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WO2024153185A1 - Conjugué anticorps-médicament contenant un agent de protéolyse de la famille bcl-2, son procédé de préparation et son utilisation - Google Patents

Conjugué anticorps-médicament contenant un agent de protéolyse de la famille bcl-2, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024153185A1
WO2024153185A1 PCT/CN2024/073029 CN2024073029W WO2024153185A1 WO 2024153185 A1 WO2024153185 A1 WO 2024153185A1 CN 2024073029 W CN2024073029 W CN 2024073029W WO 2024153185 A1 WO2024153185 A1 WO 2024153185A1
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Prior art keywords
antibody
mmol
antigen
cancer
ala
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PCT/CN2024/073029
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English (en)
Chinese (zh)
Inventor
蔡家强
肖亮
薛彤彤
宋帅
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苏州宜联生物医药有限公司
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Publication of WO2024153185A1 publication Critical patent/WO2024153185A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K47/54—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 organic compound
    • 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

Definitions

  • the present disclosure belongs to the field of medical technology, and relates to an antibody-drug conjugate, a compound, a drug-linker conjugate comprising a BCL-2 family protein degrader, and a preparation method thereof, as well as the use thereof in preventing and/or treating diseases associated with abnormal cell activity, including but not limited to preventing and/or treating tumor diseases.
  • the BCL-2 protein family is one of the core regulatory mechanisms of apoptosis (also called programmed cell death). It can receive and transmit intrinsic intracellular signals or external environmental stress signals, such as nutritional or hypoxic stress, DNA damage, excessive activation of oncogenes, endoplasmic reticulum stress, etc., and mainly plays a leading role in the intrinsic apoptosis pathway.
  • intrinsic intracellular signals or external environmental stress signals such as nutritional or hypoxic stress, DNA damage, excessive activation of oncogenes, endoplasmic reticulum stress, etc.
  • One subclass is antagonistic to cell apoptosis, including 6 proteins, namely BCL-XL, BCL-2, BCL-W, Mcl-1, BCL-B and Bfl-1, which are mainly located on mitochondria to protect mitochondria from adversity damage.
  • the other two subclasses promote cell apoptosis, and one subclass is the final executor of mitochondrial damage, including Bax and Bak.
  • the rest are all classified as BH3-only subclasses, which can directly sense various cell adversity stress signals.
  • the interaction between BCL-2 family proteins that antagonize and promote apoptosis determines the fate of cells. About 50% of tumors have abnormal overexpression of BCL-2 family proteins that antagonize apoptosis, which is an important component of resistance to chemotherapy, radiotherapy, targeted therapy and other therapies.
  • ABT-199 a highly selective inhibitor of BCL-2
  • Hypomethylating agents such as the DNA methyltransferase inhibitor 5-azacytidine
  • 5-azacytidine can reduce the expression of Mcl-1 in AML cells, thereby synergizing with selective BCL-2 inhibitors.
  • BCL-XL protein is highly expressed in a variety of blood tumors and solid tumors
  • the synergistic inhibition of BCL-XL, BCL-2 and MCL-1 can further overcome the drug resistance of ABT-199 and can be used for the treatment of solid tumors.
  • preclinical studies of Navitoclax ABT-263 found that it showed good activity in small cell lung cancer cell lines and mouse models.
  • the inhibition of BCL-XL has strong hematological toxicity and side effects.
  • the clinical trial of ABT-263 was not successful.
  • the BCL-XL protein degrader designed using the protac principle can effectively avoid the impact on platelet production (Weizhou Zhang, NATURE COMMUNICATIONS, 2021, 12, 1281), and is used for tumor treatment, such as acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, leukemia, lymphoma, esophageal cancer, lung cancer (such as small cell lung cancer, non-small cell lung cancer and lung adenocarcinoma), bladder cancer, gastric cancer, ovarian cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colon cancer, liver cancer, kidney cancer, non-Hodgkin's lymphoma, central nervous system tumors (such as glioma, glioblastoma multiforme, glioma or sar
  • ADC drugs combine the tumor targeting effect of antibodies with the high activity of bioactive molecules, becoming a biological missile with highly anticipated efficacy and safety advantages.
  • Antibodies guide ADCs to bind to target cells, achieve tumor tissue enrichment, and reduce non-target tissue exposure.
  • the bound ADCs are then internalized by cells, and small molecule drugs are released through enzymatic hydrolysis under the action of specific enzymes in cells to treat diseases.
  • ADCs composed of small molecule BCL-2 family protein degraders and tumor-targeted antibodies can achieve tumor enrichment, while utilizing the catalytic degradation activity of BCL-2 family protein degraders at low concentrations to achieve the therapeutic effect of BCL-XL degraders, while eliminating or reducing the toxic side effects caused by BCL-2 family protein inhibitors acting on non-disease tissues, thereby improving the therapeutic effect.
  • the present disclosure provides an antibody-drug conjugate comprising a BCL-2 family protein degrader, and a preparation method and use thereof.
  • the present disclosure provides an antibody drug conjugate as shown in Formula I,
  • Tb is an antibody or an antigen-binding fragment thereof
  • q is the drug-antibody coupling ratio
  • L is a linker
  • D is a chimeric fragment targeting degradation of BCL-2 family proteins.
  • the BCL-2 family protein degradation targeting chimera is selected from: selective and non-selective BCL-2 protein degradation targeting chimera, BCL-xl protein degradation targeting chimera and MCL-1 protein degradation targeting chimera.
  • the BCL-2 family protein degradation targeting chimera comprises a BCL-2 family protein binding portion and a ubiquitinating enzyme binding portion.
  • the ubiquitinase binding moiety is selected from the group consisting of an E1 ubiquitin activating enzyme, an E2 ubiquitin conjugating enzyme, and an E3 ubiquitin ligase binding moiety.
  • D has a structure shown in Formula I and is connected to the linker L via its hydroxyl or amine group;
  • B is a BCL-2 family protein binder fragment
  • Z is the connecting part between B and A
  • A is an E3 ubiquitin ligase binding fragment, which binds to the E3 ubiquitin ligase.
  • B is a structural unit of formula I-1 or I-2, wherein formula I-1 is:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, NH 2 , OH, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl and Y 1 -Y 2 ;
  • Y 1 is selected from a direct bond, a C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyl group and a C2-6 alkynyl group;
  • Y2 is selected from -OR5a , -NR5aR5b , Bit 1 is connected to Y 1 ;
  • Each M is independently selected from a direct bond, -CR 6a R 6b -;
  • R 5a , R 5b , R 6a , R 6b are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl;
  • R 6 is selected from RcSO 2 -, -NO 2 ;
  • R c is selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl;
  • n is selected from any integer between 0 and 6;
  • Bit 1 is connected to Z
  • Y3 is selected from a direct bond, -O-, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl;
  • Y 4 is selected from a direct bond, NH 2 , a 4-10 membered heterocyclyl, a C6-10 aryl, a 5-10 membered heteroaryl, wherein the 4-10 membered heterocyclyl, the C6-10 aryl, the 5-10 membered heteroaryl is optionally substituted by one or more NH 2 , OH, halogen;
  • x is 0 or 1.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, NH 2 , fluorine, chlorine, bromine, C 1-4 alkyl,
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, NH 2 , chloro, methyl,
  • R 1 and R 2 are each independently selected from H, NH 2 , halogen, or
  • R 1 and R 2 are each independently selected from H, NH 2 , chloro,
  • R 1 is H, NH 2 , or halogen, preferably halogen.
  • R 1 is H, NH 2 , or chlorine, preferably chlorine.
  • R 2 is H, or NH 2 , preferably hydrogen.
  • R 3 and R 4 are each independently H, C1-4 alkyl,
  • R 3 and R 4 are each independently selected from H, methyl,
  • R 3 is C 1-4 alkyl.
  • R 3 is methyl
  • R 4 is C1-4 alkyl, Preferably, it is C1-4 alkyl, or More preferably
  • R4 is methyl, Preferably, methyl, More preferably, it is methyl, or More preferably
  • R 5 is H, or Y 1 -Y 2 ; wherein Y 1 is a direct bond; Y 2 is Preferably
  • R5 is H.
  • R 6 is RcSO 2 —.
  • Y 1 is selected from C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl.
  • Y 1 is C 1-4 alkyl.
  • Y 1 is -CH 2 -.
  • Y 2 is selected from -OH, -NH 2 , Bit 1 is connected to Y 1 .
  • Y 2 is NH 2
  • Bit 1 is connected to Y 1 .
  • Y2 is Bit 1 is connected to Y 1 .
  • Y2 is Bit 1 is connected to Y 1 .
  • M is selected from a direct bond and CH 2 .
  • R 5a , R 5b , R 6a , R 6b are each independently selected from H and C 1-4 alkyl.
  • R 5a , R 5b , R 6a , R 6b are each independently selected from H and methyl.
  • R c is selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C3-6 cycloalkyl.
  • R c is C1-4 haloalkyl, preferably C1-2 haloalkyl, more preferably halomethyl.
  • R c is selected from methyl and trifluoromethyl.
  • R c is trifluoromethyl
  • m is selected from 0, 1, 2, 3.
  • m is 1 or 2, preferably 1.
  • Y 3 -Y 4 is
  • the C1-6 alkyl group is each independently a C1-4 alkyl group, preferably a C1-2 alkyl group, and more preferably a methyl group.
  • the halogen is each independently preferably fluorine, chlorine or bromine, more preferably chlorine.
  • the halogen in the haloalkyl group is independently preferably fluorine, chlorine or bromine, more preferably fluorine.
  • B is a structural unit of formula I-1.
  • B is a structural unit of formula I-1
  • R 1 is H, NH 2 , or halogen;
  • R 2 is H, or NH 2 ;
  • R 3 is C1-4 alkyl;
  • R 4 is C1-4 alkyl,
  • R 5 is H, or Y 1 -Y 2 ;
  • Y 1 is a direct bond, Y 2 is Position 1 is connected to Y 1 ;
  • R 6 is RcSO 2 -;
  • R c is C1-4 haloalkyl;
  • m is 1 or 2;
  • R 5a and R 5b are each independently selected from H and C1-4 alkyl.
  • B is selected from the following structures, and position 1 is connected to Z:
  • Z is selected from Bit 1 is connected to B, bit 2 is connected to A;
  • W and V are each independently selected from
  • Positions 1 and 2 can be connected to their adjacent atoms respectively;
  • M 1 , M 2 and M 3 are each independently selected from a direct bond, -O-, -S-, -NR-, -CR 2 -, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, 4-10 membered heterocyclyl, 6-12 membered spirocyclyl, 6-12 membered paracyclyl, C6-10 aryl and 5-10 membered heteroaryl, and M 1 , M 2 and M 3 are the same or different at each occurrence;
  • R is selected from H, C1-4 alkyl
  • q1, q2, q3, q4 and q5 are each independently selected from any integer between 0 and 20.
  • W and V are each independently
  • M 1 , M 2 and M 3 are each independently C 1-6 alkyl.
  • M 1 , M 2 and M 3 are each independently selected from -O-, -S-, -CR 2 -, -CH 2 CH 2 O-,
  • Z is selected from Bit 1 is connected to B, and bit 2 is connected to A.
  • Z is
  • A is selected from
  • A is selected from
  • Bit 1 is connected to Z.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • L is The structure shown in FIG. 1 , wherein L 1 is an extension unit, L 2 is a connection unit, L 3 is an amino acid unit, and L 4 is a spacer unit.
  • the present disclosure provides an antibody drug conjugate as shown in Formula II,
  • Tb is an antibody or an antigen-binding fragment thereof
  • q is the drug-antibody coupling ratio
  • L 1 is selected from:
  • Position 1 is connected to the S atom, and position 2 is connected to L 2 ;
  • L 2 is selected from Position 1 is connected to L 1 , position 2 is connected to L 3 ;
  • n is selected from any integer between 0 and 10;
  • Y is selected from CH 2 , Wherein position 2 is connected to X;
  • X is selected from CR m R n , NR m ;
  • R m , R n are each independently selected from H, Me;
  • L 3 is selected from an amino acid residue or a short peptide consisting of 2-10 amino acid residues; the amino acid residue is selected from a natural amino acid residue, a non-natural amino acid residue, an amino acid residue represented by AA 1 or a stereoisomer thereof;
  • R a and R b are each independently selected from H and And Ra and Rb are not H at the same time;
  • Ra and Rb together with the carbon atom to which they are commonly attached, form a 4-10 membered heterocyclic ring, which is optionally substituted with one or more R0 ;
  • r, r1 are each independently selected from any integer between 0 and 20;
  • R m1 and R n1 are each independently selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
  • R m1 and R n1 together with the nitrogen atom to which they are commonly attached form a 4-10 membered heterocyclic ring, wherein the 4-10 membered heterocyclic ring is optionally substituted by one or more R 0' ;
  • R 0 and R 0' are each independently selected from C1-6 alkyl, C3-6 cycloalkyl, -NR m2 R n2 and a 4-10 membered heterocyclyl optionally substituted by C1-6 alkyl;
  • R m2 and R n2 are each independently selected from H and C1-6 alkyl
  • L 4 is absent or present; when L 4 is present, L 4 is selected from Position 1 is connected to L 3 , and position 2 is connected to D;
  • the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that has tumor cell surface antigen binding activity and tumor cell endocytosis activity.
  • the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that has antigen-binding activity and has no or weak tumor cell endocytosis activity.
  • the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that binds to a non-endocytosed antigen on the surface of a tumor cell.
  • the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that does not have tumor cell endocytosis activity.
  • the antibody or antigen-binding fragment thereof is an antibody or antigen-binding fragment thereof that has the activity of binding to tumor cell surface antigens and has the activity of tumor cell endocytosis.
  • the antibody or antigen-binding fragment thereof is a non-human antibody, a humanized antibody, a chimeric antibody, or a fully human antibody.
  • the antibody or antigen-binding fragment thereof is a probody, a bispecific antibody, or a multispecific antibody.
  • the antibody or antigen-binding fragment thereof includes Fab, Fab', F(ab')2, Fd, Fv, dAb, complementarity determining region fragment, single chain antibody (eg, scFv).
  • Tb is an antibody or an antigen-binding fragment thereof having endocytosis activity.
  • Tb is an antibody or an antigen-binding fragment thereof that has the activity of binding to a tumor cell surface antigen.
  • the target of the antibody or its antigen-binding fragment is selected from: B7H3, CD20, CD19, CD30, GPNMB, Her2, Trop-2, EGFR, Her3, GD-2, CD79b and BCMA, etc.
  • Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, an anti-Trop-2 antibody or an antigen-binding fragment thereof, an anti-Her 2 antibody or an antigen-binding fragment thereof, an anti-Her3 antibody or an antigen-binding fragment thereof, or an anti-EGFR antibody or an antigen-binding fragment thereof.
  • Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, such as 1D1-01, 2E3-02 antibodies, enoblituzumab, mirzotamab, omburtamab or an antigen-binding fragment thereof.
  • the VH sequence of 1D1-01 is shown as SEQ ID NO: 1, and the VL sequence is shown as SEQ ID NO: 2.
  • the heavy chain sequence of 1D1-01 is shown as SEQ ID NO: 3, and the light chain sequence is shown as SEQ ID NO: 4.
  • the VH sequence of 2E3-02 is shown as SEQ ID NO: 5, and the VL sequence is shown as SEQ ID NO: 6.
  • the heavy chain sequence of 2E3-02 is shown as SEQ ID NO: 7, and the light chain sequence is shown as SEQ ID NO: 8.
  • Tb is an anti-B7H3 monoclonal antibody or an antigen-binding fragment thereof.
  • Tb is an anti-Trop-2 antibody or an antigen-binding fragment thereof, such as datopotamab, sacituzumab, or an antigen-binding fragment thereof.
  • Tb is an anti-Trop-2 monoclonal antibody or an antigen-binding fragment thereof.
  • Tb is an anti-Her 2 antibody or an antigen-binding fragment thereof, such as anbenitamab, coprelotamab, disitamab, gancotamab, margetuximab, pertuzumab, timigutuzumab, zanidatamab, Trastuzumab, Pertuzumab or an antigen-binding fragment thereof.
  • Tb is an anti-Her2 monoclonal antibody or an antigen-binding fragment thereof, such as trastuzumab, pertuzumab, or an antigen-binding fragment thereof.
  • Tb is an anti-Her3 antibody or an antigen-binding fragment thereof.
  • Tb is an anti-Her3 monoclonal antibody or an antigen-binding fragment thereof.
  • Tb is an anti-EGFR antibody or an antigen-binding fragment thereof, such as demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, serclutamab, tomozuotuximab, zalutumumab, Cetuximab or an antigen-binding fragment thereof.
  • an anti-EGFR antibody or an antigen-binding fragment thereof such as demupitamab, depatuxizumab, futuximab, imgatuzumab, laprituximab, losatuxizumab, matuzumab, modotuximab, necitumumab, nimotuzumab, panitumumab, pimurutamab, ser
  • Tb is an anti-EGFR monoclonal antibody or an antigen-binding fragment thereof.
  • the antibody has an antibody that binds to the B7H3 antigen but does not have endocytosis activity.
  • the Anti-B7H3 antibody has a VH of SEQ ID NO: 2 and a VL of SEQ ID NO: 1 described in WO2021168379A1.
  • the antibody has an antibody that binds to the GD-2 antigen but does not have endocytosis activity.
  • the Anti-GD2 antibody has a VH of SEQ ID NO: 4 and a VL of SEQ ID NO: 3 described in WO2021168379A1.
  • the antibody has an antibody that binds to the CD20 antigen but does not have endocytosis activity.
  • type II CD20-specific antibodies have been shown to be poorly internalized by CD20-positive target cells, other so-called “type I” CD20-specific antibodies have been found to be internalized and degraded to some extent, depending on the expression level of activating and inhibitory Fc ⁇ Rs on the target cells that interact with them.
  • the antibody has an antibody that binds to the CD20 antigen but does not have endocytosis activity is a "type II" CD20-specific antibody, such as obinutuzumab.
  • the antibody has an antibody that binds to a non-endocytic antigen (e.g., ALCAM/CD166).
  • the antibody is an antibody comprising VH of SEQ ID No: 73 and VL of SEQ ID No: 74, VH of SEQ ID No: 75 and VL of SEQ ID No: 76, VH of SEQ ID No: 77 and VL of SEQ ID No: 78, or VH of SEQ ID No: 79 and VL of SEQ ID No: 88 in EP3911682A1.
  • q is selected from any integer between 0.1-8.0. In a preferred embodiment, q is selected from any integer between 0.1-8.0.
  • q is selected from any value between 2-8.
  • q is selected from 2, 4, 6, and 8.
  • L1 is selected from:
  • the 1 position is connected to the S atom, and the 2 position is connected to L2 .
  • L2 is selected from Preferably Position 1 is connected to L1 , and position 2 is connected to L3 .
  • L2 is selected from
  • Bit 1 is connected to L1
  • bit 2 is connected to L3.
  • n is any integer between 1-8.
  • n is selected from 1, 2, and 3.
  • Y is CH 2 , Wherein position 2 is connected to X.
  • X is CH 2 , NH, or C(CH 2 ) 2 .
  • L 1 -L 2 are selected from Bit 1 is connected to S, and bit 2 is connected to L3.
  • L 1 -L 2 are selected from
  • Bit 1 is connected to S, and bit 2 is connected to L3.
  • L3 is selected from the amino acid residues Val, D-Val, Cit, Phe, Lys, Lys(Ac), Leu, Gly, Ala, Asn, Asp, Arg, AA1 , or a short peptide consisting of 2-10 amino acid residues selected from Val, Cit, Phe, Lys, D-Val, Leu, Gly, Ala, Asn, Asp, AA1 .
  • L3 is selected from Val, Cit, Lys, D-Val, Leu, Gly, Ala, Asn, AA1 , Val-Cit, Val-Lys, Cit-Val, Cit-Ala, Val-Ala, Lys-Val, Val-Lys(Ac), Phe-Lys, Phe-Lys(Ac), Ala-Ala, Val- AA1 , Ala- AA1 , Gly- AA1 , AA1- Gly, Ala-Ala-Ala, Ala-Ala-Asn, Ala-Ala-Asp, Val- AA1- Gly, Ala-AA1 - Gly, Gly- AA1 -Gly, Lys-Ala-Ala-Asn, Lys-Ala-Ala-Asp, Gly-Phe-Gly, Gly-Gly-Phe-Gly, D-Val-Leu-Lys, Gly-Gly-Arg,
  • L 3 is selected from Val-Cit, Val-Lys, Val-AA 1 and Val-AA 1 -Gly.
  • L3 is selected from Position 1 is connected to L2 , and position 2 is connected to L4 or D.
  • L3 is selected from Position 1 is connected to L2 , and position 2 is connected to L4 or D.
  • either Ra or Rb is H, and the other is
  • Ra and Rb together with the carbon atom to which they are attached, form a 5-6 membered heterocyclic ring substituted with R0 .
  • Ra and Rb together with the carbon atom to which they are attached, form a piperidine or piperazine ring substituted with R0 .
  • Ra and Rb together with the carbon atom to which they are attached, form a piperidine ring substituted with R0 .
  • Ra and Rb together with the carbon atom to which they are attached, form Carbon atom No. 1 is the carbon atom that is bonded to Ra and Rb .
  • r, r1 are each independently selected from 0, 1, 2, 3, 4, and 5.
  • r, r1 are each independently selected from 0 and 4.
  • r is 0 and r is 4.
  • R m1 and R n1 are each independently selected from H and C1-6 alkyl.
  • R m1 , R n1 are each independently selected from H, methyl, ethyl, n-propyl, and n-butyl.
  • R m1 and R n1 together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally substituted with R o' .
  • R m1 and R n1 together with the nitrogen atom to which they are attached form a piperidine ring or a piperazine ring optionally substituted with R 0 ' .
  • R m1 and R n1 together with the nitrogen atom to which they are attached form Nitrogen atom No. 1 is the nitrogen atom that is bonded to R m1 and R n1 .
  • R 0 and R 0′ are each independently selected from C1-6 alkyl, —NR m2 R n2 , and a 5-6 membered heterocyclyl optionally substituted with C1-6 alkyl.
  • R 0 is selected from C 1-6 alkyl and a 5-6 membered heterocyclyl substituted by C 1-6 alkyl, wherein the 5-6 membered heterocyclyl is selected from piperidinyl and piperazinyl.
  • R 0 is selected from methyl, ethyl, and a 5-6 membered heterocyclyl substituted with methyl, the 5-6 membered heterocyclyl being piperidinyl.
  • R 0 is selected from methyl and a 5-6 membered heterocyclyl substituted with methyl, the 5-6 membered heterocyclyl being piperidinyl.
  • R 0 is selected from methyl, ethyl and
  • R is selected from methyl
  • R 0′ is selected from C 1-6 alkyl and —NR m2 R n2 .
  • R 0′ is selected from methyl and -NR m2 R n2 .
  • R m2 and R n2 are methyl.
  • amino acid residue represented by AA 1 is selected from
  • amino acid residue represented by AA 1 is selected from
  • L4 is absent.
  • L3 is Bit 2 is connected to D.
  • L4 is selected from Bit 1 is connected to L 3 and bit 2 is connected to D.
  • the linker is selected from:
  • D is selected from the following structures, which are connected to L through the O or N atom at position 1 in the molecule:
  • D is selected from the above structures, which is connected to L3 or L4 through the O or N atom at position 1 in the molecule.
  • the antibody drug conjugate is selected from the following:
  • the antibody drug conjugate is selected from the following:
  • the present disclosure provides a drug-linker conjugate as shown in formula III,
  • Lg is a group that can react with an antibody;
  • L 1 , L 2 , L 3 , L 4 and D are defined as described in any embodiment of the present disclosure.
  • Lg is selected from halogen, sulfone, tertiary amine salt (Me 3 N + , Et 3 N + ), diazonium salt, -OMs, MeSO 2 -, CF 3 SO 3 -, p-toluenesulfonyl, Substituted phenoxy, the substituents include halogen and nitro.
  • Lg is selected from F, Cl, Br, MeSO 2 —, pentafluorophenoxy; more preferably, Lg is MeSO 2 —.
  • L1 and Lg- L1 comprise the following features
  • Lg is a leaving group when reacting with an antibody; preferably, Lg is selected from halogen, sulfone, tertiary amine salt (Me 3 N + , Et 3 N + ), diazonium salt, -OMs, MeSO 2 -, CF 3 SO 3 -, p-toluenesulfonyl; more preferably, Lg is selected from F, Cl, Br, MeSO 2 -; particularly preferably, Lg is MeSO 2 -; L 2 , L 3 , L 4 and D are defined as described in any embodiment of the present disclosure;
  • L1 When L1 is When Lg-L 1 is
  • L 2 , L 3 , L 4 and D are as described in any embodiment of the present disclosure.
  • the drug-linker conjugate is selected from the following:
  • the present disclosure provides a BCL-2 family protein degrader having a structure shown in Formula Ic, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof;
  • the BCL-2 family protein degrader is selected from the following:
  • the present disclosure provides a linker in an antibody drug conjugate, the structure of which is shown below:
  • bit 1 is connected to Tb, bit 2 is connected to D;
  • L1, L2, L3 and L4 are as described in any embodiment of the present disclosure.
  • the present disclosure provides a method for preparing an antibody drug conjugate of formula II, comprising:
  • Tb, L 1 , L 2 , L 3 , L 4 , Lg and D are as defined in any embodiment of the present disclosure.
  • the method comprises the step of coupling the antibody Tb with the drug-linker conjugate Lg- L1 - L2 - L3 - L4 -D shown in formula III in a suitable solvent and conditions to form a CS bond.
  • the ratio of the amount of Tb to the amount of the drug-linker conjugate 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 carried out in water and/or an organic solvent.
  • the organic solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, nitriles (eg, acetonitrile), alcohols (eg, methanol, ethanol), or any combination thereof.
  • the method further comprises the step of purifying the coupling product.
  • the coupling product is purified by chromatography.
  • the chromatography method comprises one or more of ion exchange chromatography, hydrophobic chromatography, reverse phase chromatography, or affinity chromatography.
  • the present disclosure provides a method for preparing a drug-linker conjugate Lg-L 1 -L 2 -L 3 -L 4 -D represented by formula III, comprising:
  • Compound IV is coupled with a dipeptide to obtain compound V, and compound V is further deprotected and coupled with the corresponding carboxylic acid to obtain target compound VI.
  • the structure of the drug, dipeptide or carboxylic acid part can also be changed to obtain other desired target products.
  • the present disclosure provides a pharmaceutical composition, which comprises 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 solvate thereof; or the aforementioned compound, or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; or the aforementioned drug-linker conjugate, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally one or more pharmaceutical excipients.
  • the present disclosure provides 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 solvate thereof; or the aforementioned compound, or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; or the aforementioned drug-linker conjugate, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; or the aforementioned pharmaceutical composition for use in the preparation of a drug for treating and/or preventing a disease associated with abnormal cell activity (e.g., a cancer disease).
  • a disease associated with abnormal cell activity e.g., a cancer disease
  • the present disclosure provides a method for preventing and/or treating a disease associated with abnormal cell activity (e.g., a cancer disease), comprising: administering to an individual in need thereof an effective amount of 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 solvate thereof; or the aforementioned compound, or a stereoisomer of the compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; or the aforementioned drug-linker conjugate, a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; or the aforementioned pharmaceutical composition.
  • a disease associated with abnormal cell activity e.g., a cancer disease
  • the cancer disease described in the present disclosure is selected from one or more of esophageal cancer (e.g., esophageal adenocarcinoma or esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, or lung adenocarcinoma), 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 (e.g., colon cancer or rectal cancer), liver cancer, kidney cancer, urothelial carcinoma, solid tumors, non-Hodgkin's lymphoma, central nervous system tumors (e.g., glioma, glioblastoma multiforme, glioma, or sarcoma), acute lymphoblastic leukemia, prostate cancer, and thyroid cancer.
  • esophageal cancer
  • the disease is selected from one or more of acute lymphoblastic leukemia, colon cancer, gastric cancer, non-small cell lung cancer and lung adenocarcinoma, preferably selected from one or more of acute lymphoblastic leukemia, colon cancer, gastric cancer and non-small cell lung cancer, and more preferably selected from one or more of gastric cancer, colon cancer and non-small cell lung cancer.
  • the cancer disease is a cancer disease associated with HER2, TROP2, B7H3, HER3, or EGFR.
  • the cancer disease is a solid tumor or a hematological tumor.
  • examples of the term "pharmaceutically acceptable salts” are organic acid addition salts formed by organic acids that form pharmaceutically acceptable anions, including but not limited to formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, ascorbates, ⁇ -ketoglutarates, ⁇ -glycerophosphates, alkylsulfonates or arylsulfonates; the arylsulfonates are benzenesulfonates or p-toluenesulfonates.
  • Suitable inorganic salts may also be formed, including but not limited to hydrochlorides, hydrobromides, hydroiodides, nitrates, bicarbonates and carbonates, sulfates or phosphates, etc.
  • 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 affording 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 it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of the present application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
  • Solid lines (-), solid wedges, or dashed wedges may be used in this disclosure to depict carbon-carbon bonds of the compounds of the present invention.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at the carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, real and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the present invention are intended to exist in the form of stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, 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 (e.g., racemic mixtures and diastereoisomer pairs).
  • the compounds of the present disclosure may exist in the form of solvates (preferably hydrates), wherein the compounds of the present disclosure contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • the amount of the polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.
  • the present disclosure further includes within its scope prodrugs of the compounds of the present invention.
  • prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compound in vivo. Therefore, in these cases, the term "administration" used in the methods of treatment of the present disclosure should include the use of one or more prodrug forms of the claimed compounds to treat various diseases or conditions, but the prodrug forms are converted into the above-mentioned compounds in vivo after administration to the individual.
  • “Design of Prodrug” ed. H. Bundgaard, Elsevier, 1985, conventional methods for selecting and preparing suitable prodrug derivatives are described.
  • the pharmaceutical excipients refer to excipients and additives used in the production of drugs and the preparation of prescriptions. They refer to substances that have been reasonably evaluated in terms of safety and are included in pharmaceutical preparations in addition to active ingredients. In addition to excipients, carriers, and improving stability, pharmaceutical excipients also have important functions such as solubilization, solubilization, and sustained and controlled release. They are important ingredients that may affect the quality, safety, and effectiveness of drugs. According to their sources, they can be divided into natural products, semi-synthetic products, and fully synthetic products.
  • solvents propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, etc.; according to their route of administration, they can be divided into oral, injection, mucosal, transdermal or topical administration, nasal or oral inhalation administration and ocular administration, etc.
  • the same pharmaceutical excipients can be used in drug preparations with different routes of administration and
  • the pharmaceutical composition can be prepared into various suitable dosage forms according to the administration route, such as injections, implants, etc.
  • the pharmaceutical composition or suitable dosage form may contain 0.01 mg to 1000 mg of the compound of the present disclosure or its pharmaceutically acceptable salt or conjugate, preferably 0.1 mg to 800 mg, preferably 0.5-500 mg, preferably 0.5 to 350 mg, and particularly preferably 1-250 mg.
  • the pharmaceutical composition can be used in the form of an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for injection.
  • the vehicles and solvents which may be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may be used as a solvent or suspending medium, such as mono- or di-glycerides.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be preventive, in terms of completely or partially preventing a disease or its symptoms; and/or therapeutic, in terms of partially or completely stabilizing or curing a disease and/or side effects caused by a disease.
  • Treatment encompasses any treatment of a patient's disease, including: (a) preventing a disease or symptom from occurring in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) suppressing the symptoms of a disease, i.e., preventing its development; or (c) alleviating the symptoms of a disease, i.e., causing the disease or symptom to regress.
  • the term "individual” includes humans or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described in the present disclosure) or normal individuals.
  • non-human animal in the present disclosure includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • the term "effective dose” refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.
  • the term "antibody drug conjugate” refers to a substance obtained by connecting a drug molecule to an antibody or its antigen binding fragment portion or a targeting portion.
  • the drug molecule is connected to the antibody or its antigen binding fragment via a connector.
  • the connector can be broken in a specific environment (e.g., an intracellular low pH environment) or under a specific action (e.g., the action of a lysosomal protease), thereby separating the drug molecule from the targeting portion or the antibody or its antigen binding fragment.
  • the connector comprises a cleavable or non-cleavable unit, such as a peptide or a disulfide bond.
  • the drug molecule and the antibody or its antigen binding fragment or the targeting portion can be directly connected by a covalent bond, and the covalent bond can be broken under a specific environment or action, thereby separating the drug molecule from the antibody or its antigen binding fragment portion or the targeting portion.
  • amino acid refers to an organic compound containing a basic amino group and an acidic carboxyl group, and is composed of an amino group (NH2), a carboxyl group (COOH) and a side chain.
  • drug refers to a BCL-2 family protein degradation targeting chimera.
  • linker refers to a fragment that connects a drug molecule to an antibody or antigen-binding fragment thereof.
  • antibody is interpreted in its broadest sense, including complete monoclonal antibodies, polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies) formed by at least two complete antibodies, as long as they have the desired biological activity.
  • antibody and “immunoglobulin” can be used interchangeably.
  • the term "monoclonal antibody” refers to an antibody derived from a population of substantially homogeneous antibodies, i.e., the antibodies constituting the population are identical except for a small number of naturally occurring mutations that may be present.
  • Monoclonal antibodies have a high specificity for one determinant (epitope) of an antigen, whereas polyclonal antibodies, in contrast, contain different antibodies for different determinants (epitopes).
  • monoclonal antibodies have the advantage that they can be synthesized without contamination by other antibodies.
  • the modifier "monoclonal” herein indicates that the antibody is characterized by being derived from a substantially homogeneous population of antibodies and should not be construed as requiring production by a particular method.
  • monoclonal antibodies also specifically include chimeric antibodies, that is, a portion of the heavy chain and/or light chain is identical or homologous to a certain type, class or subclass of antibody, and the remaining portion is identical or homologous to another type, class or subclass of antibody, as long as they have the desired biological activity (see, for example, US 4,816,567; and Morrison et al., 1984, PNAS, 81: 6851-6855).
  • Chimeric antibodies that can be used in the present disclosure include primatized antibodies, which contain variable region antigen binding sequences from non-human primates (such as ancient monkeys, orangutans, etc.) and human constant region sequences.
  • antibody fragment refers to a portion of an antibody, preferably the antigen binding or variable region.
  • antibody fragments include Fab, Fab', F(ab') 2 , Fd, Fv, dAb and complementarity determining region fragments, diabodies, linear antibodies and single-chain antibody molecules.
  • bispecific antibody also known as “bifunctional antibody conjugate” refers to a conjugate formed by a first antibody (fragment) and a second antibody (fragment) through a coupling arm, which retains the activity of each antibody and thus has bifunctionality and bispecificity.
  • multispecific antibody includes, for example, trispecific antibodies, which are antibodies with three different antigen-binding specificities, and tetraspecific antibodies, which are antibodies with four different antigen-binding specificities.
  • complete antibody refers to an antibody comprising an antigen-binding variable region and a light chain constant region (CL), a heavy chain constant region (CH1, CH2 and CH3).
  • the constant region can be a native sequence (e.g., a human native constant region sequence) or an amino acid sequence variant thereof.
  • a complete antibody is preferably a complete antibody with one or more effector functions.
  • antibody is a modified antibody, including an antibody or an antibody fragment, that can specifically bind to its target and can be coupled to a masking group, wherein the masking group refers to a cleavage constant for the binding ability of the antibody or antibody fragment to its target that is at least 100 times, 1000 times, or 10,000 times greater than the cleavage constant for the binding ability of the antibody or antibody fragment to its target without the coupled masking group.
  • a "humanized" form of a non-human (e.g., mouse) antibody refers to a chimeric antibody that contains a minimal amount of non-human immunoglobulin sequence.
  • Most humanized antibodies are those in which the hypervariable region residues of a human recipient immunoglobulin are replaced with non-human (e.g., mouse, rat, rabbit, or non-human primate) hypervariable region residues (donor antibody) having the desired specificity, affinity, and function.
  • the framework region (FR) residues of the human immunoglobulin are also replaced with non-human residues.
  • humanized antibodies may also contain residues that are not present in the recipient antibody or the donor antibody. These modifications are intended to further optimize the performance of the antibody.
  • Humanized antibodies generally contain at least one, usually two, variable regions in which all or nearly all of the hypervariable loops correspond to those of non-human immunoglobulins, while the FRs are completely or almost completely sequences of human immunoglobulins. Humanized antibodies may also contain at least a portion of an immunoglobulin constant region (Fc, usually 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 be further 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 ⁇ , respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known in the art.
  • the amino acid substitution in the antibody is substituted with L-amino acids, it is not limited thereto.
  • one or more D-amino acids may be included in the antibody peptide chain. Peptides containing D-amino acids are more stable and less prone to degradation in the oral cavity, intestinal tract or plasma than peptides containing only L-amino acids.
  • the monoclonal antibodies used in the present disclosure can be produced by many methods.
  • the monoclonal antibodies used in the present disclosure can be obtained by the hybridoma method using cells of many species (including mice, hamsters, rats and humans) (see, e.g., Kohler et al., 1975, Nature, 256: 495), or by recombinant DNA technology (see, e.g., US 4,816,567), or isolated from phage antibody libraries (see, e.g., Clackson et al., 1991, Nature, 352: 624-628; and Marks et al., 1991, Journal of Molecular Biology, 222: 581-597).
  • Tb is Trastuzumab or Pertuzumab.
  • Trastuzumab is a monoclonal antibody against Her 2, and its amino acid sequence is known to those skilled in the art. Its schematic sequence can be found, for example, in CN103319599. The last Lys is easily deleted but does not affect the biological activity, see Dick, L.W. et al., Biotechnol. Bioeng., 100: 1132-1143.
  • the anti-Trop-2 antibody is RS7 described in U.S. Patent No. 7,517,964 (i.e., Sacituzumab of the present disclosure); and hRS7 described in US2012/0237518 (i.e., Sacituzumab of the present disclosure).
  • the anti-Trop-2 antibody that can be used in the present disclosure can also be obtained by screening the method of vector design, construction, and construction of an antibody library displaying antibodies disclosed in CN103476941A, or can be obtained by screening the method of Sorrento Therapeutics, Inc. The library was screened.
  • ErbB2 and Her2/neu are used interchangeably, and both represent the native sequence human Her2 protein (Genebank accession number: X03363, see, e.g., Semba et al., 1985, PNAS, 82: 6497-6501; and Yamamoto et al., 1986, Nature, 319: 230-234) and its functional derivatives, such as amino acid sequence variants.
  • ErbB2 represents the gene encoding human Her2
  • neu represents the gene encoding rat p185neu.
  • the compounds or conjugates of the present disclosure are capable of inhibiting or killing cells expressing ErbB2 receptors, such as breast cancer cells, ovarian cancer cells, gastric cancer cells, endometrial cancer cells, salivary gland cancer cells, lung cancer cells, renal cancer cells, colon cancer cells, thyroid cancer cells, pancreatic cancer cells, bladder cancer cells or liver cancer cells.
  • cells expressing ErbB2 receptors such as breast cancer cells, ovarian cancer cells, gastric cancer cells, endometrial cancer cells, salivary gland cancer cells, lung cancer cells, renal cancer cells, colon cancer cells, thyroid cancer cells, pancreatic cancer cells, bladder cancer cells or liver cancer cells.
  • Trop-2 or TROP2 refers to human trophoblast cell-surface antigens 2, also known as TACSTD2, M1S1, GA733-1, EGP-1, which is a cell surface receptor expressed by many human tumor cells (such as breast cancer, colorectal cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer).
  • the compounds or conjugates of the present disclosure can inhibit or kill cells expressing TROP2 receptors, such as breast cancer cells, colorectal cancer cells, lung cancer cells, pancreatic cancer cells, ovarian cancer cells, prostate cancer cells or cervical cancer cells.
  • Tb is a monoclonal antibody against B7H3, or an antigen-binding fragment thereof.
  • the anti-B7H3 antibody includes all anti-B7H3 antibodies in the prior art, for example, see CN112521512, WO2021027674, WO2021021543, WO2021006619, CN111662384, CN111454357, WO2020151384, WO2020140094, WO2020103100, WO2020102779, WO2020063673, WO2020047257, WO2020041626, CN110684790, CN110642948, WO2019225787, WO2019226017, US20 190338030, CN110305213, WO2018 209346, WO2018177393, US9150656, WO2016106004, WO2016044383, WO2016033225, WO2015181267, US20120294796, WO2011109400, CN10110
  • C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
  • C1-6 alkyl refers to a straight or branched alkyl group containing 1 to 6 carbon atoms, including, for example, “C1-3 alkyl” or “C1-4 alkyl", “C1-2 alkyl", methyl, ethyl, etc. Specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.
  • C2-6 alkenyl refers to a linear, branched or cyclic alkenyl group containing at least one double bond and having 2 to 6 carbon atoms, including, for example, "C2-4 alkenyl” etc.
  • Examples thereof include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl etc.
  • C2-6 alkynyl refers to a straight or branched alkynyl group containing at least one triple bond and having 2 to 6 carbon atoms, including, for example, "C2-4 alkynyl” etc. Examples thereof include, but are not limited to, ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl etc.
  • halogen includes fluorine, chlorine, bromine, iodine.
  • C3-6 cycloalkyl refers to a saturated cyclic alkyl group containing 3 to 6 carbon atoms, including cyclopropane (ie, cyclopropyl), cyclobutane (ie, cyclobutyl), cyclopentane (ie, cyclopentyl), and cyclohexyl.
  • C1-6 alkoxy refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom, including, for example, "C1-3 alkoxy” or "C1-4 alkoxy”. Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.
  • C1-6 haloalkyl refers to an alkyl group as defined above attached to the parent molecular moiety through a halogen, including, for example, "C1-3 haloalkyl” or “C1-4 haloalkyl”. Specific examples include, but are not limited to, chloromethyl, fluoroethyl, bromo Propyl, etc.
  • the term "4-10 membered heterocyclyl” refers to a cyclic group containing 4-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom).
  • the term "4-6 membered heterocyclyl” refers to a cyclic group containing 4-6 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom).
  • the ring atoms (e.g., carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxo-substituted.
  • “4-8 membered heterocyclyl” includes, for example, “4-8 membered nitrogen-containing heterocyclyl”, “4-8 membered oxygen-containing heterocyclyl”, “4-7 membered heterocyclyl”, “4-7 membered oxygen-containing heterocyclyl”, “4-7 membered heterocyclyl”, “4-6 membered heterocyclyl”, “5-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “5-6 membered nitrogen-containing heterocyclyl”, and includes but is not limited to oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl and the like.
  • the term "4-10 membered heterocycle” refers to a ring containing 4-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom).
  • the term “5-6 membered heterocycle” refers to a ring containing 5-6 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom), including but not limited to pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran and the like.
  • 6-12 membered spirocyclyl refers to a cyclic structure containing 6-12 ring carbon atoms formed by two or more cyclic structures sharing one carbon atom.
  • the carbon atoms in the cyclic structure can be oxo-substituted.
  • 6-12 membered spirocyclyl includes, for example, “6-11 membered spirocyclyl”, “6-10 membered spirocyclyl”, “7-10 membered spirocyclyl”, “7-9 membered spirocyclyl”, “7-8 membered spirocyclyl”, “9-10 membered spirocyclyl”, “3-10 membered spirocyclyl”, etc., including but not limited to
  • 6-12-membered cycloalkyl refers to a cycloalkyl containing 6-12 ring carbon atoms formed by two or more cycloalkyls sharing two adjacent atoms, including "6-11-membered cycloalkyl”, “6-10-membered cycloalkyl”, “6-8-membered cycloalkyl”, “10-12-membered cycloalkyl”, “7-10-membered cycloalkyl", etc., including but not limited to
  • aryl refers to a monocyclic or polycyclic hydrocarbon group having aromaticity, such as a 6-10-membered aryl group, a 5-8-membered aryl group, etc. Specific examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.
  • the "6-10-membered aryl group” refers to an aryl group containing 6-10 ring atoms.
  • C6-10 aryl group refers to an aryl group containing 6-10 carbon atoms.
  • heteroaryl refers to a cyclic group with aromaticity, wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom.
  • the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxoed.
  • 5-10 yuan heteroaryl 5-6 yuan heteroaryl, 5-10 yuan nitrogen-containing heteroaryl, 6-10 yuan oxygen-containing heteroaryl, 6-8 yuan nitrogen-containing heteroaryl, 5-8 yuan oxygen-containing heteroaryl, etc.
  • furyl thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, 1,4-dioxinyl, 2H
  • the reagents and raw materials used in the present disclosure are commercially available.
  • the antibody-drug conjugate of the BCL-2 family protein degrader disclosed in the present invention can achieve at least one of the following technical effects:
  • the antibody-drug conjugates disclosed herein have targeting selectivity and can be enriched in targeted cells;
  • the antibody-drug conjugate disclosed in the present invention has extracellular lysis ability and is still effective against tumors with low or no antigen expression, thus solving the drug resistance problem related to the mechanism of antibody-drug conjugates.
  • the nuclear magnetic resonance ( 1 H NMR) was measured using a Bruker 400 MHz nuclear magnetic resonance instrument; the measurement solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexadeuterated dimethyl sulfoxide (DMSO-d 6 ); the internal standard substance was tetramethylsilane (TMS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Example 1.1 Synthesis of 6-azido-N-((S)-1-(((S)-1-((4-(hydroxymethyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide (INT1).
  • Example 1.2 Synthesis of (R)-7-(4-(3-((4-(N-(4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanoic acid (INT2).
  • compound INT2-6 300 mg, 0.27 mmol was dissolved in a mixed solution of THF (0.5 mL), EtOH (0.5 mL) and water (0.5 mL), and LiOH.H 2 O (19.40 mg, 0.81 mmol) was added under stirring to react for 1 h.
  • the reaction was detected by LCMS.
  • the reaction solution was concentrated to obtain an aqueous solution of lithium salt, and 1N HCl solution was added to adjust the pH to 2-3. Solids precipitated, which were filtered and the filter cake was dried to obtain the target compound INT2 (240 mg).
  • LCMS (ESI) [M+H] + 1116.77.
  • Example 1.3 Synthesis of allyl ((S)-3,3-dimethyl-1-((2S,4R)-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)-4-(((4-nitrophenoxy)carbonyl)oxy)pyrrolidin-1-yl)-1-oxobutan-2-yl)carbamate (INT3).
  • Example 1.4 Synthesis of tert-butyl ((S)-5-((S)-2-(6-azidohexanamido)-3-methylbutanamido)-6-((4-(hydroxymethyl)phenyl)amino)-6-oxohexyl)carbamate (INT4).
  • Example 1.7 Synthesis of (5S,8S)-8-(4-(dimethylamino)butyl)-1-(9H-fluoren-9-yl)-5-isopropyl-3,6,9,12-tetraoxo-2,15-dioxa-4,7,10,13tetraazaheptadecan-17-oic acid (INT7).
  • Example 1.8 (2S,4R)-1-((S)-2-(7-(4-((R)-3-)(4-(N-(4-(4-(S)-4-(S)-12-(S)2-amino-3-methylbutyramido)-2,17-dimethyl-3,8,11-trioxo-5-oxa-2,7,10,17-tetraazaoctadecyl)-4′-chloro-4-methyl-3,4,5,6-tetrahydro-[ Synthesis of ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (INT8).
  • Example 1.10 Synthesis of 3-(2-(4-(2-(methylsulfonyl)pyrimidin-5-yl)-1H-1,2,3-triazol-1-yl)-5-oxo-3,9,12,15,18,21,24,27,30-nonyloxy-6-azatricarboxylic acid (INT10).
  • Example 1.11 Synthesis of (2S,4R)-1-((2S)-2-(7-(4-((3R)-3-((4-(N-(4-(4-((4′-chloro-4-methyl-4-((methylamino)methyl)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanoyl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (INT11).
  • Example 1.12 Synthesis of 39-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5,34-dioxo-3,9,12,15,18,21,24,27,30-nonaoxa-6,33-diazatriacontanoic acid (INT12).
  • Example 1.13 Synthesis of 4-(4-((4′-((tert-butoxycarbonyl)amino)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (INT13).
  • Example 1.14 Synthesis of 4-(4-((3′-((tert-butoxycarbonyl)amino)-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (INT14).
  • Example 1.15 Synthesis of (R)-4-(4-(phenylthio)-3-((4-aminosulfonyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butyl)piperazine-1-carboxylic acid allyl ester (INT15).
  • INT15-3 (1.1 g, 3.15 mmol) was dissolved in 1,4-dioxane (20 mL), and N,N-diisopropylethylamine (954 mg, 9.45 mmol) and 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (1.16 g, 3.78 mmol) were added in sequence. The atmosphere was replaced with nitrogen three times. The reaction solution was stirred at 60°C for 16 h, and the reaction was monitored by LCMS.
  • Example 1.17 Synthesis of (S)-ethyl 4-(4-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4′-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate and (R)-ethyl 4-(4-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-4′-chloro-4-methyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (INT17-P1 & INT17-P2).
  • Example 2.2 Synthesis of (2S,4R)-1-((S)-2-(7-(4-(R)-3-(4-(N-(4-(((R)-4′-chloro-4-((2-hydroxy-N-methylacetylamino)methyl)-4-methyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-(((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptylamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (PL-2).
  • Example 2.5 Synthesis of N1-((4′-chloro-6-((4-(4-(((4-(4-(2-hydroxyacetyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl)piperazin-1-yl)methyl)-4-methyl-2,3,4,5-tetrahydro-[1,1′-biphenyl]-4-yl)methyl)-N10-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanamide (PL-5).
  • aqueous phase was extracted with dichloromethane (50 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was purified by column chromatography (phase A: H 2 O containing 0.1% FA, phase B: acetonitrile) to obtain the target compound DL001-2 (270 mg).
  • LCMS (ESI) [M+H] + 989.5.
  • Example 3.2 4-((S)-6-amino-2-((S)-3-methyl-2-(6-(4-(2-(methylsulfonyl)pyrimidin-5-yl)-1H-1,2,3-triazol-1-yl)hexanamido)butanamido)hexanamido)benzyl((3R,5S)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((4′-chloro-4,4-dimethyl-3,4,5,6-tetrazolyl) Synthesis of 3-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-3-yl)carbonate (DL002).
  • Example 3.5 (2S, 4R)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-(((S)-4′-chloro-4-((12S, 15S)-12-(4-(dimethylamino)butyl)-15-isopropyl-2-methyl-22-(2-(methylsulfonyl)pyrimidin-5-yl)-3,8,11,14,17-pentaoxo-5-oxa-2,7,10,13,16-pentaazadocosapenta-21-yne- Synthesis of ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (DL005).
  • Example 3.6 (2S, 4R)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-(((R)-4′-chloro-4-((12S, 15S)-12-(4-(dimethylamino)butyl)-15-isopropyl-2-methyl-22-(2-(methylsulfonyl)pyrimidin-5-yl)-3,8,11,14,17-pentaoxo-5-oxa-2,7,10,13,16-pentaaza Synthesis of ((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (DL006).
  • Example 2 Preparation and identification of antibodies: Refer to the method disclosed in WO2022170971A1 to prepare anti-B7H3 antibodies: 1D1-01 and 2E3-02; wherein 1D1-01 involves the sequence SEQ ID NO: 1 (1D1-01VH), SEQ ID NO: 2 (1D1-01VL), SEQ ID NO: 3 (1D1-01HC) and SEQ ID NO: 4 (1D1-01LC), 2E3-02 involves the sequence SEQ ID NO: 5 (2E3-02VH), SEQ ID NO: 6 (2E3-02VL), SEQ ID NO: 7 (2E3-02HC) and SEQ ID NO: 8 (2E3-02LC), see the sequence table for specific sequences.
  • 1D1-01 involves the sequence SEQ ID NO: 1 (1D1-01VH), SEQ ID NO: 2 (1D1-01VL), SEQ ID NO: 3 (1D1-01HC) and SEQ ID NO: 4 (1D1-01LC
  • 2E3-02 involves the sequence SEQ ID NO: 5 (2E3-02VH), S
  • LC represents antibody light chain
  • HC represents antibody heavy chain
  • DAR1 represents a drug-linker conjugate comprising a light chain or a heavy chain coupled to one drug
  • DAR2 represents a drug-linker conjugate comprising a light chain or a heavy chain coupled to two drug
  • DAR3 represents a drug-linker conjugate comprising a light chain or a heavy chain coupled to three drug.
  • LC, HC, DAR1, DAR2, and DAR3 are as described above.
  • DAR value Drug-antibody coupling ratio
  • Sample treatment Take 50 ⁇ g of ADC sample, dilute it to 0.5 mg/ml with ultrapure water, then add DTT (1 ⁇ l, 1 M), mix well and centrifuge to take the supernatant.
  • trastuzumab light chain was coupled to 1 toxin molecule (LC+DAR1 ratio was 91%), and the heavy chain was coupled to 2 and 3 toxin molecules (HC+DAR2 ratio was 3%, HC+DAR3 ratio was 93%), and the antibody-drug conjugation ratio (DAR value) of HER2-ADC-02 was calculated to be 7.5.
  • Drug-antibody coupling ratio (DAR value) determination method instrument information, mass spectrometry parameters: same as Example 3.2
  • Example 4.1 Detection of inhibitory activity of ADC on in vitro cell activity
  • HT29, NCI-H358 (HT29 and NCI-H358 are B7H3-positive tumor cells) and Calu-3 (Calu-3 is B7H3-negative tumor cells) tumor cells were digested by conventional methods using trypsin, and the number of cells in the tubes was collected and the corresponding detection medium was used. (containing 2% FBS) and resuspended, and 2000-5000 cells/well were added to a 96-well plate. 100uL of B7H3-ADC-01 (DAR8) diluted with 2% FBS medium was added to a 96-well plate, starting from a concentration of 150 ⁇ g/ml, and diluted 3 times (12 concentration gradients).
  • N87 (1640 + 10% FBS) tumor cells were cultured in a 37°C, 5% CO2 incubator and cell-specified culture medium according to conventional methods. N87 tumor cells were digested with trypsin, and the cells were collected and counted. The cells were resuspended to 50,000/ml in the corresponding complete culture medium and added to a 96-well plate at 100ul/well.
  • the ADC to be tested was diluted with complete culture medium, with the drug concentration starting from 125nM and 4-fold dilution for a total of 9 gradients. 100uL of the diluted ADC was added to a 96-well plate containing 100ul culture medium and cells. Incubate at 37°C 5% CO2 for 4 days.
  • GraphPad software was used to draw a dose-dependent cell proliferation inhibition graph and analyze its half-inhibitory concentration (IC50, nM).
  • test results show that the ADC molecules disclosed in the present invention have significant proliferation inhibition activity on the N87 tumor cell line.
  • the test results are shown in Table 2.
  • the cells in the 96-well plate were cultured at 37°C and 5% CO 2 .
  • the test results show that the BCL-2 family protein degrader (Payload) disclosed in the present invention has obvious proliferation inhibition activity on MOLT-4 cells.
  • the test results are shown in Table 4.

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Abstract

L'invention concerne un conjugué anticorps-médicament représenté par la formule (I) et contenant un agent de protéolyse de la famille BCL-2, et son procédé de préparation, Tb étant un anticorps, ou un fragment liant l'antigène ou une fraction de ciblage de celui-ci, q étant un rapport médicament-anticorps, L étant un agent de liaison, et D étant un fragment de chimère ciblant la protéolyse de la famille BCL-2, la chimère ciblant la protéolyse de la famille BCL-2 contenant une fraction de liaison à la protéine de la famille BCL-2 et une fraction de liaison à l'ubiquitinase. Le conjugué anticorps-médicament peut être utilisé pour prévenir et/ou traiter des maladies tumorales.
PCT/CN2024/073029 2023-01-18 2024-01-18 Conjugué anticorps-médicament contenant un agent de protéolyse de la famille bcl-2, son procédé de préparation et son utilisation WO2024153185A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109152843A (zh) * 2016-05-20 2019-01-04 豪夫迈·罗氏有限公司 Protac抗体缀合物及其使用方法
CN112105360A (zh) * 2018-01-22 2020-12-18 生物风险投资有限责任公司 用于癌症治疗的bcl-2蛋白降解剂
CN112135637A (zh) * 2018-01-10 2020-12-25 财团法人生物技术开发中心 抗体protac偶联物
CN113209306A (zh) * 2014-12-09 2021-08-06 艾伯维公司 具有细胞渗透性的bcl-xl抑制剂的抗体药物缀合物
WO2021195598A2 (fr) * 2020-03-27 2021-09-30 Angiex, Inc. Conjugués d'anticorps-agent de dégradation et leurs procédés d'utilisation
CN113660937A (zh) * 2019-02-08 2021-11-16 佛罗里达大学研究基金公司 治疗剂和治疗方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113209306A (zh) * 2014-12-09 2021-08-06 艾伯维公司 具有细胞渗透性的bcl-xl抑制剂的抗体药物缀合物
CN109152843A (zh) * 2016-05-20 2019-01-04 豪夫迈·罗氏有限公司 Protac抗体缀合物及其使用方法
CN112135637A (zh) * 2018-01-10 2020-12-25 财团法人生物技术开发中心 抗体protac偶联物
CN112105360A (zh) * 2018-01-22 2020-12-18 生物风险投资有限责任公司 用于癌症治疗的bcl-2蛋白降解剂
CN113660937A (zh) * 2019-02-08 2021-11-16 佛罗里达大学研究基金公司 治疗剂和治疗方法
WO2021195598A2 (fr) * 2020-03-27 2021-09-30 Angiex, Inc. Conjugués d'anticorps-agent de dégradation et leurs procédés d'utilisation

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