WO2024027795A1 - Conjugué anticorps-médicament contenant un composé bioactif d'agent de dégradation de protéine myc, son procédé de préparation et son utilisation - Google Patents

Conjugué anticorps-médicament contenant un composé bioactif d'agent de dégradation de protéine myc, son procédé de préparation et son utilisation Download PDF

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WO2024027795A1
WO2024027795A1 PCT/CN2023/111003 CN2023111003W WO2024027795A1 WO 2024027795 A1 WO2024027795 A1 WO 2024027795A1 CN 2023111003 W CN2023111003 W CN 2023111003W WO 2024027795 A1 WO2024027795 A1 WO 2024027795A1
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group
alkyl
aryl
antibody
pharmaceutically acceptable
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PCT/CN2023/111003
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Chinese (zh)
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童友之
薛彤彤
宋帅
肖亮
蔡家强
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苏州开拓药业股份有限公司
苏州宜联生物医药有限公司
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Publication of WO2024027795A1 publication Critical patent/WO2024027795A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure belongs to the field of medical technology and relates to antibody-drug conjugates of protein-degrading bioactive compounds, protein-degrading bioactive compounds, drug linker conjugates and their preparation methods, as well as their use in prevention and/or treatment.
  • Diseases related to abnormal cell activity including but not limited to use in the prevention and/or treatment of tumor diseases.
  • TPD Targeted Protein Degradation
  • PROTAC protein degradation targeting chimera
  • MMD molecular glue degrader
  • Myc is an important family of transcription factors, including c-Myc, n-Myc, and l-Myc, which are essential for cell growth, metabolism and tissue development. At the same time, Myc is also an important group of oncogenes. c-Myc is abnormally expressed in about 30-50% of human malignant tumors and plays a role in affecting cell growth, proliferation, differentiation, apoptosis, as well as cell metabolism and malignant transformation. plays an extremely important role. Abnormally high expression of c-Myc is associated with poor prognosis in many human cancers.
  • c-Myc due to the special protein structure of c-Myc, it directly targets inhibitors Therapeutic inhibition of c-Myc has been unsuccessful, and approaches targeting the c-Myc transcriptional machinery have had limited success. Therefore, c-Myc has long been considered an undruggable target.
  • targeted protein degraders and molecular glue degraders can change the target from “undruggable” to “druggable”.
  • drug properties such as low oral bioavailability
  • off-target The resulting dose-limiting toxicity and other problems have greatly restricted the development of this type of molecules.
  • the present invention relates to antibody drug conjugates (ADCs) and their uses.
  • ADC drugs combine the tumor targeting effect of antibodies and the high activity of biologically active compounds, becoming a biological missile with very promising efficacy and safety advantages.
  • the solubility is greatly improved, enabling intravenous administration and effectively solving pharmaceutical problems such as the bioavailability of small molecule compounds.
  • Antibodies guide ADCs to bind to target cells, achieving tumor tissue enrichment, reducing non-target tissue exposure, and reducing possible toxicity caused by systemic administration of bioactive compounds.
  • ADCs that bind to tumor cells can cleave and release bioactive molecules in the tumor microenvironment to kill tumor cells.
  • ADC can also be internalized by tumor cells and undergo enzymatic decomposition under the action of specific enzymes in the cells to release small molecule drugs to treat diseases. Therefore, it is expected that an ADC composed of a protein degrading agent and a tumor-targeting antibody can achieve tumor enrichment, eliminate or reduce the toxic side effects caused by the protein degrading agent acting on non-diseased tissues, and improve the therapeutic effect. Using ADC technology to achieve tumor targeting of protein degradation agents and reduce their toxic and side effects will have high clinical value.
  • the present disclosure provides an antibody drug conjugate represented by Formula I,
  • Tb is an antibody or its antigen-binding fragment
  • S is the sulfur atom on Tb
  • L is the linker, which covalently binds Tb and D;
  • D is the Myc protein degrader fragment
  • q is an integer selected from 1-20.
  • L is a linker that covalently binds Tb and D
  • linker L is covalently bound to the S atom on Tb and is covalently bound to D. Similar expressions below have similar meanings.
  • an antibody drug conjugate represented by Formula II is provided,
  • L 1 is a linker unit, which covalently binds the antibody or its antigen-binding fragment (Tb) to L 2 ;
  • L 2 is a connecting unit, which covalently binds the linker unit (L 1 ) and L 3 ;
  • L 3 is selected from amino acid residues or a short peptide consisting of 2-10 (such as 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acid residues; the amino acid residues are selected from natural Amino acid residues, unnatural amino acid residues or amino acid residues shown in AA 1 or their stereoisomers;
  • R x or R y is hydrogen, and the other is selected from Alternatively, R x and R y and the carbon atoms to which they are commonly connected form a 4-10 membered heterocyclic ring, which is optionally substituted by one or more R 0 ;
  • R x1 and R y1 are each independently selected from hydrogen and C 1-6 alkyl; alternatively, R x1 and R y1 and the nitrogen atoms commonly connected to them form a 4-10 membered heterocyclic ring, and the 4-10 membered heterocycle
  • the heterocycle is optionally substituted with one or more R 0' ;
  • R 0 and R 0' are each independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, -NR x2 R y2 and 4-10 membered heterocyclyl optionally substituted by C 1-6 alkyl. ;
  • R x2 and R y2 are each independently selected from hydrogen and C 1-6 alkyl;
  • L 4 is a chemical bond or spacer unit, covalently combining D and L 3 ;
  • Tb, q and D are as defined in any aspect of this disclosure.
  • the q is selected from 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 2-8, or 4-6; for example, is selected from 1-1 An integer of 10.
  • said q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
  • said q is selected from 2, 4, 6 and 8.
  • L is selected from Position 1 is connected to Tb through the S atom, and position 2 is connected to L 2 .
  • L is selected from Position 1 is connected to Tb through the S atom, and position 2 is connected to L 2 .
  • L2 is selected from Bit 1 is connected to L 1 , bit 2 is connected to L 3 ,
  • W is selected from -CH 2 -, -OCH 2 CH 2 -,
  • W' is selected from -CR x3 R y3 - and -NR x3 -,
  • R x3 and R y3 are each independently selected from hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl,
  • R x3 and R y3 together with the carbon atoms connected to them form a 3-6 membered carbocyclic ring or a 3-6 membered heterocyclic ring,
  • p is any integer selected from 0-10.
  • W is -CH2- .
  • W' is selected from -CH 2 -, -C(CH 3 ) 2 -, -N(CH 3 )- and -NH-.
  • R x3 and R y3 are each independently selected from hydrogen and methyl.
  • p is selected from 0, 1, 2, 3 and 4.
  • L2 is selected from Bit 1 is connected to L 1 , bit 2 is connected to L 3 .
  • L 1 -L 2 are selected from Position 1 is connected to Tb through an S atom, position 2 is connected to L3 , and W, W' and p are defined as described in any scheme of this disclosure.
  • L 1 -L 2 are selected from
  • Position 1 is connected to Tb through the S atom, and position 2 is connected to L 3 .
  • L 1 -L 2 are selected from Position 1 is connected to Tb through the S atom, and position 2 is connected to L 3 .
  • L 3 is selected from the amino acid residues represented by AA 1 or includes 2-10 of the amino acid residues represented by AA 1 (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 ) A short peptide composed of amino acid residues; the amino acid residues are selected from natural amino acid residues, non-natural amino acid residues or amino acid residues represented by AA 1 or their stereoisomers.
  • L3 is selected from Val-Cit, Val-Ala, Phe-Lys, Val-Lys, Val- AA1 , Ala-Ala-Ala, Ala-Ala-Asn, Val- AA1 -Gly, Gly-Gly-Phe-Gly.
  • L3 is selected from Val- AA1 -Gly.
  • the structure of the amino acid residue represented by AA 1 is as follows:
  • R x or R y is hydrogen, and the other is selected from R x1 and R y1 are each independently selected from hydrogen and C1-6 alkyl.
  • R x1 and R y1 are each independently selected from methyl, ethyl, n-propyl and n-butyl; preferably, R x1 and R y1 are both n-propyl.
  • L4 is selected from chemical bonds
  • Bit 1 is connected to L 3 and bit 2 is connected to D.
  • L 4 is Bit 1 is connected to L 3 and bit 2 is connected to D.
  • D is a Myc protein degrading agent fragment, such as a c-Myc protein degrading agent fragment, an n-Myc protein degrading agent fragment, etc.
  • D is a c-Myc protein degrader fragment.
  • D is a structural unit represented by Formula III, and D is connected to L 4 through the oxygen atom, sulfur atom or nitrogen atom it contains;
  • Q is selected from: -NR 2 -, -O-,
  • Ring A represents a heterocycloalkyl group containing at least one N atom as a heteroatom, which is connected to T or R 1 through an N atom. Ring A is optionally substituted by one or more groups selected from R 9 ;
  • T, U, and Z are each independently selected from: chemical bond, N, O, carbonyl group, C 1 -C 6 alkylene group, C 3 -C 10 cycloalkylene group, arylene group, heteroarylene group, heterocyclic ring Base, the alkylene, cycloalkylene, arylene, heteroarylene, heterocyclylene is optionally substituted by one or more R 9 ;
  • Group substitution of C 1 -C 3 alkyl, C 1 - C 3 alkoxy or -OP( O)(OM) 2 ;
  • M is independently selected from: hydrogen, C 1 -C 4 alkyl
  • R 11 and R 12 are each independently selected from: hydrogen, C 1 -C 4 alkyl, aryl, aryl-alkyl;
  • R 21 is selected from: chemical bond, C 1 -C 4 alkylene
  • R 22 and R 23 are each independently selected from: hydrogen, C 1 -C 4 alkyl, aryl, aryl-alkyl, the C 1 -C 4 alkyl, aryl, aryl-alkyl is optional Substituted with a group selected from halogen, hydroxyl, and amino;
  • a is selected from: 0, 1, 2, 3, 4 or 5;
  • b is selected from: 0, 1, 2, 3, 4 or 5;
  • n is selected from: 0, 1, 2 or 3;
  • n is selected from: 0, 1, 2, 3 or 4;
  • the structural unit represented by formula III contains at least one group selected from R 13 or R 14 .
  • D is a structural unit represented by Formula III, and D is connected to L 4 through the oxygen atom or nitrogen atom it contains;
  • Q is selected from: -NR 2 -, -O-,
  • Ring A represents a heterocycloalkyl group containing at least one N atom as a heteroatom, which is connected to T through an N atom. Ring A is optionally substituted by one or more groups selected from R 9 ;
  • T, U, and Z are each independently selected from: chemical bond, carbonyl group, C 1 -C 6 alkylene group, C 3 -C 10 cycloalkylene group, arylene group, heteroarylene group, heterocyclylene group, the above Alkylene, cycloalkylene, arylene, heteroarylene, heterocyclylene are optionally substituted by one or more R 9 ;
  • M is independently selected from: hydrogen, C 1 -C 4 alkyl
  • R 11 and R 12 are each independently selected from: hydrogen, C 1 -C 4 alkyl, aryl, aryl-alkyl;
  • R 21 is selected from: chemical bond, C 1 -C 4 alkylene
  • R 22 and R 23 are each independently selected from: hydrogen, C 1 -C 4 alkyl, aryl, aryl-alkyl, the C 1 -C 4 alkyl, aryl, aryl-alkyl is optional Substituted with a group selected from halogen, hydroxyl, and amino;
  • a is selected from: 0, 1, 2, 3, 4 or 5;
  • b is selected from: 0, 1, 2, 3, 4 or 5;
  • n is selected from: 0, 1, 2 or 3;
  • n is selected from: 0, 1, 2, 3 or 4;
  • the structural unit represented by formula III contains at least one group selected from R 13 or R 14 .
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl substituted C 1 -C 4 alkyl; most preferably, the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 CH 2 CH 2 CH 2 OH.
  • R m is selected from: hydrogen, -C 1 -C 4 alkyl.
  • the R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 Alkyl group; more preferably, the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 CH 2 SH.
  • R m is selected from: hydrogen, -C 1 -C 4 alkyl.
  • D is a structural unit represented by Formula III, and D is connected to L 4 through any hydroxyl group in R 13 or R 14 . In some embodiments, D is a structural unit represented by Formula III, and D is connected to L 4 through any hydroxyl, amino or thiol group in R 13 or R 14 .
  • the R 9 is selected from: hydrogen, C 1 -C 4 alkyl, R 13 ; more preferably, the R 9 is selected from: R 13 .
  • the R 13 is selected from: hydroxyl, R n , -OR n .
  • the R 13 is selected from: hydroxyl, thiol, amino, R n , -OR n .
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl-substituted C 1 -C 4 alkyl; most preferably, the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 CH 2 CH 2 CH 2 OH.
  • the R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 Alkyl group; more preferably, the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH.
  • the R a is selected from: phenyl, naphthyl, carbazolyl, 1-azacarbazolyl, 2-azacarbazolyl, 1,8-diazacarbazolyl, Indolyl, 7-azaindolyl, 2,3-dihydroindolyl, 2,3-dihydro-7-azaindolyl, phenoxazinyl, fluorenyl, quinolinyl, iso Quinolyl, naphthyridinyl, tetralinyl, tetrahydroquinolinyl, pyrimidinyl, triazolyl, bicyclo[1.1.1]pentyl, norbornyl, adamantyl.
  • the R a is optionally substituted by one or more R 9 , and the R 9 is selected from hydrogen, R 13 , halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, phenyl, naphthyl.
  • the R a is selected from: phenyl, naphthyl, carbazolyl, 1-azacarbazolyl, 2-azacarbazolyl, 1,8-diazacarbazolyl, Indolyl, 7-azaindolyl, 2,3-dihydroindolyl, 2,3-dihydro-7-azaindolyl, phenoxazinyl, fluorenyl, quinolinyl, iso Quinolyl, naphthyridinyl, tetralinyl, tetrahydroquinolinyl, pyrimidinyl, pyridyl, quinolyl-pyridyl, triazolyl, bicyclo[1.1.1]pentyl, norbornane base, adamantyl.
  • R 13 halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, phenyl, naphthyl.
  • the R a is selected from: phenyl, naphthyl-1-yl, naphthyl-2-yl, carbazol-9-yl, 1-azacarbazol-9-yl, 2-azacarbazole- 9-yl, 1,8-diazacarbazol-9-yl, indol-1-yl, 2,3-dihydro-indol-1-yl, 7-azaindol-1-yl , 2,3-dihydro-7-azaindolyl-1-yl, phenoxazin-10-yl, fluoren-9-yl, quinolin-4-yl, quinolin-5-yl, quinoline -8-yl, isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, 1,2,3,4-tetrahydro-1, 8-naphthyridin-1-yl, 1,2,3,4
  • the R a is optionally substituted by one or more R 9 , and the R 9 is selected from: R 13 , F, Cl, Br, cyano, methyl, ethyl, trifluoromethyl, methoxy base, ethoxy, phenyl, naphthyl-1-yl, naphthyl-2-yl.
  • the R a is selected from: phenyl, naphth-1-yl, naphth-2-yl, carbazol-9-yl, 1-azacarbazol-9-yl, 2-aza Carbazol-9-yl, 1,8-diazacarbazol-9-yl, indol-1-yl, 2,3-dihydro-indol-1-yl, 7-azaindolyl- 1-yl, 2,3-dihydro-7-azaindolyl-1-yl, phenoxazin-10-yl, fluoren-9-yl, quinolin-4-yl, quinolin-5-yl , quinolin-8-yl, isoquinolin-1-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-8-yl, 1,2,3,4-tetrahydro -1,8-naphthyridin-1-yl, 1,2,3,4-tetra
  • R a is optionally substituted by one or more R 9 , and the R 9 is selected from: R 13 , F, Cl, Br, cyano, methyl, ethyl, trifluoromethyl, methoxy, Ethoxy, phenyl, naphthyl-1-yl, naphthyl-2-yl.
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl substituted C 1 -C 4 alkyl; most preferably, R n is selected from From: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, or -CH 2 CH 2 CH 2 CH 2 OH.
  • the R n is selected from: hydroxyl hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 alkyl; more preferably, the R n is selected from : -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH.
  • the R m is selected from: hydrogen, -C 1 -C 4 alkyl.
  • the R 9 is selected from: F, Cl, Br, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, hydroxyl, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -OCH 2 OH, -OCH 2 CH 2 OH, -OCH 2 CH 2 CH 2 OH, -NHCH 2 OH, -NHCH 2 CH 2 OH, -NHCH 2 CH 2 CH 2 OH, -N(CH 3 )CH 2 OH, -N(CH 3 )CH 2 CH 2 OH, -N(CH 3 )CH 2 CH 2 CH 2 OH, -N(COCH 3 )CH 2 OH, - N(COCH 3 )CH 2 CH 2 OH, -N(COCH 3 )CH 2 CH 2 CH 2 OH, -N(SO 2 CH 3 )CH 2 OH, -N(SO 2 CH 3 )CH 2 OH
  • said R a is selected from the following groups:
  • the Ra is selected from the following groups:
  • the Q is selected from: -NR2- ,
  • the alkyl moiety is optionally substituted with one or more R 9 selected from: hydrogen, halogen, amino, cyano, carboxyl , C 1 -C 6 alkyl, C 1 -C 6 alkoxy or aromatic group; more preferably, the R 2 is selected from: R 9
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl-substituted C 1 -C 4 alkyl; most preferably, the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 CH 2 CH 2 CH 2 OH.
  • the R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 alkyl; most preferably, R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH.
  • the R m is selected from: hydrogen, -C 1 -C 4 alkyl.
  • the R 2 is further selected from: hydrogen, methyl, ethyl, -SO 2 CH 3 , -COCH 3 , -CO-isopropyl, -CO-cyclopropyl, isopropyl, Cyclopropyl, 2-methoxyethyl, 2-cyanoethyl, phenyl, naphthyl, benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylethyl, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH
  • each R 9 is independently selected from: hydrogen, R 13 , halogen, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy;
  • Each a1 is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, each a2 is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8.
  • Each a3 is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7.
  • Each a4 is independently selected from: 0, 1, 2, 3, 4, 5, 6.
  • Each a5 is independently selected. Selected from: 0, 1, 2, 3, 4, 5.
  • the R 13 is selected from: hydroxyl, R n , - OR n .
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, R n is selected from: hydroxyl-substituted C 1 -C 4 alkyl; most preferably, R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 CH 2 CH 2 CH 2 OH.
  • the R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 alkyl; Most preferably, R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH.
  • the R m is selected from: hydrogen, -C 1 -C 4 alkyl.
  • the T and Z are independently selected from: chemical bond, carbonyl group, C 1 -C 6 alkylene group or C 3 -C 10 cycloalkylene group, the C 1 -C 6 alkylene group , C 3 -C 10 cycloalkylene is optionally substituted by one or more R 9 .
  • the T and Z are independently selected from: chemical bonds, carbonyl groups, methylene groups, 1,2-ethylene groups, 1,1-cyclopropylene groups or 2,2-propylene groups.
  • Methyl, 1,2-ethylene, and 1,1-cyclopropylene are optionally substituted by one or more R 9 .
  • the R 9 is selected from: hydrogen, R 13 , C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl.
  • the R 13 is selected from: hydroxyl, R n , -OR n .
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, R n is selected from: hydroxyl-substituted C 1 -C 4 alkyl; most preferably, the R n is selected from From: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, or -CH 2 CH 2 CH 2 CH 2 OH.
  • the R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 Alkyl group; more preferably, the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH.
  • the U is selected from: C 1 -C 6 alkylene, C 3 -C 10 cycloalkylene, arylene or heteroarylene, the alkylene, cycloalkylene , arylene group and heteroarylene group are optionally substituted by one or more R 9 .
  • the U is selected from: C 2 -C 6 alkylene, C 5 -C 6 cycloalkylene, C 6 -C 10 arylene, 5-6 membered monocyclic heteroarylene, the Alkylene, cycloalkylene, arylene, heteroarylene are optionally substituted by one or more R 9 .
  • the U is selected from: 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,3 -Cyclopentylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,5- Pyridinyl, 2,5-pyrimidinyl, 2,5-thiazolyl or 2,4-oxazolyl, the 1,2-ethylene, 1,3-propylene, 1,4 -Butylene, 1,3-cyclopentylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene Phenyl, 2,5-pyridinylene, 2,5-pyrimidinyl, 2,5-thiazolylene, and 2,4-oxazolylene are optionally substituted by one or more R 9 .
  • the R 9 is selected from: hydrogen, R 13 , halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy.
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, R n is selected from: hydroxyl-substituted C 1 -C 4 alkyl; most preferably, R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 CH 2 CH 2 CH 2 OH.
  • the R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 Alkyl group; more preferably, the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH.
  • the R m is selected from: hydrogen, -C 1 -C 4 alkyl.
  • the R 9 is selected from: F, Cl, Br, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, hydroxyl, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -OCH 2 OH, -OCH 2 CH 2 OH, -OCH 2 CH 2 CH 2 OH, -NHCH 2 OH, -NHCH 2 CH 2 OH, -NHCH 2 CH 2 CH 2 OH, -N(CH 3 )CH 2 OH, -N(CH 3 )CH 2 CH 2 OH, -N(CH 3 )CH 2 CH 2 CH 2 OH, -N(COCH 3 )CH 2 OH, - N(COCH 3 )CH 2 CH 2 OH, -N(COCH 3 )CH 2 CH 2 CH 2 OH, -N(SO 2 CH 3 )CH 2 OH, -N(SO 2 CH 3 )CH 2 OH
  • said U is selected from the following groups:
  • the -TUZ- taken together form a group selected from:
  • the R 9 is selected from: hydrogen, C 1 -C 4 alkyl, R 13 ; more preferably, the R 9 is selected from: R 13 .
  • the R 13 is selected from: hydroxyl, R n , -OR n .
  • the base part is optionally substituted by one or more R 9 selected from: hydrogen, halogen, amino, cyano, carboxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or aryl ; More preferably, the
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl-substituted C 1 -C 4 alkyl; most preferably, the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 CH 2 CH 2 CH 2 OH.
  • the R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 alkyl; most preferably, R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH.
  • the R m is selected from: hydrogen, -C 1 -C 4 alkyl.
  • the R 2 is further selected from: hydrogen, methyl, ethyl, -SO 2 CH 3 , -COCH 3 , -CO-isopropyl, -CO-cyclopropyl, isopropyl, Cyclopropyl, 2-methoxyethyl, 2-cyanoethyl, phenyl, naphthyl, benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylethyl, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, R n is selected from: hydroxyl-substituted C 1 -C 4 alkyl; most preferably, R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 CH 2 CH 2 CH 2 OH.
  • the R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 alkyl; most preferably, R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH.
  • each of R 3 to R 5 is independently selected from: hydrogen, R 13 , halogen, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio group, C 1 -C 6 alkylamino group, di(C 1 -C 6 alkyl)amine group, C 3 -C 8 cycloalkyl group, the alkyl group, alkoxy group, alkylamino group , alkylthio and cycloalkyl are optionally substituted by 1-3 groups respectively selected from halogen, C 1 -C 3 alkyl or C 1 -C 3 alkoxy; when R 3 -R 5 is multiple In this case, any two adjacent ones can be combined to form a ring.
  • said R 3 is selected from: R 13 .
  • the R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; more preferably, R n is selected from: hydroxyl-substituted C 1 -C 4 alkyl; most preferably, R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH or -CH 2 CH 2 CH 2 CH 2 OH.
  • the R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl; more preferably, the R n is selected from: hydroxyl, mercapto or amino substituted C 1 -C 4 alkyl; most preferably, R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH.
  • R m is selected from: hydrogen, -C 1 -C 4 alkyl.
  • the R 4 to R 5 are each independently selected from: hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl.
  • the R 6 is selected from: hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and the alkyl and cycloalkyl are optionally selected from 1 to 3 respectively.
  • R 23 is selected from: hydrogen, C 1 -C 4 alkyl, so The C 1 -C 4 alkyl group is optionally substituted by 1 to 3 groups respectively selected from hydroxyl and amino groups.
  • R 23 is selected from: hydrogen, C 1 -C 4 alkyl, and the C 1 -C 4 alkyl is optionally substituted by 1-3 groups respectively selected from hydroxyl and amino.
  • the R 6 is selected from: hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and the alkyl and cycloalkyl are optionally selected from 1 to 3 respectively.
  • the R 6 is selected from: hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl.
  • the R a is selected from the following groups:
  • the Ra is further preferably the following group:
  • Q is selected from: -NR 2 -and
  • R n is selected from: hydroxyl-substituted C 1 -C 8 alkyl; preferably, R n is selected from: hydroxyl, mercapto or amino-substituted C 1 -C 8 alkyl;
  • R m is selected from: hydrogen and -C 1 -C 4 alkyl
  • T and Z are independently selected from: chemical bond, carbonyl group, methylene group, 1,2-ethylene group, 1,1-cyclopropylene group or 2,2-propylene group;
  • R 3 to R 6 are each independently selected from: hydrogen and C 1 -C 6 alkyl
  • X is CH 2 ;
  • a is selected from: 0, 1, 2, 3, 4 or 5;
  • b is selected from: 0, 1, 2, 3, 4 or 5;
  • n is selected from: 0, 1 or 2;
  • n is selected from: 0, 1 or 2.
  • the R a is selected from the following groups:
  • the Ra is further preferably the following group:
  • Q is selected from: -NR 2 -and
  • R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH and -CH 2 CH 2 CH 2 CH 2 OH; preferably, the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH;
  • R m is hydrogen
  • -TUZ- is not C 1-4 alkylene
  • R 3 to R 6 are each independently hydrogen
  • X is CH 2 ;
  • the R a is selected from the following groups:
  • the Ra is further preferably the following group:
  • Q is selected from: -NR 2 -and
  • R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CH 2 CH 2 CH 2 SH;
  • the R n is selected from: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH and -CH 2 CH 2 CH 2 CH 2 OH;
  • R m is hydrogen
  • R 3 to R 6 are each independently hydrogen
  • X is CH 2 ;
  • the Ra is selected from the following groups:
  • the Ra is further preferably the following group:
  • the structural unit represented by formula III is a structural unit represented by the following formula III-A
  • R 1 , R 3 , R 4 , R 5 , R 6 , Q, T, U, Z, X, Y, m and n are as defined above.
  • D is selected from
  • the antibody drug conjugate structure is shown in Formula IV,
  • Tb, S, L 1 , L 2 , R x1 , R y1 , D and q are defined as described in any scheme of this disclosure.
  • antibodies or antigen-binding fragments thereof suitable for use in the ADCs of the invention are anti-PSMA antibodies or antigen-binding fragments thereof.
  • an antibody or antigen-binding fragment thereof suitable for use in the ADC of the invention is an antibody portion that specifically binds PSMA, such as the PSMA antibodies disclosed by Progenics, or the antibodies in its PSMA ADC, such as those in US9242012B2 or WO2021/190583A1 PSMA antibodies or antigen-binding fragments thereof in ADCs or conjugates disclosed in.
  • PSMA antibodies or antigen-binding fragments thereof suitable for use in the ADC of the invention comprise known antibodies that specifically bind PSMA, such as the PSMA antibodies disclosed by Progenics, or antibody portions thereof in PSMA ADCs, such as those in US9242012B2 Or 1, 2, 3, 4, 5, or 6 CDRs of the antibody in the ADC or conjugate disclosed in WO2021/190583A1.
  • the antigen-binding region comprises an antibody known to specifically bind PSMA, such as the PSMA antibodies disclosed by Progenics, or an antibody in a PSMA ADC thereof, such as the ADC or conjugate disclosed in US9242012B2 or WO2021/190583A1
  • the 1, 2 and 3 heavy chain variable region CDRs of the antibody namely HCDR1, HCDR2 and HCDR3.
  • the antigen-binding region comprises an antibody known to specifically bind PSMA, such as the PSMA antibodies disclosed by Progenics, or the antibodies in its PSMA ADC, such as those disclosed in US9242012B2 Or 1, 2 and 3 light chain variable region CDRs of the antibody in the ADC or conjugate disclosed in WO2021/190583A1, namely LCDR1, LCDR2 and LCDR3.
  • an antibody to PSMA such as a PSMA antibody disclosed by Progenics, or an antibody in its PSMA ADC, such as an ADC disclosed in US9242012B2 or WO2021/190583A1, or the three heavy chain variable regions of an antibody in a conjugate CDRs and 3 light chain variable region CDRs.
  • the antigen-binding region comprises an antibody known to specifically bind PSMA, such as the PSMA antibodies disclosed by Progenics, or an antibody in a PSMA ADC thereof, such as the ADC or conjugate disclosed in US9242012B2 or WO2021/190583A1
  • PSMA antibodies disclosed by Progenics
  • ADC an antibody in a PSMA ADC thereof, such as the ADC or conjugate disclosed in US9242012B2 or WO2021/190583A1
  • the heavy chain variable region of the antibody, and/or the light chain variable region is provided.
  • the antigen-binding region comprises an antibody known to specifically bind PSMA, such as the PSMA antibodies disclosed by Progenics, or an antibody in a PSMA ADC thereof, such as the ADC or conjugate disclosed in US9242012B2 or WO2021/190583A1
  • PSMA antibodies disclosed by Progenics
  • ADC an antibody in a PSMA ADC thereof, such as the ADC or conjugate disclosed in US9242012B2 or WO2021/190583A1
  • the PSMA antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof containing the following CDRs: HCDR1 shown in SEQ ID No. 7, HCDR2 shown in SEQ ID No. 8, SEQ ID No. HCDR3 shown in .9, LCDR1 shown in SEQ ID No.10, LCDR2 shown in SEQ ID No.11, LCDR3 shown in SEQ ID No.12.
  • an antibody or antigen-binding fragment thereof that specifically binds PSMA comprises a heavy chain variable region (VH), wherein the VH
  • (iii) Comprises one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 1 , more preferably amino acid conservative substitution) amino acid sequence consists of the amino acid sequence, preferably, the amino acid changes do not occur in the CDR region.
  • an antibody or antigen-binding fragment thereof that specifically binds PSMA comprises a light chain variable region (VL), wherein the VL
  • (iii) Comprises one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions) compared to the amino acid sequence of SEQ ID NO:3 , more preferably amino acid conservative substitution) amino acid sequence consists of the amino acid sequence, preferably, the amino acid changes do not occur in the CDR region.
  • the PSMA antibody or antigen-binding fragment thereof contains the VH shown in SEQ ID No. 1 and the VL shown in SEQ ID No. 3.
  • the PSMA antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and/or a light chain constant region, wherein
  • (iii) Comprises one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions) compared to the amino acid sequence of SEQ ID NO:2 , more preferably the amino acid sequence consisting of the amino acid sequence consisting of the amino acid conservative substitution);
  • (iii) Comprises one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions) compared to the amino acid sequence of SEQ ID NO:4 , more preferably the amino acid sequence consists of the amino acid sequence consisting of the amino acid conservative substitution).
  • the PSMA antibody or antigen-binding fragment thereof contains: VH shown in SEQ ID No. 1 and CH shown in SEQ ID No. 2, and VL shown in SEQ ID No. 3 and CL shown in SEQ ID No.4.
  • the PSMA antibody or antigen-binding fragment thereof contains: the heavy chain shown in SEQ ID No. 5 and the light chain shown in SEQ ID No. 6.
  • the antibody drug conjugate (ADC) is selected from the following:
  • q is selected from 1-10, such as 2-8.
  • the antibody drug conjugate has a drug to antibody ratio (average DAR) of any value selected from the following range: 1.0-20.0, 1.0-18.0, 1.0-16.0, 1.0-10.0, 2.0 -14.0, 3.0-12.0, 4.0-10.0, 5.0-9.0, 6.0-8.0 or 2.0-8.0.
  • a drug to antibody ratio average DAR
  • the average DAR is any value within 2+/-0.4, 4+/-0.4, 6+/-0.4, or 8+/-0.4.
  • the average DAR is about 2.0, 4.0, 6.0, 8.0, 10.0, or 12.0.
  • the present disclosure provides a drug linker conjugate represented by Formula V,
  • L' is a linker precursor
  • D is defined as described in any scheme of this disclosure.
  • a drug linker conjugate represented by Formula VI, its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate is provided,
  • L 1 is defined as described in any aspect of this disclosure, and L 1 is not When , Lg is the leaving group when reacting with the antibody; L 2 , L 3 , L 4 and D are defined as described in any scheme of this disclosure;
  • Lg-L 1 is L 2 , L 3 , L 4 and D are as defined in any aspect of this disclosure.
  • Lg is selected from halogen, sulfone, tertiary amine (Me 3 N + , Et 3 N + ), diazonium, -OMs, MeSO 2 -, CF 3 SO 3 -, p Tosyl.
  • Lg is selected from F, Cl, Br, MeSO 2 -; more preferably; Lg is MeSO 2 -.
  • a drug linker conjugate represented by Formula VII, its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate is provided,
  • Lg, L 1 , L 2 , R x1 , R y1 and D are as described in any aspect of this disclosure.
  • the drug linker conjugate is selected from the following:
  • R 1 , Q, T, U, Z, Y, X, R 3 , R 4 , R 5 , R 6 , m, and n are as described in any aspect of this disclosure.
  • the compound of Formula VIII has the structure shown in Formula VIII-A below
  • R 1 , R 3 , R 4 , R 5 , R 6 , Q, T, U, Z, X, Y, m and n are as defined above.
  • the structure of the protein-degrading bioactive compound is as follows:
  • a method for preparing an antibody-drug conjugate represented by Formula I includes: performing a coupling reaction between Tb and a drug linker conjugate represented by Formula V in a solvent to form C-S key steps.
  • the molar ratio of the Tb to the drug linker conjugate represented by Formula V is 1:(1-20), such as 1:2, 1:4, 1:6, 1:8, 1:10, 1:12, 1:14, 1:16, 1:18, 1:(10-20), 1:(12-20), 1:(14-20), 1:(16-20 ) or 1:(18-20).
  • the coupling reaction is performed in water and/or organic solvents.
  • the organic solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or any of them. combination.
  • the method further includes the step of purifying the coupling product.
  • the coupling product is purified by chromatography.
  • the chromatography method includes one or more of ion exchange chromatography, hydrophobic chromatography, reversed phase chromatography, or affinity chromatography.
  • the method is carried out at -20-100°C, such as 0-50°C, preferably room temperature.
  • the disclosure provides a method for preparing a drug linker conjugate
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned antibody drug conjugate, or a stereoisomer of the antibody drug conjugate, a prodrug thereof, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides the aforementioned antibody drug conjugate, or the stereoisomer of the antibody drug conjugate, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate. or the aforementioned drug linker conjugate, its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate; or the aforementioned pharmaceutical composition is used in the preparation of Use in medicines for the treatment and/or prevention of diseases associated with abnormal cellular activity, such as cancer diseases.
  • the present disclosure also provides methods for preventing and/or treating diseases related to abnormal cell activity (such as cancer diseases), which include administering to an individual the aforementioned antibody drug conjugate, or a stereoisomer of the antibody drug conjugate. body, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate; or the aforementioned drug linker conjugate, its stereoisomer, its prodrug, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof; or the aforementioned pharmaceutical composition.
  • diseases related to abnormal cell activity such as cancer diseases
  • the present disclosure also provides the aforementioned antibody drug conjugate, or the stereoisomer of the antibody drug conjugate, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate; or Such as the aforementioned drug linker conjugates, their stereoisomers, their prodrugs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates; or the aforementioned pharmaceutical compositions, which are used to treat and /or prevent diseases, such as those associated with abnormal cellular activity (e.g., cancer diseases).
  • diseases such as those associated with abnormal cellular activity (e.g., cancer diseases).
  • the cancer disease is a solid tumor or a hematological tumor.
  • the cancer disease is selected from the group consisting of esophageal cancer (eg, esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumors, lung cancer (eg, small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma , bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal cancer, urothelial cancer, solid tumors, non-Hodge cancer Gold lymphoma, central nervous system tumors (such as glioma, glioblastoma multiforme, glioma, or sarcoma), prostate cancer, or thyroid cancer.
  • esophageal cancer eg, esophageal adenocarcinoma and esophageal squamous cell carcinoma
  • brain tumors eg, e
  • protein degrader refers to a class of compounds, preferably small molecule compounds, that can induce and ubiquitylate a protein of interest through E3 ligases and then degrade it through the proteasome.
  • Myc protein degrading agent refers to a protein degrading agent that has the ability to degrade Myc family proteins, such as a protein degrading agent that has the ability to degrade c-Myc protein and a protein degrading agent that has the ability to degrade n-Myc protein.
  • c-Myc protein degrading agent refers to a protein degrading agent that has the ability to degrade c-Myc protein.
  • protein degradation targeting chimera generally includes three parts: an E3 ubiquitin ligase ligand and a target protein ligand, two active ligands through a specially designed Linker structure Linked together, by recruiting E3 ubiquitin ligase to the target protein, it ubiquitinates the target protein and then degrades the target protein.
  • MLD molecular glue degrader
  • the term "pharmaceutically acceptable salt” means a salt that retains the biological effects and properties of the antibody-drug conjugate or drug-linker conjugate of the invention, and the salt is biologically or Other aspects are not undesirable.
  • the conjugates of the present invention may exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts.
  • a pharmaceutically acceptable acid addition salt means that the conjugate in the present invention is formed with an organic or inorganic acid.
  • Salts, organic or inorganic acids include but are not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, formazan Sulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc.
  • Pharmaceutically acceptable base addition salts refer to salts formed by the conjugate in the present invention and organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or Magnesium salts; organic base salts, such as ammonium salts formed with organic bases containing N groups.
  • alkali metal salts such as lithium, sodium or potassium salts
  • alkaline earth metal salts such as calcium or Magnesium salts
  • organic base salts such as ammonium salts formed with organic bases containing N groups.
  • compositions can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.
  • stereoisomer means an isomer formed due to at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three or four) asymmetric centers they can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual of diastereomers.
  • Certain individual molecules may also exist as geometric isomers (cis/trans).
  • compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers).
  • tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. wait. It is to be understood that the scope of the present disclosure encompasses all such products in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99 %) isomers or mixtures thereof.
  • the carbon-carbon bonds of the compounds of the invention may be depicted in this disclosure using solid lines (—), solid wedges, or dashed wedges.
  • the use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, a racemic mixture, etc.).
  • the use of solid or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to demonstrate that the stereoisomers shown exist. When present in a racemic mixture, solid and imaginary wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the present invention are intended to exist as stereoisomers (which includes cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, They exist in the form of geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereoisomers).
  • the present disclosure also includes all pharmaceutically acceptable isotopic compounds that are identical to the compounds of the invention except that one or more atoms are assigned the same atomic number but an atomic mass or mass number that is different from the atomic mass or mass that predominates in nature Atomic substitution of numbers.
  • isotopes suitable for inclusion in the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen (e.g. 2 H, 3 H); isotopes of carbon (e.g. 11 C, 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g.
  • Iodine isotopes such as 123 I and 125 I
  • Nitrogen isotopes such as 13 N and 15 N
  • Oxygen isotopes such as 15 O, 17 O and 18 O
  • Phosphorus isotopes such as 32 P
  • isotopes of sulfur e.g. 35 S.
  • the compounds of the present disclosure may exist in the form of solvates, preferably hydrates, wherein the compounds of the present disclosure comprise a polar solvent as a structural element of the crystal lattice of the compound, in particular such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular such as water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the invention ie substances formed in the body upon administration of the compounds of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc. of the administered compound.
  • the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce metabolites thereof.
  • the present disclosure further includes within its scope prodrugs of the compounds of the invention.
  • prodrugs will be functional group derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Therefore, in these instances, the term “administering" as used in the treatment methods of the present disclosure shall include the treatment of various diseases or conditions with prodrug forms of one or more of the claimed compounds, but in The prodrug form is converted in vivo to the compound described above upon administration to an individual.
  • “Design of Prodrug” ed. H. Bundgaard, Elsevier, 1985, general methods for selecting and preparing suitable prodrug derivatives are described.
  • the pharmaceutical excipients refer to the excipients and additives used in the production of drugs and preparation of prescriptions. They refer to excipients and additives that have been reasonably evaluated in terms of safety in addition to active ingredients and are included in pharmaceutical preparations. substance in.
  • pharmaceutical excipients also have important functions such as solubilization, dissolution, and sustained and controlled release. They are important ingredients that may affect the quality, safety, and effectiveness of drugs. According to their origin, they can be divided into natural products, semi-synthetic products and fully synthetic products.
  • solvents can be divided into: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, Glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesive agents, antioxidants, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers, surface active agents Agents, foaming agents, defoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants, etc.; can be divided according to their route of administration for mouth Oral administration, injection, mucous membrane, transdermal or topical administration, nasal or oral inhalation administration and ocular administration, etc.
  • the same pharmaceutical excipients can be used in pharmaceutical preparations with different
  • the pharmaceutical composition can be prepared into various suitable dosage forms according to the route of administration.
  • suitable dosage forms for example, tablets, capsules, granules, oral solutions, oral suspensions, oral emulsions, powders, tinctures, syrups, injections, suppositories, ointments, creams, pastes, ophthalmic preparations, pills, implants agents, aerosols, powder mist, sprays, etc.
  • the pharmaceutical composition or suitable dosage form may contain 0.01 mg to 1000 mg of the compound of the present disclosure (including conjugates) or a pharmaceutically acceptable salt thereof, suitably 0.1 mg to 800 mg, preferably 0.5-500 mg. , preferably contains 0.5 to 350 mg, particularly preferably 1 to 250 mg.
  • the pharmaceutical composition can be administered in the form of injection, including injection liquid, sterile powder for injection and concentrated solution for injection.
  • carriers and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may be used as solvents or suspending media, such as mono- or diglycerides.
  • the pharmaceutical composition may be administered in the form of an infusion.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) preventing the disease or symptoms in a patient who is susceptible to the disease or condition but has not yet been diagnosed with the disease; (b) suppressing the symptoms of the disease , i.e., arresting its progression; or (c) alleviating the symptoms of a disease, i.e., causing regression of the disease or symptoms.
  • the term "individual” includes humans or non-human animals.
  • Exemplary human subjects include human subjects (referred to as patients) suffering from a disease, such as those described in this disclosure, or normal subjects.
  • non-human animals in this disclosure includes all vertebrate animals, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • the term "effective dose” refers to an amount of an antibody-drug conjugate, drug-linker conjugate, compound or composition that when administered will alleviate to a certain extent one or more symptoms of the condition being treated. .
  • the terms "antibody drug conjugate” and "ADC” refer to a substance obtained by connecting a biologically active compound fragment (drug molecule) to an antibody or its antigen-binding fragment portion.
  • the bioactive compound fragment is linked to the targeting moiety via a linker.
  • the linker can be cleaved in a specific environment (such as an intracellular low pH environment) or under a specific action (such as the action of a lysosomal protease), thereby allowing the bioactive compound (such as a c-Myc protein degrader) fragment to interact with the target. Separation into parts or antibodies or antigen-binding fragments thereof.
  • the linker comprises a cleavable or non-cleavable units such as peptides or disulfide bonds.
  • the bioactive compound fragment is directly connected to the targeting moiety or antibody or antigen-binding fragment thereof by a covalent bond, which can be broken under specific circumstances or effects, thereby rendering the bioactive compound The fragment is partially separated from the antibody or antigen-binding fragment thereof.
  • the 1-position of L is connected to Tb through an S atom
  • the 1-position of L is responsible for opening the disulfide bond (for example, the disulfide bond can be opened by reducing the disulfide bond through the reducing agent TCEP).
  • the disulfide bond which generates the sulfhydryl group -SH), is connected to the sulfhydryl group contained in Tb (such as an antibody) itself.
  • the -S- between L and Tb is not an additional external sulfur atom.
  • -S- is not another external sulfur atom, but the thiol group and L contained in Tb itself after opening the disulfide bond, for example 1 bits are connected to form -S-.
  • unsubstituted means that the referenced group is not substituted with a substituent, it being understood that the referenced group will contain an appropriate number of hydrogen atoms to comply with valence rules.
  • the term "substituted by” refers to the independent presence of one or more substituents at any carbon (or nitrogen) position of the molecule, preferably 1-5 (such as 1, 2, 3, 4 or 5 ) substituent, most preferably 1-3 substituents, the substituent may be: hydroxyl, mercapto, carboxyl, cyano, nitro, halogen (preferably, 1, 2 or 3 halogen, especially on the alkyl group, especially on the alkyl group Methyl, for example trifluoromethyl), alkyl (preferably C 1 -C 10 , more preferably C 1 -C 6 ), haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl (especially phenyl ), heteroaryl, heterocyclyl, alkoxy (preferably C 1 -C 6 alkoxy), aryloxy (preferably phenoxy), thioether (C 1 -C 6 alkylthio or arylthio) Such as
  • alkyl refers to a straight-chain, branched-chain fully saturated hydrocarbon group that may be optionally substituted, preferably C 1 -C 10 , more preferably C 1 -C 8 , C 1 -C 6 , or C 1 -C 4 alkyl.
  • alkyl groups are methyl, ethyl, Propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl, etc.
  • alkylene refers to a divalent group formed by further removing one hydrogen atom from an alkyl group.
  • cycloalkyl refers to a cyclic alkyl group that may be optionally substituted, preferably C 3 -C 20 , more preferably C 3 -C 15 , or C 3 -C 8 cycloalkyl.
  • Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl or cycloheptyl, among others.
  • cycloalkylene refers to a divalent group formed by further removing one hydrogen atom from a cycloalkyl group.
  • bridged cyclic group refers to a cyclic structure formed by two or more cyclic structures that may be optionally substituted and share two non-adjacent carbon atoms with each other, preferably C 5 -C 15 , more preferably C 6 -C 12 , or C 7 -C 10 bridged ring group.
  • Examples of bridged cyclic groups are bicyclo[1.1.1]pentyl, norbornyl, adamantyl and the like.
  • alkynyl refers to a linear, branched or cyclic C 2 -C 10 (preferably C 2 -C 8 ) hydrocarbon group containing at least one C ⁇ C bond.
  • aryl refers to C 6 -C 16 having a single ring (such as phenyl) or a condensed ring (such as naphthyl, anthracenyl, phenanthrenyl, fluorenyl, etc.) that may be optionally substituted.
  • Aromatic hydrocarbon groups preferably C 6 -C 10 aromatic hydrocarbon groups.
  • arylene refers to a divalent group formed by further removing one hydrogen atom from an aryl group.
  • heteroaryl refers to an optionally substituted 5- containing one or more (eg, 1, 2, 3, or 4) heteroatoms selected from N, O, S, or P.
  • a 16-membered aromatic group is preferably a 5- to 10-membered aromatic group, and more preferably a 5- to 6-membered aromatic group.
  • heteroaryl groups include imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridyl Azinyl, pyrimidinyl, pyridazinyl, indolyl, azaindolyl (such as 7-azaindolyl), benzimidazolyl, benzopyrazolyl, benzofuranyl, benzothienyl , benzothiazolyl, dibenzofuranyl, dibenzothienyl, quinolyl, isoquinolinyl, naphthyridinyl, carbazolyl, azacarbazolyl (such as 1-azacarbazolyl, 2-azacarbazolyl, 1,8-diazacarbazolyl), indolaziny
  • heteroaryl refers to a bivalent group formed by further removing one hydrogen atom from a heteroaryl group.
  • heterocyclyl refers to an optionally substituted group containing one or more (eg, 1, 2, 3 or 4) selected from N, O, S, SO, SO 2 or P Partially unsaturated or completely unsaturated 3-20-membered cyclic group of heteroatoms, preferably 3-10-membered cyclic group, more preferably 3-6-membered cyclic group; more preferably 5-6-membered cyclic group group; the heterocyclic group contains 1-19 carbon atoms, preferably 2-10 carbon atoms, and more preferably 3-5 carbon atoms.
  • heterocyclyl examples include: aziridinyl, oxetanyl, azetidinyl, oxetanyl, 1,4-benzodioxanyl, 1,3-benzo Dioxolyl, dihydroimidazolyl, dihydropyranyl, dihydrofuryl, dioxanyl, ethyleneureido, 1,3-dioxolyl, 1, 3-dioxanyl, 1,4-dioxanyl, imidazolinyl, indolinyl, morpholinyl, pyridone, 2-pyrrolidone, piperazinyl, homopiperazinyl, piperidinyl, homo Piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl, tetra
  • heterocyclylene refers to a bivalent group formed by further removing one hydrogen atom from the heterocyclyl group.
  • heterocycloalkyl refers to a fully saturated heterocyclyl group.
  • fused arylcycloalkyl refers to a group formed by the fusion of the above-mentioned aryl group and cycloalkyl group.
  • fused arylheterocyclyl refers to a group formed by the fusion of the above-mentioned aryl group and heterocyclyl.
  • fused heteroarylcycloalkyl refers to a group formed by the fusion of the above-mentioned heteroaryl and cycloalkyl.
  • fused heteroarylheterocyclyl refers to a group formed by the fusion of the above-mentioned heteroaryl and heterocyclyl.
  • aryl-alkyl means that the above-mentioned aryl group and alkyl group are connected through a single bond, and other parts are connected through the alkyl group.
  • heterocycle refers to an optionally substituted heterocyclic ring containing one or more (eg, 1, 2, 3, or 4) selected from N, O, S, SO, SO 2, or P Atomically partially unsaturated or fully unsaturated 3-20-membered cyclic groups, preferably 4-10-membered cyclic groups, 3-7-membered cyclic groups, more preferably 3-6-membered cyclic groups, including But it is not limited to pyrrolidine, dihydropyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran, pyrrolidone and other rings.
  • the term "carbocyclic ring” refers to a partially unsaturated or fully unsaturated 3-10-membered cyclic group in which all ring atoms are carbon atoms, preferably a 3-7-membered cyclic group, and more preferably a 3-6-membered cyclic group. cyclic group.
  • the carbon atoms in the cyclic structure can be oxo-substituted, including but not limited to cyclopropane, cyclobutane and other rings.
  • halogen refers to F, Cl, Br, I.
  • drug refers to a substance that inhibits or prevents the function of a cell and/or causes cell death or destruction.
  • linker refers to a fragment that connects a biologically active compound fragment (drug molecule) to an antibody moiety.
  • the linker prior to being attached to the antibody or antigen-binding fragment thereof (i.e., the linker precursor), has functional groups that can form bonds with functional groups of the antibody or antigen-binding fragment thereof.
  • the "... bioactive compound fragment” refers to the antibody-drug conjugate (or antibody-drug conjugate (ADC)) known in the art, which is used in tumors.
  • ADC antibody-drug conjugate
  • biologically active drugs such as small molecule cytotoxic drugs, which include groups after losing one atom or atomic group
  • derivatives thereof For example, its precursor part (fragment or group).
  • drug do not only refer to “drugs” that have been approved by the medical regulatory authorities, but also include any compounds with potential therapeutic biological activity in clinical practice, or in R&D and academic research.
  • the biologically active compound includes the Myc protein degrading agent of the present invention.
  • linker unit is a component of an antibody-drug conjugate or a drug-linker conjugate or a linker, and its function is to connect the antibody or antigen-binding fragment thereof that binds to the target with the antibody-drug conjugate. connected to the rest.
  • the linker unit can connect the Tb unit to L 2. Specific examples include but are not limited to (where 1 position is connected to the antibody or its antigen-binding fragment, and 2 position is connected to L 2 or L 3 ):
  • linking unit is a component of an antibody-drug conjugate or a drug-linker conjugate or a linker, which functions to combine the linker unit with an amino acid residue or consists of 2-10 amino acid residues. composed of short peptides.
  • the presence of the connecting unit can connect L 1 to L 3 . Specific examples include but are not limited to (where 1 is connected to the connector unit and 2 is connected to L 3 ):
  • spacer unit is a component of an antibody-drug conjugate or a drug-linker conjugate or a linker, which is used to bind the Myc protein degrader fragment to an amino acid residue or consists of 2-10 A short peptide consisting of amino acid residues, or which may provide additional structural components to further facilitate the release of the Myc protein-degrading agent from the remainder of the antibody drug conjugate.
  • the presence of a spacer unit can connect D to L 3 . Specific examples include but are not limited to (where 1 bit is connected to L 3 and 2 bits are connected to D):
  • antibody is taken in its broadest interpretation and includes intact monoclonal antibodies, polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, as long as they have the required required biological activity.
  • antibody and “immunoglobulin” are used interchangeably.
  • PSMA antibody refers to an antibody that is capable of binding (human) PSMA with sufficient affinity such that the antibody can be used as a therapeutic targeting (human) PSMA.
  • the (human) PSMA antibody binds (human) PSMA with high affinity in vitro or in vivo.
  • the binding is measured, for example, by radioimmunoassay (RIA), biofilm thin layer interferometry (BLI), MSD assay, or surface plasmon resonance (SPR), or flow cytometry.
  • antibody fragment includes a portion of an intact antibody.
  • the antibody fragment is an antigen-binding fragment.
  • Antigen-binding fragment refers to a molecule distinct from an intact antibody that contains a portion of an intact antibody and binds the antigen to which the intact antibody binds.
  • antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; dAb (domain antibody); linear antibodies; single chain antibodies (such as scFv); single domain antibodies such as VHH ; Diavalent antibodies or fragments thereof; or camelid antibodies.
  • the term "monoclonal antibody” refers to an antibody derived from a population of antibodies that is substantially homogeneous, that is, the individual antibodies that make up the population are identical except for the possible presence of a small number of natural mutations.
  • Monoclonal antibodies have high specificity for one determinant (epitope) of an antigen, whereas polyclonal antibodies contain different antibodies directed against different determinants (epitope).
  • epitopope epitope
  • the advantage of monoclonal antibodies is that they can be synthesized without contamination from other antibodies.
  • the modifier "monoclonal” here indicates that the antibody is characterized by being derived from a substantially homogeneous population of antibodies and should not be construed as requiring that it be prepared by a specific method.
  • monoclonal antibodies also specifically include chimeric antibodies, that is, a part of the heavy chain and/or light chain is identical or homologous to a certain type, type or subtype of antibody, and the remaining part is identical to another type of antibody.
  • a sort of, Antibodies of another class or subclass are the same or homologous as long as they have the desired biological activity (see, eg, US 4,816,567; and Morrison et al., 1984, PNAS, 81:6851-6855).
  • Chimeric antibodies useful in the present disclosure include primatized antibodies comprising variable region antigen-binding sequences and human constant region sequences from non-human primates (eg, monkeys, orangutans, etc.).
  • a "humanized" form of a non-human (eg, murine) antibody refers to a chimeric antibody that contains a minimal amount of non-human immunoglobulin sequence.
  • Most humanized antibodies are human recipient immunoglobulins whose hypervariable region residues have been replaced with non-human ones (e.g., mouse, rat, rabbit, or non-human primate) that have the desired specificity, affinity, and function. Hypervariable region residues (donor antibody).
  • donor antibody In some embodiments, framework region (FR) residues of human immunoglobulins are also replaced with non-human residues.
  • humanized antibodies may also contain residues that are not found in either the recipient antibody or the donor antibody. These modifications are intended to further optimize the antibody's performance.
  • Humanized antibodies generally contain at least one, and usually two, variable regions, in which all or nearly all hypervanable loops correspond to those of non-human immunoglobulins, while the FRs are entirely or almost entirely human immunoglobulins. Protein sequence.
  • the humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc, typically a human immunoglobulin Fc).
  • Fc immunoglobulin constant region
  • Intact antibodies can be divided into different "classes” based on the amino acid sequence of the heavy chain constant region.
  • the five main classes are IgA, IgD, IgE, IgG and IgM, several of which can also be divided into different "subclasses” (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.
  • the heavy chain constant regions of different classes of antibodies are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ .
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known in the art.
  • Monoclonal antibodies used in the present disclosure can be produced by a number of methods.
  • monoclonal antibodies useful in the present disclosure can be obtained by hybridoma methods using cells from a number of species, including mouse, hamster, rat, and human (see, e.g., Kohler et al., 1975, Nature, 256:495). Either prepared by recombinant DNA technology (see, e.g., US 4,816,567), or isolated from a phage antibody library (see, e.g., Clackson et al., 1991, Nature, 352:624-628; and Marks et al., 1991, Journal of Molecular Biology , 222:581-597).
  • DAR drug to antibody ratio
  • the DAR of an ADC can range from 1 to 20, but depending on the number of attachment sites on the antibody, higher loadings are also possible.
  • the term DAR may be used when referring to the amount of drug loaded onto a single antibody, or alternatively, when referring to the average or mean DAR of a group of ADCs. DAR can also be calculated as the average DAR of the population of molecules in the product, i.e.
  • the average DAR value of the antibody drug conjugate of the invention is 1.0-20.0, such as 1.0-18.0, 1.0-16.0, 2.0-14.0, 3.0-12.0, 4.0-10.0, 5.0-9.0, 6.0- 8.0, 1.0-8.0, 2.0-6.0, such as 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 ,3,3.1,3.2,3.3,3.4,3.5,3.6,3.7,3.8,3.9,4,4.1,4.2,4.3,4.4,4.5,4.6,4.7,4.8,4.9,5.0,5.1,5.2,5.3,5.4 ,5.5,5.6,5.7,5.8,5.9,6.0,6.1,6.2,6.3,6.4,6.5,6.6,6.7,6.8,6.9,7.0,7.1,7.2,7.3,7.4,7.5,7.6,7.7,7.8.0 ,7.9,8,8.1,8.2,8.3,8.4,
  • the term “comprises” or “includes” means the inclusion of the stated element, integer or step, but not the exclusion of any other element, integer or step.
  • combinations of the stated elements, integers, or steps are also encompassed unless otherwise specified.
  • reference is made to an antibody variable region that "comprises” a particular sequence it is also intended to encompass antibody variable regions that consist of that particular sequence.
  • the reagents and raw materials used in this disclosure are all commercially available.
  • the antibody-conjugated drugs of the protein-degrading bioactive compounds disclosed in the present disclosure can be used for the treatment of various hematological tumors and solid tumors, and have better therapeutic effects and/or better therapeutic effects than the corresponding protein-degrading bioactive compounds. Low side effects;
  • the conjugate of the present invention has better solubility and excellent chemical stability, and has a high drug-antibody ratio
  • the linker in the conjugate of the present invention has high plasma stability, but at the same time can be cleaved in the tumor microenvironment (both within tumor cells and outside tumor cells), so it can be used in tumors with low antigen expression or no antigen expression. produce good anti-tumor effects;
  • the conjugate (including ADC) of the present invention has better tumor tissue targeting, that is, the ability to enrich in the tumor microenvironment, increases the concentration ratio of bioactive molecules in the tumor and blood, and reduces the concentration ratio of the conjugate.
  • Mechanism-related toxicities with higher therapeutic index
  • the conjugate of the present invention has high stability in body circulation, reduces the shedding of drug molecules in non-target tissues, and reduces the "off-target” toxicity caused by the shedding of toxins in non-target tissues;
  • the bioactive molecules of the conjugate have higher anti-tumor cell activity and therefore have excellent by-stander effect.
  • the conjugate can more effectively kill tumor cells with high antigen expression and tumors. Tumor cells with low or no antigen expression in tissues; and/or
  • the disclosed drug-linker conjugate utilizes the extracellular cleavage ability of its linker in the tumor microenvironment to form an antibody-conjugated drug with an antibody without cell endocytosis ability. This type of antibody-conjugated drug still has high Antitumor activity.
  • Figure 1 Shows the degradation ability of compound D-2 and compound D-4 on c-Myc and GSPT1 proteins in HL60 cells.
  • Figure 2 shows that the ADC of the present invention can significantly degrade c-Myc protein in 22RV1 cells.
  • the measuring instrument of nuclear magnetic resonance uses a Bruker 400MHz nuclear magnetic resonance instrument; the measuring solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexadeuterated dimethyl sulfoxide (DMSO-d 6 ); the internal standard substance is tetramethylsilane (TMS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ESI Agilent 6120B
  • D-4-B is obtained by referring to the synthesis method of D-4.
  • Example 1.4-C 2-(2,6-dioxopiperidin-3-yl)-N-(4-((2-mercapto-N-(2-(naphthyl-1-yl)ethyl)) Synthesis of acetamido)methyl)benzyl)-1-oxoisoindoline-5-carboxamide (D-4-C)
  • D-4-C is prepared from D-4-C-1.
  • the specific reaction equation and operation steps are as follows:
  • Example 1.7-A 4-((4-(3-chloro-4-(hydroxymethyl)phenyl)piperazin-1-yl)methyl)-N-((2-(2,6-di Oxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl (D-7-A)
  • D-7-A-2 is synthesized as follows:
  • Step 2 and Step 3 For the synthesis operation of D-8-2 and D-8-3, please refer to D-7-4 and D-7
  • Example 1.9-A 4-((4-(3-chloro-4-methylphenyl)piperazin-1-yl)methyl)-N-((2-(2,6-dioxopiperine) (Din-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(2-hydroxyethoxy)benzamide (D-9-A)
  • D-9-A-1 instead of D-9-4, refer to the preparation method of D-9 to obtain D-9-A
  • D-9-A-1 is prepared as follows:
  • Example 1.9-B 4-((4-(3-chloro-4-methylphenyl)-2-(hydroxymethyl)piperazin-1-yl)methyl)-N-((2-( 2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzamide (D-9-B)
  • D-9-B-1 instead of D-9-2, refer to the preparation method of D-9 to obtain D-9-B.
  • D-9-B-1 is synthesized as follows:
  • D-11-4 and D-11 refer to the preparation methods of D-7-4 and D-7 respectively, and finally D-11 is obtained.
  • step 2 refers to the preparation of D-8, and D-12 is obtained.
  • D-13-A was prepared by referring to the method of D-13.
  • D-13-B-2 was prepared by referring to the D-13 method.
  • D-14 is prepared from D-13 by reduction.
  • the specific method is as follows:
  • D-15-3 and D-15-4 For the synthesis operations of D-15-3 and D-15-4, refer to the preparation methods of D-7-4 and D-7 respectively, and then use the obtained D-15-4 as raw material to prepare D-15 according to the following method:
  • D-16-2, D-16-3, D-16-4 and D-16-5 refer to D-13-1, D-13-A-1, D-7-4 and D-7 respectively. , obtain D-16-5; then use D-16-5 as raw material and synthesize D-16 by referring to the preparation method of D-8.
  • D-17-4 refers to the preparation method of D-15-2.
  • D-17-5 and D-17-6 refer to the preparation methods of D-7-3 and D-7 respectively to obtain intermediate D-17- 6; Then use D-17-6 as raw material and refer to step 5 corresponding to D-15 to obtain D-17.
  • Example 2.1 N-((10S,13S)-10-(4-(dipropylamino)butyl)-1,1,1-trifluoro-14-methyl-6,9,12-trioxo -3-oxa-5,8,11-triazapentadecan-13-yl)-6-(2-(methanesulfonyl)pyrimidin-5-yl)hex-5-ynamide (L-1 )Synthesis
  • step 2 To the DMF solution of L-1-3 obtained in step 2, add L-1-4 (7.0 g, 12.7 mmol) and DMF (35 mL). Cool the reaction solution to -15°C, add DMTMM (4.2g, 15.2mmol), -10°C The reaction was stirred for 2 h. Pour the reaction solution into DCM (200 mL), and wash the organic phase with 2% NaHCO 3 aqueous solution (100 mL*3), water (100 mL) and saturated NaCl aqueous solution (50 mL).
  • Example 2.2 N 6 ,N 6 -dipropyl-N 2 -((6-(2-(methanesulfonyl)pyrimidin-5-yl)hex-5-ynyl)-L-valine)- Synthesis of L-lysine (L-2)
  • Example 3.1 2-(2,6-dioxopiperidin-3-yl)-N-(4-((12S,15S)-12-(4-(dipropylamino)butyl)-15 -Isopropyl-22-(2-(methylsulfonyl)pyrimidin-5-yl)-2-(2-(naphthyl-1-yl)ethyl)-3,8,11,14,17-penta Oxo-5-oxa-2,7,10,13,16-pentaazabis-21-yn-1-yl)benzyl)-1-oxoisoindoline-5-methyl Synthesis of Amide (DL-1)
  • VH amino acid sequence SEQ ID NO:1 Connect the VH amino acid sequence SEQ ID NO:1 to the heavy chain constant region amino acid sequence of IgG1 (SEQ ID NO:2), and then construct it into pcDNA3.4 through codon optimization and gene synthesis (Shanghai Baiying Biotechnology Co., Ltd.) On the carrier, it is named B21231602H.
  • VL amino acid sequence SEQ ID NO:3 Connect the VL amino acid sequence SEQ ID NO:3 to the light chain constant region amino acid sequence of IgG1 (SEQ ID NO:4), and then construct it into pcDNA3.4 through codon optimization and gene synthesis (Shanghai Baiying Biotechnology Co., Ltd.) On the carrier, it is named B21231602L.
  • PSMA mAb shows heavy chain amino acid sequence
  • light chain amino acid sequence is SEQ ID NO: 6
  • the purpose of this experiment is to study the affinity of PSMA mAb (prepared in Example 4.1) to human PSMA protein and provide a basis for PSMA mAb in vitro and in vivo efficacy testing.
  • the negative control is human IgG1 with native sequence.
  • ELISA coating buffer carbonate buffer, pH 9.5, Biolegend, 421701
  • dilute human PSMA protein purchased from: Acrobiosystems product number, PSA-H52H3
  • ELISA wash buffer purchased from: Multiscience, product number, EK0011
  • 300ul/well wash three times, and pat the plate dry.
  • Add 100ul/well of ELISA assay dilute buffer purchased from: biolegend Cat. No. 421203 to the enzyme plate, and incubate at 37°C for 1 hour. Clean again.
  • the results show that PSMA mAb has good binding activity to human PSMA protein, and the negative control human IgG1 does not bind to human PSMA.
  • the EC50 was calculated based on binding curve fitting.
  • the EC50 value of PSMA mAb for human PSMA protein was 6.67nM.
  • the purpose of this experiment is to study the endocytic activity of PSMA mAb (Progenics) in 22RV cells and provide a basis for the in vivo and in vitro efficacy testing of PSMA mAb (Progenics).
  • the PSMA antibody showed an increasing internalization rate as the incubation time prolonged, that is, the endocytic activity increased with the prolongation of the incubation time, and finally reached a saturation state.
  • the internalization rate % was calculated, that is, when the PSMA antibody was incubated with 22RV1 cells for 18 hours, the internalization rate was 60%.
  • PSMA mAb (8.84mg/mL) obtained in Example 4.1, dilute it with 0.005mL of 20mM PB+100mM disodium edetate solution (pH 7.6), adjust the pH to 7.45 with 0.5M Na 2 HPO 4 solution, and add Mix 20mM TCEP (tris(2-carboxyethyl)phosphine, 0.0082ml, 0.164 ⁇ mol) solution and leave it at room temperature for 90 minutes. Add a solution of DL-1 (0.470 mg, 12 times the molar amount of antibody material) in dimethyl sulfoxide (0.0558 mL) to the above solution, mix well, and let stand at room temperature for 2 hours.
  • DL-1 (0.470 mg, 12 times the molar amount of antibody material
  • the method for measuring DAR value is as follows:
  • Example 5.1 Using a similar operation to Example 5.1, replacing DL-1 with DL-2, ADC-002, the coupling product of DL-2 and PSMA mAb, was obtained.
  • the DAR value determined by mass spectrometry was 8.0.
  • LC represents the antibody light chain
  • HC represents the antibody heavy chain
  • DAR1 represents the conjugate containing a light chain or heavy chain coupled to a toxin linker
  • DAR2 represents a conjugate containing a light chain or heavy chain coupled to two toxin linkers.
  • Conjugates DAR3 represents conjugates containing three toxin linkers coupled to a light or heavy chain.
  • LC, HC, DAR1, DAR2, and DAR3 are as described above.
  • Example 6.1 Test of protein degradation activity of protein-degrading bioactive compounds on c-Myc and GSPT1 proteins
  • Cell culture conditions The cells in the examples of the present invention were all purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences. Among them, human acute promyelocytic leukemia cells (HL60 cells) were cultured in RPMI-1640 (meilunbio, MA0215) + 20% FBS (manufacturer: BI, product number: 04-001-1ACS) + 1% penicillin/streptomycin (manufacturer: Hyclone, Cat. No.: SH40003.01) culture medium. Cell culture conditions were all 5% CO2 concentration and 37% humidity. When the coverage rate reaches about 80%, the cells are passaged in a ratio of 1:3.
  • the HL60 cells are in the exponential growth phase, the HL60 cells are plated into a 6-well plate with 1 ⁇ 10 6 cells per well.
  • the compound of the present invention is added to culture the cells, and the protein is extracted after 6 hours of drug treatment.
  • BCA protein concentration determination kit from Thermo Fisher, Cat. No. 23225
  • BSA standard determination solution obtained in the above step 2.2 for the Western blotting (WB) experiment according to Table 1 below.
  • WB Western blotting
  • Table 1 below. (can be diluted and tested), use a 96-well plate to add samples, add PBS to each well to 20 ⁇ l, add 200 ⁇ l BCA working solution (prepared according to the kit), mix well and place it at 60°C for 10 minutes, then detect the absorbance at 562nm. After recording the readings, use the standard concentration gradient to make a standard curve, and substitute the sample absorbance to calculate the sample protein concentration.
  • PVDF membrane (Millipore, Cat. No. ISEQ00010) by wet transfer method (PVDF membrane needs to be activated with methanol for 1 minute before use), 300mA, 2h, during the transfer process Generates a lot of heat and requires an ice box to cool down.
  • the protein degradation ability in the above cells was tested respectively, and the results are shown in Figure 1.
  • the Blank group represents the DMSO blank group without adding the test compound.
  • Figure 1 shows that compound D-2 and compound D-4 can completely degrade c-Myc and GSPT1 proteins in HL60 cells at lower concentrations (3-10 nM).
  • Example 6.2 Detection of inhibitory activity of protein-degrading bioactive compounds on HL60 cells
  • HL60 cells Count the HL60 cells in the logarithmic growth phase and spread them evenly in a 96-well transparent bottom white plate.
  • the number of cells is 20,000 per well and 100 ⁇ L per well.
  • test results showed that all the tested compounds had potent proliferation inhibitory activity on HL60 cells.
  • Example 6.3 Detection of inhibitory activity of compounds or ADC on 22RV1 cells in vitro
  • Count the 22RV1 Cell Bank of the Chinese Academy of Sciences, TCHu100 cells in the logarithmic growth phase and spread them evenly in a 96-well transparent bottom white plate.
  • the number of cells is 10,000-20,000 per well, 100 ⁇ L per well.
  • test results show that the ADC molecules disclosed in the present invention have tumor cell killing effect, and compared with the small molecules themselves, the anti-proliferative activity after being prepared into ADC is significantly improved.
  • Example 6.4 ADC drug degradation test on c-Myc protein in 22RV1 cells
  • Cell culture conditions The cells in this example were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences. Among them, human prostate cancer cells (22RV-1 cells) were cultured in RPMI-1640 (meilunbio, MA0215) + 10% FBS (manufacturer: BI, product number: 04-001-1ACS) + 1% penicillin/streptomycin (manufacturer: Hyclone , Catalog No.: SH40003.01) in culture medium. Cell culture conditions were all 5% CO2 concentration and 37% humidity. When the coverage rate reaches about 80%, the cells are passaged in a ratio of 1:3.
  • the 22RV-1 cells are in the exponential growth phase, the 22RV-1 cells are plated into a 6-well plate, with 1 ⁇ 10 6 cells per well.
  • the ADC drug of the present invention is added to culture the cells, and the protein is extracted after 6 hours of drug treatment.
  • BCA protein concentration determination kit from Thermo Fisher, Cat. No. 23225
  • BSA standard determination solution and the supernatant for Western blotting (WB) experiment obtained in step 2.2 according to Table 1 in Example 6.1 (upper The clear solution can be diluted and tested)
  • WB Western blotting
  • the clear solution can be diluted and tested
  • use a 96-well plate to add samples, make up each well to 20 ⁇ l with PBS, then add 200 ⁇ l BCA working solution (prepared according to the kit), mix well and place it at 60°C for 10 minutes before detecting at 562nm.
  • Absorbance, after recording the reading use the standard concentration gradient to make a standard curve, and substitute it into the sample absorbance to calculate the sample protein concentration.
  • PVDF membrane (Millipore, Cat. No. ISEQ00010) by wet transfer method (PVDF membrane needs to be activated with methanol for 1 minute before use), 300mA, 2h, during the transfer process Generates a lot of heat and requires an ice box to cool down.
  • test results are shown in Figure 2 (where Ctrl refers to the use of solvent instead of drug in step 2.1 cell treatment, that is, the solvent control group).
  • the results show that the prepared ADC can significantly degrade the c-Myc protein in 22RV1 cells.
  • Human peripheral blood mononuclear cells hPBMCs in the logarithmic growth phase (purchased from Shanghai Aoneng Biotechnology Co., Ltd., the culture medium is RPMI1640 (Meilun Bio, MA 0215), containing 10% FBS (gibco, 16000-044) and 1 % penicillin/streptomycin (Hyclone, SV30010); human prostate cancer cell Vcap (purchased from ATCC, the culture medium is DMEM (Hyclone, product number: SH30022.01) + 10% FBS (manufacturer: BI, product number: 04-001- 1ACS) + 1% penicillin/streptomycin (Manufacturer: Hyclone, Catalog No.: SH40003.01), count the cells, and spread them evenly in a 96-well transparent bottom white plate. The number of cells is 5,000 to 10,000 per well, 100 ⁇ L per well.
  • ADC has reduced inhibitory activity on PSMA-negative HL60 cells and normal human cell hPBMC cells. After being prepared into ADC, the therapeutic window is greatly improved.
  • FLOH1 PSMA gene name
  • the expression levels of FLOH1 in different cell lines can be found in The Human Protein Atlas (https://www.proteinatlas.org/). The data shows that FLOH1 is not expressed in HL60 cells; Vcap and 22RV1 express FLOH1. Detailed results See Table 7.
  • mice NOD/SCID mice, male, 4-6 weeks old, purchased from Vitong Lever Experimental Animal Co., Ltd.
  • 22RV1 cells are cultured in RPMI-1640 culture medium containing 10% fetal calf serum and passaged in about 3-4 days. After the cells grow to a sufficient number, adjust the cell concentration with a mixture of pre-cooled PBS and Matrigel (1:1). to approximately 2.5 ⁇ 10 7 cells/mL.
  • NOD/SCID mice were adapted to the laboratory environment for 3-5 days. 22RV1 cells were subcutaneously inoculated on the right front back at a volume of 5 ⁇ 10 6 cells/mouse and an inoculation volume of 0.2 ml (containing 50% Matrigel). Wait until the tumor grows to When the diameter is about 100 ⁇ 150mm 3 , they are randomly divided into groups and experiments are carried out.
  • the tumor-bearing nude mice enrolled in Table 8 were administered according to the following regimen.
  • Vehicle indicates that the vehicle replaced the drug as a control group.
  • TGI% (1-T/C) * 100% (T and C are the values of the treatment group and the control group, respectively.
  • V Relative tumor volume
  • ADC-002 has a significant anti-tumor growth effect on the 22RV1 transplanted tumor model.
  • D21 the body weight of all tested dose groups decreased slightly during the administration, and there was no obvious drug toxicity.

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Abstract

Un conjugué anticorps-médicament contenant un composé bioactif d'agent de dégradation de protéine Myc, son procédé de préparation et son utilisation dans la prévention et/ou le traitement de maladies associées à une activité cellulaire anormale, notamment, mais sans s'y limiter, une utilisation dans la prévention et/ou le traitement de maladies néoplasiques.
PCT/CN2023/111003 2022-08-04 2023-08-03 Conjugué anticorps-médicament contenant un composé bioactif d'agent de dégradation de protéine myc, son procédé de préparation et son utilisation WO2024027795A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101287498A (zh) * 2005-06-20 2008-10-15 Psma开发有限公司 Psma抗体-药物缀合物
CN102264720A (zh) * 2008-10-29 2011-11-30 细胞基因公司 用于治疗癌症的异吲哚啉化合物
CN103396397A (zh) * 2013-08-14 2013-11-20 中国人民解放军军事医学科学院毒物药物研究所 来那度胺衍生物及其作为药物的用途
US20160082120A1 (en) * 2014-09-23 2016-03-24 Genentech, Inc. METHODS OF USING ANTI-CD79b IMMUNOCONJUGATES
CN106456794A (zh) * 2014-05-22 2017-02-22 斯索恩生物制药有限公司 接头药物与抗体的位点特异性缀合以及所得adc
WO2021004391A1 (fr) * 2019-07-08 2021-01-14 苏州开拓药业股份有限公司 Inhibiteur de protéine c-myc, son procédé de préparation et son utilisation
WO2021069705A1 (fr) * 2019-10-09 2021-04-15 Monte Rosa Therapeutics Composés d'iso-indolinone

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101287498A (zh) * 2005-06-20 2008-10-15 Psma开发有限公司 Psma抗体-药物缀合物
CN102264720A (zh) * 2008-10-29 2011-11-30 细胞基因公司 用于治疗癌症的异吲哚啉化合物
CN103396397A (zh) * 2013-08-14 2013-11-20 中国人民解放军军事医学科学院毒物药物研究所 来那度胺衍生物及其作为药物的用途
CN106456794A (zh) * 2014-05-22 2017-02-22 斯索恩生物制药有限公司 接头药物与抗体的位点特异性缀合以及所得adc
US20160082120A1 (en) * 2014-09-23 2016-03-24 Genentech, Inc. METHODS OF USING ANTI-CD79b IMMUNOCONJUGATES
WO2021004391A1 (fr) * 2019-07-08 2021-01-14 苏州开拓药业股份有限公司 Inhibiteur de protéine c-myc, son procédé de préparation et son utilisation
WO2021069705A1 (fr) * 2019-10-09 2021-04-15 Monte Rosa Therapeutics Composés d'iso-indolinone

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