投下一步。
实施例22化合物22的合成
将上步所得化合物21溶于5ml干燥DMF中，再加入MC-OSu(106.5mg，0.345mmol)、DIEA(114ul，0.69mmol)室温下搅拌反应1小时。HPLC监测反应。反应结束后，室温下油泵减压旋干。制备纯化。冻干得产品40mg，LC-MS：[M+H]+＝＝1066.1。
实施例23化合物23的合成
于固相合成器内加入10g 2-氯三苯甲基氯树脂(0.95mol/g)，加入100mL二氯甲烷溶胀0.5h。抽干溶剂，加入二氯甲烷100mL、Fmoc-Lys(Boc)-OH(10g，21.6mmol)及DIEA(7mL，43.4mmol)，室温，氮气鼓吹约3h，加入甲醇20mL,鼓气30min，抽干溶剂，依次加入二氯甲烷、甲醇、二氯甲烷洗涤，抽干溶剂，加入20％哌啶/DMF溶液，鼓气1h，抽干溶剂，依次用DMF、二氯甲烷各洗3次，抽干溶剂。
另取250mL单口瓶，加入Fmoc-Lys(Boc)-OH(15g，32.4mmol)、HATU(12.3g，32.4mmol)、HoBt(4.37g，32.4mmol)、DIEA(64.8mmol，10.6mL)及DMF50mL，搅拌约30min。将此混合液加至上述固相合成器中，鼓气2h，用Kaiser试剂检测，原料反应完全，抽干溶剂，依次加入DMF、二氯甲烷各洗3次。再加入20％哌啶/DMF溶液，鼓气1h，抽干溶剂，依次用DMF、二氯甲烷各洗3次，抽干溶剂。
预先于250mL单口瓶，加入Fmoc-Lys(Boc)-OH(15g，32.4mmol)、HATU(12.3g，32.4mmol)、HoBt(4.37g，32.4mmol)、DIEA(64.8mmol，10.6mL)及DMF50mL，搅拌约30min。将此混合液加至上述固相合成器中，鼓气2h，用Kaiser试剂检测，原料反应完全，抽干溶剂，依次加入DMF、二氯甲烷各洗3次。
向树脂中加入三氟乙酸/水/苯甲硫醚(90/8/2)混合液100mL，氮气鼓气2h，抽干，收集滤液，用二氯甲烷洗3次树脂，合并洗液与滤液。减压浓缩除去大部分溶剂，加入乙醚析晶，析出白色固体，过滤烘干得10g。LC-MS：[M+H]+＝625。
实施例23化合物23的合成
于250mL单口瓶中加入化合物Fmoc-Lys-Lys-Lys-OH(8g，12.8mmol)，TMSCl(8mL，64mmol)及二氯甲烷100mL，50℃反应3h，冷却至0℃，加入DIEA(18mL，100mmol)，再滴加MMtCl(13g，42mmol)的二氯甲烷混合液，滴毕，室温过夜。TLC检测，反应完毕后减压浓缩除去大部分二氯甲烷，加入甲叔醚析晶，过滤，烘干，得化合物23为黄色固体6.8g。
实施例24化合物24的合成
于100mL单口瓶中加入化合物23(6g，4mmol)、对氨基苄醇(0.85g，4mmol)、HATU(3.16g，8.3mmol)、HoBt(1.1g，8.3mmol)、DIEA(1.3mL，8.3mmol)及DCM50mL，氮气保护室温反应3h。TLC检测，反应完毕后，减压浓缩除去大部分二氯甲烷，加入甲叔醚析晶，过滤，烘干得固体化合物24 5.6g。
实施例25化合物25的合成
取烘干的50mL三口瓶，加入SN38-OTBS(196mg，0.38mmol)、三光气(52mg，0.175mmol)，DMAP(166mg，1.35mmol)及10mL重蒸二氯甲烷，氮气保护，反应约15min，加入化合物24(300mg，0.194mmol)的二氯甲烷溶液6mL，反应约20min，TLC检测(DCM/MeOH＝10/1)，反应完毕，加入甲醇，常温浓缩除去二氯甲烷，残余物刮板纯化，得产品化合物25 232mg。
实施例26化合物26的合成
于25mL单口瓶中加入化合物25(230mg，0.1mmol)、二氯甲烷4mL及哌啶0.4mL，室温反应30min。向反应瓶中加入水洗涤三次，无水硫酸钠干燥。过滤，向滤液中加入MC-OSu(67mg,0.2mmol)及DIEA(35uL,0.2mmol),室温反应，TLC监测。反应完后，浓缩除去大部分二氯甲烷，残余物刮板纯化，得产品化合物26 162mg。
实施例27化合物27的合成
于25mL单口瓶中加入化合物5(162mg，0.079mmol)，TBAF(41mg,0.158mmol)及二氯甲烷5mL，室温反应，TLC监测。原料反应完后，再加入二氯乙酸0.25mL及苯甲醚0.25mL，室温反应约1h，TLC监测。反应液浓缩，制备纯化，冻干得产品35mg。TOF-MS：[M+H]+＝1119
实施例28化合物28的合成
于250ml单口瓶中加入27 30g(64mmol，1.0eq)，氮气置换三次后加入20％的三氟乙酸的二氯甲烷溶液215ml，室温搅拌1-2h，TLC监控，基本反应完全，减压浓缩除去三氟乙酸和二氯甲烷，浓缩液直接投下一步反应。LC-MS,[M+H]+＝369.4
实施例29化合物29的合成
于250ml单口瓶中加入化合物28 20g(54mmol，1.0eq)，加入二氯甲烷150ml，再加入三乙胺约36ml(270mmol，5.0eq)将溶液调pH至9左右，加入Teoc-OSu 17g(65mmol，1.2eq)，室温下搅拌过夜，TLC监控，基本反应完全。将不溶物过滤，滤液减压浓缩后柱纯化(二氯甲烷：甲醇＝60:1)，减压浓缩得23.5g化合物29。LC-MS：[M+Na]+＝535.7。
实施例30化合物30的合成
于500ml单口瓶中加入化合物29 23.5g(45.84mmo，1.0eql)、对氨基苯甲醇11.3g(91.76mmol，2.0eq)，加入DM F 100ml溶解，氮气置换3次，冰水浴下加入DIEA 17.75g(137.34mmol，3.0eq)、HATU 19.15g(50.38mmol，1.1eq)，室温反应4-5h，TLC监控，基本反应完全。加入饱和柠檬酸和EA萃取分液，EA相水洗涤1次，合并水相，EA反萃1次，合并EA相，无水Na2SO4干燥过滤浓缩，柱层析纯化(流动相DCM：MeOH＝120:1)，浓缩得化合物30 15g。LC-MS：[M+H]+＝618.8
实施例31化合物31的合成
于250ml单口瓶中加入化合物30 11g(17.80mmol)，加入20％哌啶的二氯甲烷溶液66ml，室温搅拌3-4h，TLC监控，基本反应完全。用饱和柠檬酸洗涤后，直接柱层析纯化(流动相DCM：MeOH＝50:1)，浓缩得泡沫状固体化合物31 5.1g。LC-MS：[M+H]+＝396.6
实施例32化合物32的合成
于250ml单口瓶中加入31 5.1g(14.28mmol，1.0eq)、化合物14 9.47g(14.28mmol，1.0eq)，加入DMF 50ml溶解，于0℃下搅拌加人HATU 5.97g(15.70mmol，1.1eq)、DIEA5.536g(42.84mmol，3.0eq)，室温搅拌反应3-4h，TLC监控，基本反应完全。加入20％柠檬酸，EA萃取分液，水相再反萃1次，合并EA相，加入无水Na2SO4干燥过滤浓缩得棕黄色油状物，柱层析纯化(流动相DCM：MeOH＝50:1～20:1)浓缩得32 11g。LC-MS：[M+H]+＝1042.2
实施例33化合物33的合成
于严格干燥氮气保护的100ml三口瓶中加入SN-38-OTBS 2.5g(4.9mmol，1.03eq)、三光气474mg(1.6mmol，0.33eq)、DMAP 1.773g(14.5mmol，3.0eq)，用针头加入重蒸DCM25ml，室温下搅拌10-20min，取样加甲醇监控，TLC监控，SN-38-OTBS全部被活化。用针头吸取重蒸DCM 15ml溶解化合物32 5g(4.8mmol，1.0eq)注入到反应瓶中，室温搅拌反应40-60min，取样加甲醇，TLC监控，基本反应完全，直接柱层析纯化(流动相DCM：MeOH＝100:1)，在33℃-36℃下浓缩得淡黄色固体化合物33 4g。LC-MS：[M+H]+＝1574.9
实施例34化合物34的合成
于100ml单口瓶中加入化合物33 1g(0.6mmol)，Pd/BaSO4 454.5mg，甲醇50ml，氢气置换三次，5-10℃下反应4-5h，TLC监控，基本反应完全，将反应液过滤，滤液在33-35℃下减压浓缩得泡沫状固体化合物34 800mg。LC-MS：[M+H]+＝1260.5
实施例35化合物35的合成
于50ml单口瓶中加入34 1g(0.8mmol，1.0eq)，Mc-OSu 295.6mg(14mmol，1.75eq)，DIEA 271mg(2.1mmol，2.6eq)，DMF 20ml，氮气置换三次，室温搅拌1-2h后直接HPLC制备纯化得化合物35。LC-MS：[M+H]+＝1453.7。
实施例36化合物36的合成
于50ml单口瓶中加入化合物35 95mg(0.065mmol，1.0eq)，ZnBr2 292mg(1.3mmol，20eq)，分子筛干燥的硝基甲烷12ml，氮气置换一次后在8.8℃下反应18-32h后直接HPLC制备纯化得化合物化合物36。LC-MS：1195.2[M+H]+
实施例37 ADC C-L01的合成
依通用步骤A，以化合物6为原料偶联制备抗体药物偶联物，以下简称ADC药物，编号C-L01。
实施例38 ADC C-E05的合成
依通用步骤A，以化合物19为原料偶联制备ADC药物，编号C-E05。
实施例39 ADC C-L05的合成
依通用步骤A，以化合物22为原料偶联制备ADC药物，编号C-L05。
实施例40 ADC C-L06的合成
依通用步骤A，以化合物36为原料偶联制备ADC药物，编号C-L06。
实施例41单体率及DAR测定
对实施例37至40得到的ADC药物利用HIC进行单体率及DAR测定，测定结果如下表1所示：
表1单体率及DAR测定结果
| ADC | 单体率 | DAR |
| C-L01 | 87.80％ | 6.47 |
| C-E05 | 96.13％ | 7.41 |
| C-L05 | 86.23％ | —— |
| C-L06 | 94.65％ | 6.35 |
注:“—”代表未进行相关实验，
单体率是抗体在与payload偶联形成ADC后聚集程度的体现，单体率约高，证明偶联ADC亲水性越高。实验结果表明，本专利所设计的payload分子在形成ADC药物后相对于对照分子C-L01在亲水性方面相当(C-L05)或有明显提高(C-E05、C-L06)，达到了预期目的。
实施例42细胞IC50测定
对实施例37至40得到的ADC药物采用MTT法进行体外IC50测定，针对BXPC-3、Fadu、A431三个细胞系进行测定，测定结果如下表2所示：
表2体外IC50测定测定结果
| ADC | BXPC-3 | Fadu | A431 |
| C-L01 | 10.37 | 0.65 | 3.73 |
| C-E05 | 32.41 | 0.53 | 7.06 |
| C-L05 | 31.72 | 1.60 | 6.74 |
| C-L06 | 10.11 | 0.50 | 2.31 |
实验结果表明，本专利所设计的payload分子在形成ADC药物后相对于对照分子C-L01在细胞水平上表现出相当的活性，达到了预期目的。
实施例43体内活性测定
对实施例37至40得到的ADC药物进行体内药效实验测试，体外培养人咽鳞癌细胞A431，按细胞数量5×106接种于裸鼠背部皮下，待肿瘤长到70～90mm3后，分组，给予ADC药物10mg/kg(尾静脉注射Days 0,4,7,11,14,18,21,25给药)，同时设溶媒对照组，定期称体重、测量肿瘤体积，通过考察ADC药物的抑瘤疗效等指标，来评价药物对于A431模型的药效。实验结果如图1所示，小鼠体重变化情况如图2所示，图1结果表明，具有亲水碳酸酯型抗体药物偶联物相对于溶媒对照组的具有优良的体内药效。图2结果表明，本专利所设计的亲水性碳酸酯型抗体药物偶联物在动物中表现出优良的安全性。
Claims (10)
1.结构式(I)的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，
其中，A为能与靶点结合的配体部分；
D为含羟基的药物单元；
La为任意的连接单元；
Lb为由2-3个亲水氨基酸组成的亲水单元；
Lc为间隔单元，间隔单元Lc与药物单元D之间通过碳酸酯键连接，药物单元D与碳酸酯共用氧原子；
n选自2-20的整数。
2.如权利要求1所述的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，其特征在于，连接单元La包含结构：
其中，L2为
或单键；
n1-n5分别选自1～8的整数。
3.如权利要求1所述的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，其特征在于，药物单元D为微管蛋白结合剂、DNA烷化剂、DNA嵌入剂、酶抑制剂、免疫调控剂、肽、核苷酸中的至少一种。
4.如权利要求1所述的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，其特征在于，组成亲水单元Lb的亲水氨基酸为丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸、缬氨酸或2、3-二氨基丙酸中的至少一种。
5.如权利要求1所述的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，其特征在于，连接单元Lc包含以下结构，
其中，R为任选的取代基团。
6.如权利要求5所述的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，其特征在于，R为H、卤素、C1-4的烷基、OR1、SR1、NR1R2、SO2R1、CONHR1、CN或COOR1中的至少一种，其中，R1和R2可独立的选自于H、C1-4的烃基、苯基或者取代苯基。
7.如权利要求1或4所述的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，其特征在于，亲水单元Lb为由谷氨酸、赖氨酸或2、3-二氨基丙酸中的至少一种组成的寡肽。
8.如权利要求1所述的亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐，其特征在于，亲水单元Lb选自以下结构或其药学上可接受的盐：
9.一种包括权利要求1至8任一所述亲水碳酸酯型抗体药物偶联物或其药学上可接受的盐的药物组合物。
10.根据权利要求9所述的药物组合物，特征在于，所述药物组合物为抗肿瘤药物、抗免疫疾病药物或抗感染性疾病药物，其中，抗肿瘤药物中包括抗癌药物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811223058 | 2018-10-19 | ||
| CN2018112230587 | 2018-10-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111001012A true CN111001012A (zh) | 2020-04-14 |
Family
ID=70111475
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910915742.XA Pending CN111001012A (zh) | 2018-10-19 | 2019-09-26 | 一种亲水碳酸酯型抗体偶联药物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111001012A (zh) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022205111A1 (zh) * | 2021-03-31 | 2022-10-06 | 上海复旦张江生物医药股份有限公司 | 一种伊喜替康衍生物的制备方法及其中间体 |
| US11744897B2 (en) | 2020-10-27 | 2023-09-05 | Elucida Oncology, Inc. | Folate receptor targeted nanoparticle drug conjugates and uses thereof |
| US11806405B1 (en) * | 2021-07-19 | 2023-11-07 | Zeno Management, Inc. | Immunoconjugates and methods |
| WO2023214849A1 (ko) * | 2022-05-04 | 2023-11-09 | 주식회사 피노바이오 | Ddx5 단백질에 결합하는 캄토테신계 약물이 산 민감성 링커에 연결된 접합체 및 이를 이용한 면역접합체 |
| US20240016949A1 (en) * | 2020-12-04 | 2024-01-18 | Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. | Antibody-drug conjugate, and intermediate thereof, preparation method therefor, and application thereof |
| WO2024049220A1 (ko) * | 2022-08-30 | 2024-03-07 | 주식회사 피노바이오 | 캄토테신계 약물이, 항원 결합 친화도가 낮은 항체에 링커를 통해 연결된 항체-약물 접합체 |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110070156A1 (en) * | 2002-06-14 | 2011-03-24 | Immunomedics, Inc. | Combining Radioimmunotherapy and Antibody-Drug Conjugates for Improved Cancer Therapy |
| US20110076287A1 (en) * | 2008-02-01 | 2011-03-31 | Robert L Cohen | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
| CN104147612A (zh) * | 2014-08-22 | 2014-11-19 | 亚飞（上海）生物医药科技有限公司 | 一种肿瘤微环境特异激活的小分子靶向偶联体及其用途 |
| US20160122430A1 (en) * | 2014-10-31 | 2016-05-05 | Abbvie Biotherapeutics Inc. | Anti-cs1 antibodies and antibody drug conjugates |
| US20170313781A1 (en) * | 2016-04-27 | 2017-11-02 | Immunomedics, Inc. | Efficacy of anti-trop-2-sn-38 antibody drug conjugates for therapy of tumors relapsed/refractory to checkpoint inhibitors |
| US20180110772A1 (en) * | 2012-12-13 | 2018-04-26 | Immunomedics, Inc. | Therapy for metastatic urothelial cancer with the antibody-drug conjugate, sacituzumab govitecan (immu-132) |
| US20180280532A1 (en) * | 2017-04-03 | 2018-10-04 | Immunomedics, Inc. | Subcutaneous administration of antibody-drug conjugates for cancer therapy |
-
2019
- 2019-09-26 CN CN201910915742.XA patent/CN111001012A/zh active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110070156A1 (en) * | 2002-06-14 | 2011-03-24 | Immunomedics, Inc. | Combining Radioimmunotherapy and Antibody-Drug Conjugates for Improved Cancer Therapy |
| US20130209356A1 (en) * | 2002-06-14 | 2013-08-15 | Immunomedics, Inc. | Combining Radioimmunotherapy and Antibody-Drug Conjugates for Improved Cancer Therapy |
| US20110076287A1 (en) * | 2008-02-01 | 2011-03-31 | Robert L Cohen | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
| US20180110772A1 (en) * | 2012-12-13 | 2018-04-26 | Immunomedics, Inc. | Therapy for metastatic urothelial cancer with the antibody-drug conjugate, sacituzumab govitecan (immu-132) |
| CN104147612A (zh) * | 2014-08-22 | 2014-11-19 | 亚飞（上海）生物医药科技有限公司 | 一种肿瘤微环境特异激活的小分子靶向偶联体及其用途 |
| US20160122430A1 (en) * | 2014-10-31 | 2016-05-05 | Abbvie Biotherapeutics Inc. | Anti-cs1 antibodies and antibody drug conjugates |
| US20170313781A1 (en) * | 2016-04-27 | 2017-11-02 | Immunomedics, Inc. | Efficacy of anti-trop-2-sn-38 antibody drug conjugates for therapy of tumors relapsed/refractory to checkpoint inhibitors |
| US20180280532A1 (en) * | 2017-04-03 | 2018-10-04 | Immunomedics, Inc. | Subcutaneous administration of antibody-drug conjugates for cancer therapy |
Non-Patent Citations (1)
| Title |
|---|
| SERENGULAM V. GOVINDAN等: "Improving the Therapeutic Index in Cancer Therapy by Using Antibody−Drug Conjugates Designed with a Moderately Cytotoxic Drug" * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11744897B2 (en) | 2020-10-27 | 2023-09-05 | Elucida Oncology, Inc. | Folate receptor targeted nanoparticle drug conjugates and uses thereof |
| US11957760B2 (en) | 2020-10-27 | 2024-04-16 | Elucida Oncology, Inc. | Folate receptor targeted nanoparticle drug conjugates and uses thereof |
| US20240016949A1 (en) * | 2020-12-04 | 2024-01-18 | Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. | Antibody-drug conjugate, and intermediate thereof, preparation method therefor, and application thereof |
| WO2022205111A1 (zh) * | 2021-03-31 | 2022-10-06 | 上海复旦张江生物医药股份有限公司 | 一种伊喜替康衍生物的制备方法及其中间体 |
| US11806405B1 (en) * | 2021-07-19 | 2023-11-07 | Zeno Management, Inc. | Immunoconjugates and methods |
| WO2023214849A1 (ko) * | 2022-05-04 | 2023-11-09 | 주식회사 피노바이오 | Ddx5 단백질에 결합하는 캄토테신계 약물이 산 민감성 링커에 연결된 접합체 및 이를 이용한 면역접합체 |
| WO2024049220A1 (ko) * | 2022-08-30 | 2024-03-07 | 주식회사 피노바이오 | 캄토테신계 약물이, 항원 결합 친화도가 낮은 항체에 링커를 통해 연결된 항체-약물 접합체 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108853514B (zh) | 具有两种不同药物的抗体药物偶联物 | |
| CN111001012A (zh) | 一种亲水碳酸酯型抗体偶联药物 | |
| JP6363125B2 (ja) | 巨大分子共役体からの徐放 | |
| CN109316605B (zh) | 叶酸受体结合配体-药物偶联物 | |
| KR101413955B1 (ko) | 아지리디닐-에포틸론 화합물 | |
| CN108452321B (zh) | 一种带酸性自稳定接头的抗体-药物偶联物 | |
| CN111689980A (zh) | 一种喜树碱药物及其抗体偶联物 | |
| WO2019034176A1 (zh) | 一种喜树碱-抗体偶联物 | |
| JP2010526091A (ja) | 癌の処置のための生物学的な標的基の改変 | |
| JP2010526091A5 (zh) | ||
| JP2021138761A (ja) | 四級化チューブリシン化合物の複合体 | |
| JP2011102329A (ja) | ヘテロ二官能性重合体生物複合体 | |
| JPH10513187A (ja) | 高分子量のポリマーを基剤とするプロドラッグ | |
| AU2017265310B2 (en) | Multi-arm polymeric targeting anti-cancer conjugate | |
| WO2022078259A1 (zh) | 一种氘代的喜树碱衍生物及其抗体药物偶联物 | |
| CN110974975B (zh) | 一种快速释放的抗体药物偶联物 | |
| KR102279429B1 (ko) | 멀티 암 표적 항암 콘쥬게이트 | |
| KR20220143908A (ko) | 표적 전달 및 활성화의 면역 자극성 접합 복합체의 제조 및 용도 | |
| WO2022056696A1 (zh) | 一种喜树碱类药物及其抗体偶联物 | |
| CN115160403A (zh) | 特异性拓扑异构酶抑制剂和可用于抗体药物偶联物及其制备方法 | |
| US11319341B2 (en) | Immune-stimulating soluble doxorubicin-conjugated complex | |
| CN109125736B (zh) | 非天然鹅膏毒肽类抗体偶联物 | |
| US11596643B2 (en) | Pectin-adriamycin conjugate as well as preparation method and use thereof | |
| WO2023208168A1 (zh) | 一种包含亲水性糖结构的配体-药物偶联物 | |
| RU2793125C2 (ru) | Конъюгат антитело-лекарственное средство, имеющий кислотный самостабилизирующийся участок соединения |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210520 Address after: 611130 Chengdu cross strait science and Technology Industry Development Park, Wenjiang District, Chengdu City, Sichuan Province Applicant after: Sichuan Baili Pharm Co.,Ltd. Applicant after: Chengdu duote antibody medicine Co.,Ltd. Address before: 611130 Chengdu cross strait science and Technology Industry Development Park, Wenjiang District, Chengdu City, Sichuan Province Applicant before: Sichuan Baili Pharm Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 610041 Chengdu Cross Strait Science and Technology Industry Development Park, Wenjiang District, Chengdu City, Sichuan Province Applicant after: SICHUAN BAILI PHARM Co.,Ltd. Applicant after: Chengdu bailidote Biological Pharmaceutical Co.,Ltd. Address before: 611130 Chengdu cross strait science and Technology Industry Development Park, Wenjiang District, Chengdu City, Sichuan Province Applicant before: SICHUAN BAILI PHARM Co.,Ltd. Applicant before: Chengdu duote antibody medicine Co.,Ltd. |