WO2023109965A1 - 一种喜树碱类化合物及其偶联物 - Google Patents

一种喜树碱类化合物及其偶联物 Download PDF

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WO2023109965A1
WO2023109965A1 PCT/CN2022/139765 CN2022139765W WO2023109965A1 WO 2023109965 A1 WO2023109965 A1 WO 2023109965A1 CN 2022139765 W CN2022139765 W CN 2022139765W WO 2023109965 A1 WO2023109965 A1 WO 2023109965A1
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structural formula
compound
compound shown
prodrug
pharmaceutically acceptable
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PCT/CN2022/139765
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English (en)
French (fr)
Chinese (zh)
Inventor
周伟
徐辉
朱会凯
王珍珍
谭小钉
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Jiangsu Mabwell Health Pharmaceutical R&d Co Ltd
Mabwell Shanghai Bioscience Co Ltd
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Jiangsu Mabwell Health Pharmaceutical R&d Co Ltd
Mabwell Shanghai Bioscience Co Ltd
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Priority to KR1020247023132A priority Critical patent/KR20240120744A/ko
Priority to US18/720,569 priority patent/US20250059201A1/en
Priority to CN202280083630.2A priority patent/CN118414339A/zh
Priority to EP22906709.5A priority patent/EP4450506A4/en
Priority to MX2024007498A priority patent/MX2024007498A/es
Priority to CA3241157A priority patent/CA3241157A1/en
Application filed by Jiangsu Mabwell Health Pharmaceutical R&d Co Ltd, Mabwell Shanghai Bioscience Co Ltd filed Critical Jiangsu Mabwell Health Pharmaceutical R&d Co Ltd
Priority to AU2022408887A priority patent/AU2022408887A1/en
Priority to JP2024535725A priority patent/JP2024545233A/ja
Publication of WO2023109965A1 publication Critical patent/WO2023109965A1/zh
Anticipated expiration legal-status Critical
Priority to ZA2024/05368A priority patent/ZA202405368B/en
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    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
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    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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Definitions

  • the invention belongs to the field of biotechnology, and more specifically, the invention relates to a new-type camptothecin analog and its application in the preparation of drugs, especially antibody-drug conjugates.
  • DNA topoisomerase is a class of essential enzymes widely present in organisms. It is a general term for enzymes that catalyze the mutual conversion of DNA topological isomers. It is mainly divided into topoisomerase I (Topoisomerase I, Topo I) and topoisomerase I. Constructase II (Topoisomerase II, Topo II) two types. Among them, topoisomerase I is highly expressed in a variety of tumor cells such as colon cancer, cervical cancer, and ovarian cancer, and its content is much higher than that of normal tissues or cells, and its activity is greatly increased in tumor cells in the S phase. Inhibitors of topoisomerase I activity can selectively inhibit DNA replication of proliferative tumor cells.
  • topoisomerase I is the main target of camptothecin (CPT) and its analogs.
  • Camptothecin is a cytotoxic quinoline alkaloid that stabilizes normally dissociated topoisomerase I and the covalent compound of the DNA strand to form a ternary complex. With the formation of the ternary complex, CPT inhibits the DNA cleavage and relinking reactions initially mediated by topoisomerase I, thereby inhibiting DNA synthesis, leading to cell death, and exerting anticancer effects.
  • Antibody-drug conjugate is a new type of tumor treatment drug composed of an antibody or antibody-like ligand, a small molecule drug, and a linker that couples the ligand to the drug. Combining the anti-tumor activity of small molecule drugs and the high selectivity, stability and good pharmacokinetic characteristics of antibodies or antibody-like ligands has become a hot spot in the field of tumor treatment.
  • the ADC drugs prepared by camptothecin (CPT) compounds at home and abroad mainly include:
  • ADC drugs have shown certain therapeutic effects, but there are also certain problems.
  • the half-life of IMMU-132 in plasma is only about 12h, which may lead to problems such as increased side effects, such as diarrhea, fatigue, nausea, febrile neutrophils, etc.
  • Different degrees of toxic reactions such as cytopenia and leukopenia (US2014/0170063A1).
  • the random coupling of DS-1062 and DS-7300 will result in greater heterogeneity of ADC products.
  • camptothecin compounds there are still relatively few types of ADCs containing camptothecin compounds, and there are disadvantages such as a relatively narrow range of target population, poor monotherapy effect, and strong side effects. Therefore, there is still a need to develop new camptothecin compounds and corresponding ADCs to meet the therapeutic needs.
  • the object of the present invention is to provide a compound with a new structure and an antibody-drug conjugate prepared therefrom.
  • the compound with the new structure is a camptothecin compound itself, or a camptothecin or a camptothecin compound A compound formed by linking a compound with a linker.
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • drug-containing linker refers to a compound obtained by directly or indirectly covalently bonding a drug (such as a small molecule drug, such as a camptothecin compound) to a linker.
  • a group when a group is substituted, it may be substituted by one or more substituents, the number of substituents being dependent on the number of hydrogen atoms contained in the group, all of which may be substituted.
  • the present invention provides camptothecin compounds.
  • the camptothecin compound is a compound represented by structural formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 , R 2 , R 3 , R 4 are independently hydrogen, halogen, hydroxyl, C1-6 alkoxy, amino or substituted amino, C1 -7 alkyl or substituted C1-7 alkyl, or any two of R 1 , R 2 , R 3 , R 4 together with the carbon atoms they are connected to form a C3-6 cyclic alkyl group.
  • the C1-6 alkoxy groups include straight-chain or branched C1-6 alkoxy groups, preferably straight-chain Or a branched C1-3 alkoxy group, more preferably a methoxy group.
  • R 1 , R 2 , R 3 , and R 4 are independently substituted amino groups
  • the substituted amino groups are amino groups substituted by one or more substituents selected from methyl and ethyl.
  • R 1 , R 2 , R 3 , and R 4 are independently C1-7 alkyl or substituted C1-7 alkyl
  • the C1-7 alkyl or substituted C1-7 alkyl includes linear or branched Chain C1-7 alkyl or substituted C1-7 alkyl
  • the substituted C1-7 alkyl is C1-7 alkyl substituted by one or more substituents selected from cyclopropyl and cyclobutyl or
  • the straight or branched C1-7 alkyl or substituted C1-7 alkyl is preferably C1-3 alkyl or substituted C1-3 alkyl, such as methyl, halomethyl (preferably trifluoromethyl).
  • G is hydrogen, halogen, methyl or methoxy.
  • G is hydrogen, fluorine or chlorine.
  • Y is oxygen, sulfur, sulfone, sulfoxide, methylene or substituted methylene.
  • Substituted methylene can be that one hydrogen of methylene is substituted, also can be that two hydrogens are substituted simultaneously, and substituent can be benzyl or alkyl; When substituent is alkyl, described alkyl and R3 And/or R 4 and the carbon atoms connected to them can constitute a C3-6 membered ring or spiro ring structure.
  • the substituent of the substituted methylene group is preferably an alkyl group, more preferably a linear or branched C1-4 alkyl group.
  • Y is oxygen, sulfur, sulfone or sulfoxide; or, preferably, Y is oxygen, sulfur or methylene.
  • X is oxygen or sulfur
  • n 0 or 1.
  • R 1 , R 2 , R 3 , R 4 are independently hydrogen, halogen (such as fluorine), C1-7 alkyl or substituted C1-7 alkyl, or R 1 , R 2 , R 3 , R Any two of 4 together with the carbon atoms to which they are attached constitute a C3-6 cyclic alkyl group (for example a C3-5 cyclic alkyl group). Further, R 1 and R 2 may be the same; and/or, R 3 and R 4 may be the same.
  • Y is a methylene group substituted by an alkyl group, and the alkyl group, R 3 and/or R 4 and the carbon atoms connected to them may form a C3-6 membered ring or spiro ring structure.
  • X may be oxygen
  • X is oxygen
  • G is hydrogen
  • halogen eg fluorine or chlorine
  • Y and R 1 , R 2 , R 3 , R 4 are as defined above.
  • X is oxygen
  • G is hydrogen
  • Y is methylene or substituted methylene, oxygen or sulfur
  • R 1 , R 2 , R 3 , R 4 are as defined above.
  • X is oxygen
  • G is fluorine
  • Y is methylene or substituted methylene, oxygen or sulfur
  • R 1 , R 2 , R 3 , R 4 are as defined above.
  • X is oxygen
  • G is chlorine
  • Y is methylene or substituted methylene, oxygen or sulfur
  • R 1 , R 2 , R 3 , R 4 are as defined above.
  • X is oxygen
  • G is methyl
  • Y is methylene or substituted methylene, oxygen or sulfur
  • R 1 , R 2 , R 3 , R 4 are as defined above.
  • X is oxygen
  • G is methoxy
  • Y is methylene or substituted methylene, oxygen or sulfur
  • R 1 , R 2 , R 3 , R 4 are as defined above.
  • X is oxygen
  • G is hydrogen
  • Y is oxygen, sulfone or sulfoxide
  • R 1 , R 2 , R 3 , R 4 are as defined above.
  • X is oxygen
  • G is hydrogen
  • Y is sulfone or sulfoxide
  • R 1 , R 2 , R 3 , R 4 are as defined above.
  • the compound shown in the structural formula I provided by the present invention is further a compound shown in the structural formula IA:
  • the groups R 1 , R 2 , R 3 , R 4 have the same definitions as the groups R 1 , R 2 , R 3 , R 4 in the structural formula I above, but R 1 , R 2 , R 3 , R 4 is not simultaneously hydrogen.
  • the camptothecin compound is a compound represented by structural formula II or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R is C1-5 alkyl or C1-5 alkyl substituted by one or more substituents, C3-6 cyclic alkyl or substituted by C3-6 cyclic alkyl, phenyl or substituted phenyl substituted by one or more substituents.
  • R 5 is C1-5 alkyl or substituted C1-5 alkyl, said C1-5 alkyl includes straight or branched C1-5 alkyl. Further, R 5 is a C1-4 linear alkyl group.
  • R is a substituted C1-5 alkyl or a substituted C3-6 cyclic alkyl
  • the substituents are selected from the group consisting of halogen, hydroxyl, methoxy, trifluoromethyl, amino or substituted amino, methylsulfonyl and C3 -6 cyclic alkyl group; and wherein the substituted amino group is an amino group substituted by one or more substituents selected from methyl and ethyl.
  • R 5 is a substituted phenyl group
  • the substituent is selected from alkyl (such as C1-6 alkyl, preferably C1-3) or halogen.
  • G is hydrogen, halogen (eg fluorine), methyl or methoxy.
  • G is hydrogen, fluorine or chlorine.
  • X is oxygen or sulfur.
  • n 0 or 1.
  • the compound shown in the structural formula II provided by the present invention is further a compound shown in the structural formula IIA:
  • the group R 5 has the same definition as the group R 5 in formula II above, except that R 5 cannot be n-butyl.
  • the compound in the first aspect of the present invention, has the following structure:
  • the present invention provides a drug-containing linker having the structure shown in the general formula "L-A-CPT", wherein L represents a linker for an antibody-drug conjugate (ADC), A represents one or more amino acids, and CPT For camptothecin compounds.
  • L represents a linker for an antibody-drug conjugate (ADC)
  • A represents one or more amino acids
  • CPT For camptothecin compounds.
  • the drug-containing linker having a structure represented by general formula L-A-CPT is a compound represented by structural formula III or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.
  • E is selected from the group wherein, Indicates the site of attachment to M:
  • E-1 E-2: E-3: E-4: E-5: and E-6:
  • M is phenylene or phenylene substituted by one or more substituents, or a chemical bond; in substituted phenylene, the substitution The group is selected from alkyl (such as C1-C6 alkyl, preferably C1-C4 alkyl), haloalkyl (such as halogenated C1-C6 alkyl, preferably halogenated C1-C4 alkyl, such as trifluoromethyl), alkyl Oxy (eg C1-C6 alkoxy, preferably C1-C4 alkoxy, preferably methoxy), halogen, ester, amido and cyano; preferably, M is halogen-substituted phenylene.
  • alkyl such as C1-C6 alkyl, preferably C1-C4 alkyl
  • haloalkyl such as halogenated C1-C6 alkyl, preferably halogenated C1-C4 alkyl, such as trifluoromethyl
  • SP 1 is selected from C1-8 alkylene, C1-8 cycloalkylene or C1-21 (preferably C1-16, more preferably C1-11 ) straight-chain heteroalkylene, the C1-21 straight-chain heteroalkylene contains 1-11 (preferably 1-6) heteroatoms selected from N, O or S, wherein the C1-8 alkylene
  • the group, C1-8 cycloalkylene and C1-21 linear heteroalkylene are each independently optionally substituted with one or more substituents selected from hydroxyl, amino, sulfonic acid and cyano.
  • SP is selected from -NH(CH2CH2O)aCH2CH2CO-, -NH(CH2CH2O)aCH2CO-, -S(CH2)aCO- or a chemical bond, wherein a is An integer of 1-20, preferably an integer of 1-10, more preferably an integer of 1-6.
  • A represents 2-4 amino acids.
  • A when A represents 2 amino acids, it can be NH-Phe-Lys-CO, NH-Val-Ala-CO, NH-Val-Lys-CO, NH-Ala-Lys-CO, NH-Val-Cit-CO , NH-Phe-Cit-CO, NH-Leu-Cit-CO, NH-Phe-Arg-CO or NH-Gly-Val-CO, preferably NH-Phe-Lys-CO, NH-Val-Ala-CO Or NH-Val-Cit-CO; when A represents 3 amino acids, it can be NH-Glu-Val-Ala-CO, NH-Glu-Val-Cit-CO or NH-Ala-Ala-Ala-CO, preferably NH-Glu-Val-Ala-CO or NH-Ala-Ala-Ala-CO; when A represents 4 amino acids, it can be NH-Phe-Lys-CO, NH-Val
  • CPT is a compound of the class of camptothecins.
  • R 6 , R 7 are independently hydrogen, halogen or Ar'S
  • Ar' is phenyl or phenyl substituted by one or more substituents, in In the substituted phenyl group, the substituent is selected from alkyl (such as C1-C6 alkyl, preferably C1-C4 alkyl), alkoxy (such as C1-C6 alkoxy, preferably C1-C4 alkoxy, Preference is given to methoxy), halogen, ester, amido and cyano.
  • Ar' is benzene
  • CPT is the compound shown in structural formula I or structural formula IA provided in the first aspect of the present invention above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and corresponding specific compounds.
  • CPT is the compound shown in the structural formula I provided in the first aspect of the present invention above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • the groups G, X, Y, R 1 , R 2 , R 3 , R 4 , n are the same as the groups G, X, Y, R 1 , R 2 , R in the structural formula I in the first aspect above 3 , R 4 , and n have the same definitions.
  • CPT is the compound shown in the structural formula IA provided in the first aspect of the present invention above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • the groups R 1 , R 2 , R 3 , R 4 have the same definitions as the groups R 1 , R 2 , R 3 , R 4 in the structural formula IA in the first aspect above, but R 1 , R 2 , R 3 and R 4 can be hydrogen at the same time.
  • R6 and R7 can be hydrogen at the same time, or hydrogen at the same time.
  • R 1 , R 2 , R 3 , and R 4 in the structural formula IA may be hydrogen at the same time, or they may not be hydrogen at the same time.
  • R 1 , R 2 , R 3 , and R 4 in the structural formula IA are not hydrogen at the same time; when R 6 and R 7 are not hydrogen at the same time , R 1 , R 2 , R 3 , and R 4 in the structural formula IA may be hydrogen at the same time, or hydrogen at the same time.
  • the compound shown in Structural Formula I or Structural Formula IA is connected to the carboxyl group of A via its amino group (see Structural Formula I or Structural Formula IA respectively) through an amide bond, that is, the amino group of the compound shown in Structural Formula I or Structural Formula IA An amide bond is formed with the carboxyl group of A in formula III or IIIA.
  • CPT is the compound shown in structural formula II or structural formula IIA provided in the first aspect of the present invention above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof , and the corresponding specific compounds.
  • CPT is the compound shown in the structural formula II provided in the first aspect of the present invention above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • the groups G, R 5 , X, n are the same as the definitions of the groups G, R 5 , X, n in the structural formula II in the first aspect above.
  • CPT is the compound shown in the structural formula IIA provided in the first aspect of the present invention above or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • the group R 5 has the same definition as the group R 5 in formula IIA in the first aspect above, but may be n-butyl.
  • the compound shown in Structural Formula II or Structural Formula IIA is connected to the carboxyl group of A through its amino group (see Structural Formula II or Structural Formula IIA respectively) through an amide bond, that is, the amino group of the compound shown in Structural Formula II or Structural Formula IIA and The carboxyl group of A in structure III or IIIA forms an amide bond.
  • CPT in structural formula III and structural formula IIIA, can be an exteacan derivative shown in structural formula IV or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R is hydrogen , trifluoromethyl, C1-5 alkyl or C1-5 alkyl substituted by one or more substituents, C3- 6 cyclic alkyl or C3-6 cyclic alkyl substituted by one or more substituents, or halogen.
  • R is a substituted C1-5 alkyl or a substituted C3-6 cyclic alkyl
  • the substituents are selected from halogen, hydroxyl, methoxy, trifluoromethyl, amino or substituted amino, methylsulfonyl and C3-6 cyclic alkyl; and wherein the substituted amino group is an amino group substituted by one or more substituents selected from methyl and ethyl.
  • R6 and R7 can be hydrogen at the same time, or hydrogen at the same time.
  • R8 in Formula IV may or may not be hydrogen.
  • R6 and R7 when R6 and R7 are hydrogen at the same time, R8 may be hydrogen or not be hydrogen.
  • the compound shown in structural formula IV is connected to the carboxyl group of A via its hydroxyl group (see structural formula IV) that is connected to the same carbon as R 8 through a self-releasing structure, such as
  • the solid line indicates the linking position with the carboxyl group of A in the structural formula III or IIIA
  • the wavy line indicates the linking position with the hydroxyl group in the structural formula IV.
  • M is preferably phenylene or substituted phenylene
  • SP1 is C1-21 (preferably C1-16, more preferably C1- 11) Straight-chain heteroalkylene, which contains 1-11 (preferably 1-6) heteroatoms selected from N, O or S.
  • the compound shown in the structural formula III and the structural formula IIIA provided by the present invention is further a compound shown in the structural formula V.
  • R 6 and R 7 are independently Ar'S, and Ar' is a phenyl group or a phenyl group substituted by one or more substituents.
  • the substituents are selected from alkyl groups (such as C1-C6 Alkyl, preferably C1-C4 alkyl), alkoxy (eg C1-C6 alkoxy, preferably C1-C4 alkoxy, preferably methoxy), halogen, ester, amido and cyano.
  • Ar' is phenyl, 4-methylformyl substituted phenyl or 4-formylmorpholine substituted phenyl
  • Xh and Yh are independently hydrogen, halogen, haloalkyl (such as halogenated C1-C6 alkyl, preferably halogenated C1-C4 alkyl, such as trifluoro methyl) or alkoxy (eg C1-C6 alkoxy, preferably C1-C4 alkoxy, eg methoxy).
  • halogen such as halogenated C1-C6 alkyl, preferably halogenated C1-C4 alkyl, such as trifluoro methyl
  • alkoxy eg C1-C6 alkoxy, preferably C1-C4 alkoxy, eg methoxy
  • m is any integer from 1 to 10, preferably 1 to 5, more preferably 3-5.
  • A represents 2-4 amino acids, as defined above.
  • Structural Formula V the definition of CPT and its connection relationship in Structural Formula V are the same as CPT in Structural Formula III and Structural Formula IIIA, as defined above.
  • the compound shown in the structural formula V provided by the present invention is further a compound shown in the structural formula V-A:
  • the groups A, G, Y, R 1 , R 2 , R 3 , R 4 , X, n are the same as the groups A, G, Y, R 1 , R 2 , The definitions of R 3 , R 4 , X and n are the same.
  • G is hydrogen, fluorine or chlorine.
  • Y is methylene, sulfur or oxygen.
  • the compound shown in the structural formula V-A provided by the present invention is further a compound shown in the structural formula V-A-1:
  • the compound shown in the structural formula V provided by the present invention is further a compound shown in the structural formula V-B:
  • the groups A, G, R 5 , X, n are the same as the definitions of the groups A, G, R 5 , X, n in the above formula III or IIIA.
  • the compound represented by the structural formula V-B provided by the present invention is further a compound represented by the structural formula V-B-1:
  • the compound shown in the structural formula V provided by the present invention is further a compound shown in the structural formula V-C:
  • the groups A and R 8 have the same definitions as the groups A and R 8 in the above structural formula III or IIIV.
  • the compound shown in the structural formula V provided by the present invention is further a compound shown in the structural formula VI:
  • A represents 2-4 amino acids, as defined above.
  • CPT is a camptothecin compound.
  • the definition of CPT and its connection relationship in formula VI are the same as CPT in formula III and formula IIIA, as defined above.
  • the compound shown in the structural formula VI provided by the present invention is further a compound shown in the structural formula VI-A:
  • the groups A, G, Y, R 1 , R 2 , R 3 , R 4 , X, n are the same as the groups A, G, Y, R 1 , R in the above structural formula III or structural formula IIIA 2 , R 3 , R 4 , X, and n have the same definitions.
  • G is hydrogen, fluorine or chlorine.
  • Y is methylene, sulfur or oxygen.
  • the compound shown in the structural formula VI-A provided by the present invention is further a compound shown in the structural formula VI-A-1:
  • the groups A, G, R 5 , X, n are the same as the definitions of the groups A, G, R 5 , X, n in the above structural formula III or the structural formula IIIA.
  • the compound shown in structural formula VI-B is further a compound shown in structural formula VI-B-1:
  • the compound shown in the structural formula VI provided by the present invention is further a compound shown in the structural formula VI-C:
  • the definitions of the groups A and R 8 are the same as the definitions of the groups A and R 8 in the above structural formula III or the structural formula IIIA.
  • the structural formula VC can be further structured as shown in the structural formula VI-C.
  • the compound in the second aspect of the present invention, has the following structure:
  • the present invention provides a structure composed of the above structural formulas I, I-A, II, II-A, III, III-A, V, V-A, V-A-1, V-B, V-B-1, V-C, VI, VI-A, VI- Antibody drug conjugates prepared from compounds shown in A-1, VI-B, VI-B-1, VI-C or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs and antibodies or antibody fragments United things.
  • the antibody or antibody fragment targets a tumor-associated antigen such as HER2, B7H3, HER3, CD19, CD20, CD22, CD30, CD33, CD37, CD45, CD56, CD66e, CD70, CD74, CD73, CD79b, CD138, CD147, CD223, EpCAM, Mucin 1 (Mucin1), STEAP1, GPNMB, FGF2, FOLR1, EGFR, EGFRvIII, Tissuefactor, c-MET, FGFR, Nectin 4, AGS-16, Guanylyl cyclase C (Guanylyl cyclase C), Mesothelin (Mesothelin), SLC44A4, PSMA, EphA2, AGS-5, GPC-3, c-KIT, RoR1, PD-L1, CD27L, 5T4, Mucin16, NaPi2b, STEAP, SLITRK6, ETBR, BCMA, Trop-2, CEACAM5, SC-16
  • the antibody drug conjugate has the general formula In the structure shown, wherein mAb represents an antibody or an antibody fragment, the groups M, SP 1 , SP 2 , A and CPT are the same as those defined in the above structural formula III or structural formula IIIA for the groups M, SP 1 , SP 2 , A and CPT .
  • N is 1-10, preferably 1-8 (for example, 1-5), more preferably 3-8.
  • EL is selected from the following groups, wherein, Indicates that it is linked to cysteine in mAb, Indicates that it is connected to M:
  • E L -1a and/or EL -1b E L -2: E L -3: E L -4: E L -5: E L -6:
  • the mAb may be an IgG antibody or fragment thereof targeting any of the above tumor-associated antigens, preferably an IgG1 subtype antibody or fragment thereof.
  • the antibody-drug conjugate has a structure represented by the following general formula VII or general formula VIII:
  • N is 1-10, preferably 1-8 (eg 1-5), more preferably 3-8.
  • Ab corresponds to the above general formula mAbs in.
  • the definitions of the groups A and CPT are the same as the definitions of the groups A and CPT in the structural formula III or the structural formula IIIA provided in the second aspect above.
  • the antibody-drug conjugates represented by general formulas VII and VIII provided in the third aspect of the present invention can generate prodrug metabolites in cells (such as tumor cells).
  • the groups A and CPT have the same definitions as the groups A and CPT in the formula III or IIIA provided in the second aspect above.
  • the prodrug metabolite of the antibody drug conjugate prepared using the compound of formula VI-A is the compound shown in structural formula IX-A:
  • the groups A, G, Y, R 1 , R 2 , R 3 , R 4 , X, n are the same as the structural formula III provided in the second aspect above or the groups A, G, G, Y, R 1 , R 2 , R 3 , R 4 , X, and n have the same definitions.
  • the compound shown in the structural formula IX-A provided by the present invention is further a compound shown in the structural formula IX-A-1:
  • the prodrug metabolite of the antibody drug conjugate prepared using the compound of formula VI-B is a compound shown in structural formula IX-B:
  • the groups A, G, R 5 , X, n have the same definitions as the groups A, G, R 5 , X, n in the formula III or IIIA provided in the second aspect above.
  • the groups A and R8 have the same definitions as the groups A and R8 in the structural formula III or the structural formula IIIA provided in the second aspect above.
  • the present invention provides the use of the compound according to the present invention or its pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs or antibody-drug conjugates in the preparation of drugs for treating tumors.
  • the tumor is cancer.
  • the tumor and tumor-associated antigens such as HER2, B7H3, HER3, CD19, CD20, CD22, CD30, CD33, CD37, CD45, CD56, CD66e, CD70, CD74, CD73, CD79b, CD138, CD147, CD223, EpCAM , Mucin 1 (Mucin 1), STEAP1, GPNMB, FGF2, FOLR1, EGFR, EGFRvIII, Tissue factor (Tissuefactor), c-MET, FGFR, Nectin 4, AGS-16, Guanylyl cyclase C (Guanylyl cyclase C), Mesothelin, SLC44A4, PSMA, EphA2, AGS-5, GPC-3, c-KIT, RoR1, PD-L1, CD27L, 5T4, Mucin16, NaPi2b, STEAP, SLITRK6, ETBR, BCMA, Positive or high expression of Trop-2, CEACAM5,
  • the tumor is colorectal cancer, bladder cancer, breast cancer, pancreatic cancer, liver cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, gastric cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, esophageal squamous Cell carcinoma, head and neck squamous cell carcinoma, melanoma, leukemia, lymphoma, glioma, glioblastoma.
  • the present invention provides a method for treating tumors using a compound according to the present invention or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug or an antibody drug conjugate, the method comprising administering the A subject in need thereof is administered the compound or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug or antibody drug conjugate thereof.
  • the tumor is cancer.
  • the tumor and tumor-associated antigens such as HER2, B7H3, HER3, CD19, CD20, CD22, CD30, CD33, CD37, CD45, CD56, CD66e, CD70, CD74, CD73, CD79b, CD138, CD147, CD223, EpCAM , Mucin 1 (Mucin 1), STEAP1, GPNMB, FGF2, FOLR1, EGFR, EGFRvIII, Tissue factor (Tissuefactor), c-MET, FGFR, Nectin 4, AGS-16, Guanylyl cyclase C (Guanylyl cyclase C), Mesothelin, SLC44A4, PSMA, EphA2, AGS-5, GPC-3, c-KIT, RoR1, PD-L1, CD27L, 5T4, Mucin16, NaPi2b, STEAP, SLITRK6, ETBR, BCMA, Positive or high expression of Trop-2, CEACAM5,
  • the tumor is colorectal cancer, bladder cancer, breast cancer, pancreatic cancer, liver cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, gastric cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, esophageal squamous Cell carcinoma, head and neck squamous cell carcinoma, melanoma, leukemia, lymphoma, glioma, glioblastoma.
  • the subject is a mammal, preferably a primate, more preferably a human.
  • FIG. 1 HIC analysis results of the antibody drug conjugate of the present invention.
  • Figure 2 The pharmacodynamic results of the antibody-drug conjugate of the present invention in a mouse model of pancreatic cancer.
  • Fig. 3 The pharmacodynamic results of the antibody-drug conjugate of the present invention in a mouse model of bladder cancer.
  • Fig. 4 The pharmacodynamic results of the antibody-drug conjugate of the present invention in a mouse model of lung cancer.
  • Fig. 7 Research results of the antibody-drug conjugates of the present invention inducing tumor cell apoptosis.
  • Fig. 8 The dose-effect curve of the binding of the antibody-drug conjugate and antibody of the present invention to tumor cells.
  • camptothecin compound of the present invention can be obtained by the Friedlander reaction of the compound shown in formula A and the CDE tricyclic compound, and the general reaction formula is as follows:
  • the CDE tricyclic compound was purchased from MCE:
  • HCDE tricyclic compounds were prepared according to Bioorganic and Medicinal Chemistry, 2010, vol.18, #9, p.3140-3146:
  • the aminolactam compound is prepared according to the method of the patent publication CN106349233A.
  • the diaminoethyl ester intermediate was dissolved in dichloromethane (200ml), triethylamine (20.2g, 0.2mol, 2eq) was added, the temperature was cooled to below 10°C in an ice bath, and acetic anhydride (25.5g, 0.25mol, 2.5 eq).
  • Compound A3 was synthesized according to the method of patent publication US2004266803A.
  • step 1
  • the A4-2 intermediate was prepared from the A4-1 compound according to the literature method.
  • step 1
  • step 1
  • the A1-4 compound (1.25g, 5mmol, 1eq) was dissolved in 150ml of tetrahydrofuran, cooled to -60°C, added LDA (2M in THF, 7.6ml, 15.2mmol, 3.04eq ), after the addition was completed, the reaction was stirred at -60°C for 30 minutes.
  • MeI (1.45g, 10.21mmol, 2.04eq) was added, after the addition was complete, the dry ice bath was removed, the temperature was raised naturally, and the reaction was carried out overnight at room temperature.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • Embodiment group 1.2 camptothecin compounds synthesis (Friedlander reaction)
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • Embodiment 1.2.16 Synthesis of camptothecin compound 18
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • GGFG-Dxd is synthesized according to the method described in the patent publication (US20190151328A1):
  • the BL linker compound was synthesized according to the method described in the patent publication WO2018/095422A1:
  • BL linker compound (857mg, 1mmol), GGFG-Dxd (840mg, 1mmol, 1eq), DIPEA (323mg, 2.5mmol, 2.5eq), HATU (570mg, 1.5mmol, 1.5eq), dissolved in 30ml DCM, stirred reaction 2h.
  • the reaction solution was cooled to 5-10°C, 1N hydrochloric acid (20ml) was added, and stirred for 0.5h.
  • the layers were separated, the aqueous phase was extracted with DCM (30ml*2), and the organic phases were combined.
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and spin-dried.
  • BL linker compound (857mg, 1mmol), HoSu (138mg, 1.2mmol, 1.2eq), DCC (310mg, 1.5mmol, 1.5eq) were dissolved in 30ml DCM, stirred at room temperature for 3h, the reaction solution was suction filtered, and the filtrate was A- DCM solution of Osu. The filtrate was added to the mixed solution of the crude intermediate 2-2, DIPEA (323 mg, 2.5 mmol, 2.5 eq), and DCM (30 ml), and the reaction was stirred for 3 h. The reaction solution was cooled to 10°C, 1N hydrochloric acid (20ml) was added, and stirred for 0.5h.
  • Boc-Gly-OH (175mg, 1mmol), A1 compound (176mg, 1mmol, 1eq), DIPEA (322mg, 2.5mmol, 2.5eq), HATU (456mg, 1.2mmol, 1.2eq) were dissolved in 30ml DCM, and the reaction was stirred 2h.
  • BL linker compound (318mg, 0.37mmol), HoSu (51mg, 0.44mmol, 1.2eq), DCC (114mg, 0.56mmol, 1.5eq) were dissolved in 30ml DCM, stirred at room temperature for 3h, and the reaction solution was suction filtered. The filtrate was added to the mixed solution of the crude intermediate 3-4, DIPEA (120mg, 0.93mmol, 2.5eq), DCM (30ml), and stirred for 3h. The reaction solution was cooled to 10°C, 1N hydrochloric acid (20ml) was added, and stirred for 0.5h. The layers were separated, the aqueous phase was extracted with DCM (30ml*2), and the organic phases were combined.
  • the synthetic route is as follows:
  • BL linker compound (146mg, 0.17mmol), HoSu (25mg, 0.21mmol, 1.2eq), DCC (54mg, 0.26mmol, 1.5eq) were dissolved in 20ml DCM, stirred at room temperature for 3h, and the reaction solution was suction filtered. The filtrate was added to the mixed solution of the crude intermediate 5-1, DIPEA (56mg, 0.43mmol, 2.5eq), and DCM (20ml), and the reaction was stirred for 3h. The reaction solution was cooled to 5-10°C, 1N hydrochloric acid (20ml) was added, and stirred for 0.5h. The layers were separated, the aqueous phase was extracted with DCM (30ml*2), and the organic phases were combined.
  • Embodiment group 3 compares the synthesis of drug-containing linker
  • the synthetic route is as follows:
  • Linker L-C was synthesized according to the method similar to drug-containing linker L-1.
  • the antibody is reduced to open the disulfide bond, and then coupled with the linker to form a bridged antibody-drug conjugate.
  • Antibody reduction use Sephadex G25 carrier NAP-25 chromatographic column to replace 120mg antibody sample to pH 7.0 containing 50mM sodium chloride, 50mM sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution, and the antibody The concentration was diluted to 10mg/ml. Take 10ml of antibody samples totaling 100mg, and add 10mg/ml TCEP (Sigma-Aldrich) aqueous solution at an antibody-TCEP molar ratio of 1:10 equivalent, and the volume of TCEP aqueous solution added is 2.1ml. After 2 hours of incubation, use the Sephadex G25 chromatographic column reaction solution to replace to a pH 6.5 buffer solution containing 50mM sodium chloride, 50mM sodium dihydrogen phosphate-disodium hydrogen phosphate buffer.
  • TCEP Sigma-Aldrich
  • the NAP-25 chromatographic column with Sephadex G25 carrier was used to replace the reaction solution to the disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution with pH 8.0 to remove the excess drug-containing linker, and heated in a water bath at 37°C for 3 hours.
  • Purification of antibody-drug conjugates Concentrate the above samples using AMICOM ultrafiltration centrifuge tubes, and concentrate the samples to about 15 mg/mL. Add 50mM disodium hydrogen phosphate-sodium dihydrogen phosphate+3M ammonium phosphate buffer solution until the conductivity is 100ms/cm. Load the sample to TOYOPEAL Butyl-650M filler (purchased from TOSOH) hydrophobic column, phase A is 50mm disodium hydrogen phosphate-sodium dihydrogen phosphate + 0.6M ammonium sulfate, phase B is buffered with 50mm disodium hydrogen phosphate-sodium dihydrogen phosphate solution. Phase B was eluted with a 0-100% gradient of 8 column volumes, and the main peak was collected.
  • the concentration of the antibody-drug conjugate can be obtained by measuring the UV absorbance at 280 nm and the characteristic absorption wavelength of small molecules, and then performing the following calculations.
  • the concentration of the antibody-drug conjugate has the following relationship:
  • MW ADC is the molecular weight of the antibody-drug conjugate
  • MW Ab is the molecular weight of the antibody
  • MW D is the molecular weight of the drug-containing linker
  • Sample preparation Dilute the sample to 2.0mg/ml with mobile phase B, centrifuge at 12000rpm for 10min, and take the supernatant for HPLC analysis;
  • Mobile phase A 1.5M (NH4) 2 SO 4 +25mM PB, pH 7.0;
  • Mobile phase B 25mM PB+20%IPA, pH 7.0;
  • Sample preparation Dilute the sample to 2.0mg/ml with mobile phase B, centrifuge at 12000rpm for 10min, and take the supernatant for HPLC analysis;
  • Mobile phase B 25mM PB+20%IPA, pH 7.0;
  • Sample preparation Dilute the sample to 2.0mg/ml with mobile phase B, centrifuge at 12000rpm for 10min, and take the supernatant for HPLC analysis;
  • Sample treatment Take an appropriate amount of sample in an ultrafiltration tube, replace it with 50mM NH4HCO3 replacement buffer (pH7.1), add buffer, and ultrafiltration centrifuge (13000g*5min). Add 8 ⁇ l of PNGase F enzyme to the replaced sample, incubate at 37°C for 5 hours for desugaring treatment, after the incubation, centrifuge at 12000rpm for 5 minutes, take the supernatant into the injection vial as the test sample for use.
  • Mobile phase 50mM ammonium acetate, pH 7.0;
  • Atomizer pressure 20psig
  • Sheath gas temperature 325°C
  • Sheath gas flow 12L/min
  • Sample processing After diluting the sample to about 1.0 mg/ml with mobile phase, centrifuge at 12000 rpm for 10 min, and take the supernatant for sample analysis.
  • Sample pretreatment Process the sample according to the method described in the patent publication (US 10227417 B2).
  • each of the targeting Trop-2 antibody hTINA1 (prepared according to the sequence of Datopotamab in WHO Drug Information) and h23-12 were respectively combined with drug-containing linkers MWD-L1 and MWC- ADCs were prepared from L2, MWC-L3, MWF-L6, MWD-L7, MWD-L8, MWD-L9 and MWF-L8.
  • the bridged ADC drugs 1a, 1b, 1c, 1d, 1j, 1k, 1l, 1m, 1n, 1o, and 1p were obtained; the intermediate samples of 1d without hydrophobic chromatography were collected and saved as intermediate sample 1j.
  • each of the targeting Trop-2 antibodies hTINA1 and h23-12 were mixed with MC-GGFG-Dxd, L-A, L-B, L-J, MWS-L7, L-I and MWS-L6 respectively to prepare ADCs to obtain random coupling ADC 1e, 1f, 1g, 1h, 1i, 1q, 1r, 1s, 1t, and 1u.
  • the DAR value, concentration and Purity was measured.
  • reverse action chromatography 4.2f in group 4 of this embodiment to measure the DAR value of ADC samples (1e, 1h, 1q, 1r, 1s, 1t and 1u) containing MC-GGFG-Dxd drug-containing linker
  • reverse Chromatography 4.2g measures the DAR value of ADC samples (1f, 1g, 1i) containing L-A or L-B drug-containing linkers; use 4.2a ultraviolet spectrophotometry and 4.2d size exclusion chromatography in Example Group 4 to determine The concentration and purity of non-bridging ADC drugs (1e-1i) were determined.
  • h23-12 is a monoclonal antibody with the following sequence:
  • Heavy chain CDR1 SYWMH (SEQ ID NO: 1)
  • Heavy chain CDR2 EITPSDNYGSYNQKFKG (SEQ ID NO: 2)
  • Heavy chain CDR3 GHGNYVSFDY (SEQ ID NO: 3)
  • HER-2-targeting antibody trastuzumab (CAS: 180288-69-1, purchased from Shanghai Roche Pharmaceutical Co., Ltd.) was mixed with the drug-containing linker MWD -L1, MWD-L2, MWE-L4, MWF-L6, MWD-L8, MWD-L9, L-C, MWC-L3 were used to prepare bridging ADC 2a, 2b, 2c, 2h, 2i, 2d, 2l.
  • the DAR value, concentration and Purity was measured.
  • Her2-ADC-1 Trastuzumab MWC-L1 3.9 4.6 98.0% 2b
  • Her2-ADC-2 Trastuzumab MWC-L2 4.0 3.8 99.2%
  • Her2-ADC-3 Trastuzumab MWE-L4 4.0 3.7 97.5% 2d
  • Her2-ADC-4 Trastuzumab L-C 3.9 3.8 97.72
  • Her2-ADC-5 Trastuzumab L-A 4.3 4.8 99.0% 2f
  • Her2-ADC-6 Trastuzumab L-B 4.1 6.2 98.6% 2g
  • Her2-ADC-7 Trastuzumab MC-GGFG-Dxd 4.0 6.6 99.8% 2 hours
  • Her2-ADC-8 Trastuzumab MWD-L8 4.0 7.5 98.9% 2i
  • Her2-ADC-9 Trastuzumab MWD-L9 4.0 7.8
  • the Trop2 samples (1a, 1h, 1j) and Her2 samples (2b, 2e) prepared in Example 1 and Example 2 were analyzed by hydrophobic chromatography using 4.2b in Group 4 of this example as follows to compare the results of different connection techniques. Drug Heterogeneity of ADCs.
  • Her2-ADC-2 Comparing Her2-ADC-2 and Her2-ADC-5, it can be seen that the ADC drug Her2-ADC-2 prepared using the drug-containing linker MWC-L2 has better uniformity than Her2-ADC-5 prepared using the known linker L-A .
  • Oral epithelial cancer cells KB (purchased from: ATCC) were cultured in DMEM medium supplemented with 10% FBS; human gastric cancer cells NCI-N87 (purchased from: ATCC) were cultured in RPMI1640 medium supplemented with 10% FBS; human colon cancer cells HT29 (purchased from: From: ATCC) was cultured using RPMI1640 medium supplemented with 10% FBS; human pancreatic adenocarcinoma cell BxPC-3 (purchased from: ATCC) was cultured using RPMI1640 medium supplemented with 10% FBS.
  • the data is fitted with 4 parameters using prism7 software, and the maximum killing formula is: 1-(OD450 value of the maximum killing well-OD450 value of the culture base)/(OD450 value of the cell maximum growth well-OD450 value of the culture base)*100 %.
  • the results are shown in Table 4.
  • Her2-targeting ADC samples prepared above were diluted with the complete medium, sequentially diluted to 50ug/ml, and then diluted in a 4-fold gradient, with a total of 9 gradients plus a zero point, and three replicate wells were set for all samples.
  • Column 11 should set up a negative control (cells + medium) and a blank control (no cells, pure medium), and then place it in a cell incubator and incubate for 120 hours or 168 hours (see table for details). Take out the cell culture plate, add 40 ⁇ l/well of MTS, and react in a 37°C incubator for 2-4h; take out the cell plate, and read the OD value at 490nm.
  • the above-prepared ADC samples targeting Trop2 were diluted with the complete medium, sequentially diluted to 50ug/ml, and then 4-fold serially diluted, a total of 9 gradients plus a zero point, and three replicate wells were set for all samples.
  • Column 11 should set up a negative control (cells + medium) and a blank control (no cells, pure medium), and then place them in a cell incubator and incubate for 120 hours. Take out the cell culture plate, add 40 ⁇ l/well of MTS, and react in a 37°C incubator for 2-4h; take out the cell plate, and read the OD value at 490nm.
  • Example 5.4 In vitro pharmacodynamic study of different ADC toxins on low-abundance tumors and cells with low antigen expression near tumor cells
  • Cell HS-746T was purchased from ATCC; the cells were cultured with RPMI 1640/IMEM (1:1) culture medium containing 10% fetal bovine serum (FBS), and penicillin and streptomycin were added to the culture medium at the same time, at 37°C, containing 5 cultured in an incubator with % CO2 air.
  • RPMI 1640/IMEM (1:1) culture medium containing 10% fetal bovine serum (FBS), and penicillin and streptomycin were added to the culture medium at the same time, at 37°C, containing 5 cultured in an incubator with % CO2 air.
  • the cells were treated with 0.1 ⁇ g/mL and 1 ⁇ g/mL Trop2-ADC-1, Trop2-ADC-2, Trop2-ADC-5, Trop2-ADC-10, Trop2-ADC-14 respectively for 168 hours, Collect the cells and count them; then incubate the cells with the above-mentioned Trop2-ADC labeled with Dylight 488 NHS Ester at 4°C in the dark for 1 hour, centrifuge to remove the supernatant, resuspend in phosphate buffer (PBS, pH7.4), wash with PBS (pH7.4) was washed three times, and the number of Hs746t cells was calculated by flow cytometer BD ACCURI C6 PLUS.
  • PBS phosphate buffer
  • pH7.4 wash with PBS
  • KPL-4 cells and MDA-MB-468 cells were purchased from ATCC, and the cells were cultured with RPMI 1640/IMEM (1:1) culture medium containing 10% fetal bovine serum (FBS), and penicillin and streptomycin were added to the culture medium at the same time , cultured at 37°C in an incubator containing 5% CO2 air.
  • RPMI 1640/IMEM (1:1) culture medium containing 10% fetal bovine serum (FBS), and penicillin and streptomycin were added to the culture medium at the same time , cultured at 37°C in an incubator containing 5% CO2 air.
  • HER2-positive KPL-4 cells and HER2-negative MDA-MB-468 cells were co-inoculated, or HER2-negative MDA-MB-468 cells were inoculated alone, after 168 hours of drug treatment, the cells were collected, and the cells were mixed with Dylight 488 NHS Ester
  • the labeled anti-HER2 antibody was incubated at 4°C in the dark for 1 hour, centrifuged to remove the supernatant, resuspended in PBS (pH 7.4), washed three times with PBS, and calculated by flow cytometer BD ACCURI C6 PLUS to calculate KPL-4 and MDA- MB-468 cell ratio, and calculate the respective cell numbers.
  • each ADC group has better tumor inhibitory effect on negative cells.
  • the comparison of the number of positive cells and the number of negative cells in each concentration group can be known.
  • the bystander killing effect of MWF-L6 and MWC-L2 was better than that of the control group GGFG-DXD and L-B.
  • BxPc-3 cells Human pancreatic cancer BxPc-3 cells, which were purchased from the Cell Bank of the Chinese Academy of Sciences, were used. BxPc-3 cells were cultured in 10-cm culture dishes adherently. The culture conditions were RPMI 1640 medium plus 10% fetal bovine serum, penicillin and streptomycin, and cultured at 37°C in an incubator containing 5% CO2. Subculture 2-3 times a week, when the cells are in the exponential growth phase, trypsinize, collect the cells, count and inoculate.
  • the antibody-drug conjugates Trop2-ADC-1, Trop2-ADC-2, Trop2-ADC-3, and Trop2-ADC-5 containing different drug linkers were used to conduct group comparison studies under different dosage group conditions (Table 13).
  • the mice were administered intravenously (IV), with an administration volume of 10 mL/kg; the solvent group was administered the same volume of solvent (physiological saline); see Table 13 for the specific dosage and regimen.
  • the tumor volume was measured twice a week, the body weight of the mice was weighed, and the data were recorded.
  • HT1376 cells Human bladder cancer HT1376 cells were purchased from the Cell Bank of the Chinese Academy of Sciences. HT1376 cells were cultured in 10-cm culture dishes adherently. The culture conditions were RPMI 1640 culture medium plus 10% fetal bovine serum, penicillin and streptomycin, and cultured at 37°C in an incubator containing 5% CO2. Subculture 2-3 times a week, when the cells are in the exponential growth phase, trypsinize, collect the cells, count and inoculate.
  • the lung cancer cell Calu-3 which was purchased from the Cell Bank of the Chinese Academy of Sciences, was used. Calu-3 cells were cultured in 10-cm culture dishes adherently. The culture conditions were RPMI 1640 culture medium plus 10% fetal bovine serum, penicillin and streptomycin, and cultured at 37°C in an incubator containing 5% CO2. Subculture 2-3 times a week, when the cells are in the exponential growth phase, trypsinize, collect the cells, count and inoculate.
  • the antibody-drug conjugate Trop2-ADC-14 was taken as an example, and a group comparison study was carried out on Trop2-ADC-14 under different dosage groups (Table 15).
  • the mice were administered intravenously (IV), with an administration volume of 10 mL/kg; the solvent group was administered the same volume of solvent (physiological saline); see Table 15 for the specific dosage and regimen.
  • the tumor volume was measured twice a week, the body weight of the mice was weighed, and the data were recorded.
  • Table 15 The curative effect of Trop2-ADC-14 on human lung cancer Calu-3 subcutaneously transplanted tumor in nude mice (TGI% calculated according to tumor volume).
  • TROP2-positive BxPC-3 cells purchased from ATCC
  • TROP2-negative HT-29 cells purchased from ATCC
  • TROP2-negative HT-29 cells were co-seeded or TROP2-negative HT-29 cells were seeded in a 6-well plate alone. After being treated with Trop2-ADC-14 (10, 30, 100 ng/mL) or DS-1062a (100, 300 ng/mL) for 144 hours, the cells were collected and counted.
  • Trop2-ADC-14 has a strong bystander effect, killing TROP2-positive cells and killing TROP2-negative cells at the same time; Trop2-ADC-14 has a bystander effect at 30 ng/mL that is comparable to that of the reference drug DS.
  • the effect of -1062a was comparable at 300ng/mL (5A in Figure 5), and the results suggested that the bystander effect of Trop2-ADC-14 was stronger than that of the reference drug DS-1062 as a whole.
  • Both Trop2-ADC-14 and DS-1062a had no significant effect on the proliferation of TROP2-negative HT-29 cells cultured alone (5B in Figure 5).
  • the SRB method was used to detect the effects of antibody-drug conjugates or camptothecin compounds on the proliferation of tumor cells cultured in vitro for adherent cells. Inoculate a certain number of cells in the logarithmic growth phase in a 96-well culture plate, and after growing overnight, add different concentrations of antibodies, antibody-drug conjugates or camptothecin compounds. After 144 hours, fix with trichloroacetic acid. After staining with SRB (prepared with 1% glacial acetic acid, concentration 4mg/mL), add 10mM Tris solution to each well to dissolve. Read the OD value with a microplate reader at a wavelength of 510 nm.
  • Inhibition rate (%) (OD value control well-OD value administration well)/OD value control well ⁇ 100%
  • MTT method was used to detect the effects of antibody-drug conjugates or camptothecin compounds on the proliferation of tumor cells cultured in vitro.
  • a certain number of cells in the logarithmic growth phase were inoculated in a 96-well culture plate, and after the adherent growth overnight, different concentrations of antibody-drug conjugates or camptothecin compounds were added.
  • MTT was added to each well, and culture was continued for 4 hours at 37° C. in a 5% CO2 saturated humidity incubator. Add 100 ⁇ L triple solution to each well, and measure the OD value at 570 nm and 690 nm wavelengths on a microplate reader.
  • BxPC-3 cells purchased from: ATCC
  • Trop2-ADC-14, Trop2-ADC-14mAb i.e. antibody h23-12
  • incubate 37°C 3, 6, 12, 18, 24 and 48 hours.
  • Trop2-ADC-14 and h23-12 were endocytosed by the cells after incubation with TROP2-positive cells BxPC-3; endocytosis was time-dependent, and the internalized drugs gradually increased with time; Trop2-ADC-14 internalized drug more than antibody h23-12 at 24 hours.
  • BxPC-3 cells (purchased from ATCC) were inoculated in 6-well plates, treated with Trop2-ADC-14 (0.020, 0.196, 1.963nM), DS-1062 (0.020, 0.196, 1.963nM), Trop2-ADC-14mAb (ie Antibody h23-12) (6.728nM) and compound 3 (0.1, 1, 10nM) were treated for 120 hours, the cells were collected, Annexin-V-FITC and PI were added, stained at room temperature for 15 minutes in the dark, and finally 300 ⁇ l 1x binding buffer was added Resuspend and detect apoptosis with a flow cytometer (BD AccuriTMC6 Plus flow cytometer), with 1 ⁇ 10 4 cells in each sample gate. The experimental data were analyzed with BD CSamplerTMPlus C6 Plus software. The results are shown in Figure 7.
  • Trop2-ADC-14 0.196nM can obviously induce the degradation of pro-PARP, a marker protein of apoptosis, and induce the hydrolysis of pro-caspase 3 into active protein caspase 3 (cleaved-caspase 3), and the apoptosis-inducing effect has concentration-dependent; the apoptosis-inducing effect of Trop2-ADC-14 cells was significantly stronger than that of DS-1062a at the same concentration, and the apoptosis-inducing effect of the latter was not obvious at 0.196nM; the small molecule toxin compound 3 also concentration-dependently induced BxPC- 3 cell apoptosis; antibody h23-12 had no obvious apoptosis effect on BxPC-3 cells.
  • Trop2-ADC-14 and antibody h23-12 bind to TROP2-positive tumor cell BxPC-3 in a concentration-dependent manner, and the binding EC50 is 1296.0 ⁇ 155.6ng/mL and 1137.5 ⁇ 128.0ng/mL, respectively, suggesting that both The binding ability is equivalent to that of TROP2-positive cells; as a control, Trop2-ADC-14, antibody h23-12, and TROP2-negative cells HT-29 have no obvious binding.

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