WO2023041007A1 - 抗her2抗体药物偶联物及其组合物和用途 - Google Patents

抗her2抗体药物偶联物及其组合物和用途 Download PDF

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WO2023041007A1
WO2023041007A1 PCT/CN2022/119215 CN2022119215W WO2023041007A1 WO 2023041007 A1 WO2023041007 A1 WO 2023041007A1 CN 2022119215 W CN2022119215 W CN 2022119215W WO 2023041007 A1 WO2023041007 A1 WO 2023041007A1
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cancer
antibody
drug conjugate
optionally substituted
pharmaceutically acceptable
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French (fr)
Chinese (zh)
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陈天玺
徐同杰
唐小齐
丰巍伟
张正平
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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    • 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
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    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
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    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • the present invention relates to antibody drug conjugates comprising linked antibody moieties, intermediate linker moieties and cytotoxic drug moieties.
  • the present invention also relates to the use of the antibody-drug conjugate in the preparation of medicines for treating cancer.
  • HER2 human epidermal growth factor receptor 2, human epidermal growth factor receptor 2, also known as ErbB-2 (Receptor tyrosine-protein kinase erbB-2), is the human epidermal growth factor receptor (HER/EGFR/ERBB) family Members of this family include EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4).
  • the HER2 protein has an extracellular ligand-binding domain (domain I-IV), a transmembrane domain, and an intracellular domain.
  • HER2 forms heterodimers with any of the other three receptors (ErbB-1, ErbB-3, ErbB-4), and dimerization results in autophosphorylation of tyrosine residues within the receptor cytoplasmic domain , and activate a variety of signaling pathways, including MAPK (mitogen-activated protein kinase), PI3K/Akt (phosphoinositide 3-kinase), PKC (protein kinase C), STAT (Signal transducer and activator of transcription). Amplification or overexpression of the HER2 gene plays an important role in the occurrence and development of some invasive breast cancers. 15%-30% of breast cancer patients are HER2 positive. HER2 is an important biomarker and therapeutic target for breast cancer patients. In addition, 7%-34% of gastric cancer patients overexpress HER2, and 30% of salivary duct carcinoma HER2 overexpresses.
  • Antibody-Drug Conjugate is a class of drugs that combines the high specificity of therapeutic antibodies and the high killing activity of cytotoxic drugs, in which the therapeutic antibody part and the cytotoxic drug part pass through the middle linker Partial connection.
  • ADC drugs there are at least ten ADC drugs on the market worldwide.
  • Cytotoxic drugs brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, and belantamab mafodotin all use auristatins that act on microtubules, and Trastuzumab emtansine uses maytansinoid toxin molecules that act on microtubules.
  • Gemtuzumab ozogamicin and inotuzumab ozogamicin use calicheamicin toxin molecules that act on DNA
  • trastuzumab deruxtecan and sacituzumab govitecan both use camptothecin toxoid molecules
  • loncastuximab tesirine uses PBD dimers that act on DNA.
  • Eribulin (Formula I below) is a synthetic analogue of the natural marine product halichondrin B, which inhibits the growth phase of microtubules, which acts through a tubulin-based anti-mitotic mechanism, resulting in G2/M cell Arrest of the cycle, disruption of the mitotic spindle, and ultimately apoptosis after prolonged mitotic arrest. Eribulin is currently approved for the treatment of metastatic breast cancer and soft tissue sarcoma.
  • ADC drugs combine the dual advantages of high potency of cytotoxic small molecules and high selectivity of antibodies to specific tumor cells.
  • ADC Antibody Drug Conjugate
  • the present invention provides an antibody-drug conjugate, wherein the antibody or its antigen-binding fragment is coupled to the cytotoxic drug eribulin or its derivative; preferably, the antibody or its antigen-binding fragment specifically binds to HER2.
  • the present invention provides an antibody drug conjugate having the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein Ab represents an antibody moiety, L represents a linker moiety, and U represents For the cytotoxic drug part, n is an integer or decimal selected from 1 to 10.
  • Ab represents an antibody moiety
  • L represents a linker moiety
  • U represents For the cytotoxic drug part
  • n is an integer or decimal selected from 1 to 10.
  • the antibody portion Ab is linked to the linker portion through a specific functional group, and the antibody portion can specifically bind to an antigen.
  • the present invention provides an antibody drug conjugate having the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein the cytotoxic drug moiety U is coupled to the antibody moiety Ab through a linker moiety L couplet.
  • the linker part L of the present invention can be connected to the antibody part by any method known in the art, preferably the linker part and the antibody part are connected through sulfhydryl and/or amino groups.
  • the linker moiety of the invention is linked to the antibody moiety via a sulfhydryl group.
  • the present invention provides an antibody drug conjugate having the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein the cytotoxic drug moiety U is coupled to the antibody moiety Ab via a linker moiety L , the linker portion may be a cleavable linker or a non-cleavable linker.
  • the linker moiety of the present invention is a cleavable linker, such as a low pH-dependent degradable type (including hydrazone bonds, carbonate bonds, etc.), a proteolytic type (including peptidyl bonds), or a high glutathione-dependent degradable type. Glycopeptide concentration degradation type (including disulfide bonds), etc.
  • the cleavable linker can be broken within the target cell, thereby releasing the cytotoxic drug.
  • the linker moiety of the present invention is a non-cleavable linker, such as maleimidocaproyl and the like.
  • the present invention provides an antibody drug conjugate of the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody portion Ab is combined with one or more cytotoxic drugs Part U coupling
  • cytotoxic drugs can be selected from alkaloids, anti-metabolites, antitumor antibiotics, alkylating agents and platinums, etc.
  • preferred cytotoxic drugs are microtubule inhibitors cytotoxic drugs (including Maytansinoids, orlistatins, eribulins, etc.) or cytotoxic drugs that act on DNA (including calicheamicins, duocarmycins, PBD (pyrrolobenzodiazepines), topoisomerase I inhibitors classes, etc.).
  • the cytotoxic drug moiety U of the antibody-drug conjugate having the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof provided by the present invention is a microtubule inhibitor.
  • the cytotoxic drug moiety U of the antibody-drug conjugate of the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof provided by the present invention is eribulin or its derivative.
  • the cytotoxic drug moiety is connected to the linker moiety through a functional group, and the cytotoxic drug molecule will be dissociated in tumor cells, thereby exerting an anti-tumor effect.
  • the present invention provides an antibody drug conjugate having the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein Ab represents an antibody moiety, L represents a linker moiety, and U represents Cytotoxic drug moiety, n is an integer or decimal selected from 1 to 10, wherein the antibody drug conjugate comprises the structure shown in the following formula IIa:
  • R a is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R b is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R a and R b together with the atoms to which they are attached form an optionally substituted 5- to 8-membered heterocyclic group.
  • each of R a and R b is independently selected from a hydrogen atom, methyl, ethyl, propyl or isopropyl.
  • the R a and R b are hydrogen atoms.
  • the antibody drug conjugate comprises the structure described in Formula IIa-1 below:
  • the present invention provides an antibody drug conjugate having the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein Ab represents an antibody moiety, L represents a linker moiety, U represents a cytotoxic drug moiety, n is an integer or decimal selected from 1 to 10, wherein -U is a structure shown in formula IIa,
  • R a is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R b is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R a and R b together with the atoms to which they are attached form an optionally substituted 5- to 8-membered heterocyclic group.
  • each of R a and R b is independently selected from a hydrogen atom, methyl, ethyl, propyl or isopropyl.
  • the R a and R b are hydrogen atoms.
  • the -U is the structure shown in Formula IIa-1.
  • the antibody-drug conjugate of the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof provided by the present invention comprises the structure shown in the following formula IIIa:
  • R a is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R b is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R a and R b together with the atoms to which they are attached form an optionally substituted 5- to 8-membered heterocyclic group.
  • each of R a and R b is independently selected from a hydrogen atom, methyl, ethyl, propyl or isopropyl.
  • the R a and R b are hydrogen atoms.
  • the antibody drug conjugate comprises the structure described in Formula IIIa-1 below:
  • the antibody-drug conjugate of the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof provided by the present invention has the structure shown in the following formula IV:
  • Ab represents the antibody portion
  • n is an integer or decimal selected from 1-10;
  • R a is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R b is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R a and R b together with the atoms to which they are attached form an optionally substituted 5- to 8-membered heterocyclic group.
  • the R a and R b are each independently selected from a hydrogen atom or a C 1-5 alkyl group (preferably a C 1-4 alkyl group, such as a C 1-3 alkyl group).
  • each of R a and R b is independently selected from a hydrogen atom, methyl, ethyl, propyl or isopropyl.
  • said R a and R b are hydrogen atoms.
  • the present invention provides an antibody drug conjugate represented by the following formula IV-1 or a pharmaceutically acceptable salt or solvate thereof,
  • n is an integer or a decimal selected from 1 to 10.
  • the n is 2-4.5, 2.2-4.5, 2.2-2.7, 2.5-4.5, 2.7-4.5 , 3.3-4.5, 3.4-4.5, 3.5-4.5, 3.9-4.5, 3.3-4, 3.3-3.9, 3.4-3.9, 7-8, 7-7.5, 7-7.8, 7.1-7.5, 7.1-7.8, 7.5 -7.8, or 7.5-8.
  • the n is about 2.2, about 2.7, about 3.3, about 3.4, about 3.9, about 4, about 7, about 7.1, about 7.5, about 7.8, or about 8.
  • the amount of the cytotoxic drug conjugated with the antibody part in the antibody drug conjugate (ADC) of the present invention can vary, so that the antibody drug conjugate provided in the present invention or its pharmaceutically acceptable salt or solvate can be Heterogeneous, that is, the antibody-drug conjugates of the present invention or pharmaceutically acceptable salts or solvates thereof include antibodies or antigen-binding fragments thereof conjugated with different amounts of cytotoxic drugs, such as 1 molecule of antibody or antigen-binding fragments thereof There are 0 (ie no cytotoxic drugs), 1, 2, 3, 4, 5, 6, 7, 8 or other more molecular cytotoxic drugs coupled.
  • DAR drug-to-antibody ratios
  • DAR is about 3.9 or "n is about 3.9” refers to an antibody drug conjugate or a pharmaceutically acceptable salt or solvate thereof comprising each molecule of antibody or antigen-binding fragment thereof conjugated with different A heterogeneous mixture of cytotoxic drugs (e.g., 0, 1, 2, 3, 4, 5, 6, 7, or 8 cytotoxic drugs conjugated to each antibody or antigen-binding fragment thereof), but the cytotoxic drugs are The average molar ratio of antibodies or antigen-binding fragments thereof is about 3.9.
  • cytotoxic drugs e.g., 0, 1, 2, 3, 4, 5, 6, 7, or 8 cytotoxic drugs conjugated to each antibody or antigen-binding fragment thereof
  • the cytotoxic drugs are The average molar ratio of antibodies or antigen-binding fragments thereof is about 3.9.
  • “DAR is about 8" or “n is about 8” means that the average molar ratio of cytotoxic drug to antibody or antigen-binding fragment thereof in the ADC is about 8.
  • the present invention provides an antibody drug conjugate having the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein Ab (antibody part) can specifically bind to a tumor antigen
  • the tumor antigen can be selected from any tumor therapy target known in the art, non-limiting examples of the target include HER2, HER3, EGFR, CD20, CD30, CD33, CD47, CD79b, VEGF, VEGFR, MET , RET, PD-1 or PD-L1.
  • the present invention provides an antibody drug conjugate represented by formula IV-1 or a pharmaceutically acceptable salt or solvate thereof, wherein the Ab (antibody part) can specifically bind to a tumor antigen, so
  • the tumor antigen can be selected from any tumor treatment target known in the art, non-limiting examples of the target include HER2, HER3, EGFR, CD20, CD30, CD33, CD47, CD79b, VEGF, VEGFR, MET, RET, PD-1, or PD-L1.
  • Ab in the antibody drug conjugate or a pharmaceutically acceptable salt or solvate thereof, is an anti-HER2 antibody or an antigen-binding fragment thereof.
  • the Ab is an anti-HER2 antibody or an antigen-binding fragment thereof
  • the anti-HER2 antibody or an antigen-binding fragment thereof comprises heavy chain CDR (HCDR) 1 of the amino acid sequence shown in SEQ ID NO: 1, comprising SEQ ID NO: 1 HCDR2 of the amino acid sequence shown in ID NO: 2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 3, light chain CDR (LCDR) 1 comprising the amino acid sequence shown in SEQ ID NO: 4, comprising SEQ ID NO: 5 LCDR2 showing the amino acid sequence, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.
  • HCDR heavy chain CDR
  • HCDR2 of the amino acid sequence shown in SEQ ID NO: 2
  • HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 3
  • light chain CDR (LCDR) 1 comprising the amino acid sequence shown in SEQ ID NO: 4
  • LCDR2 showing the amino acid sequence
  • LCDR3 comprising the amino acid sequence shown in
  • the CDR amino acid sequences of the anti-HER2 antibodies or antigen-binding fragments thereof are provided in Table S1 below.
  • the antibody moiety of the antibody-drug conjugate of the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof provided by the present invention is Trastuzumab (Trastuzumab), which Has the sequence shown in Table S1 below.
  • the anti-HER2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region
  • the heavy chain variable region comprises at least 80% of the amino acid sequence shown in SEQ ID NO:7. %, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, An amino acid sequence of 97%, 98%, 99% or 100% identity
  • said light chain variable region comprising at least 80%, 81%, 82%, 83%, 84% of the amino acid sequence shown in SEQ ID NO:8 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical Sexual amino acid sequence.
  • the anti-HER2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 7, the light chain The variable region comprises the amino acid sequence shown in SEQ ID NO:8.
  • the amino acid sequence of the heavy chain variable region of the anti-HER2 antibody or an antigen-binding fragment thereof is shown in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO: 8 .
  • the anti-HER2 antibody or antigen-binding fragment thereof may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of said constant region.
  • the constant region is from a human immunoglobulin heavy chain, such as IgGl, IgG2, IgG3, and IgG4 or heavy chains of other classes of immunoglobulins, preferably IgGl.
  • the constant region may comprise any of the modifications described herein, such as insertions, deletions, substitutions or chemical modifications of amino acids.
  • the constant region comprises mutations that alter effector function.
  • any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype.
  • the anti-HER2 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, the heavy chain comprising at least 80%, 81%, 82%, 83% of the amino acid sequence shown in SEQ ID NO: 9 %, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or An amino acid sequence with 100% identity, said light chain comprising at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% of the amino acid sequence shown in SEQ ID NO: 10 Amino acid sequences that are %, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.
  • the anti-HER2 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence shown in SEQ ID NO: 9, and the light chain comprising the amino acid sequence set forth in SEQ ID NO: 10 The amino acid sequence shown.
  • the amino acid sequence of the heavy chain of the anti-HER2 antibody or antigen-binding fragment thereof is shown in SEQ ID NO: 9, and the amino acid sequence of the light chain is shown in SEQ ID NO: 10.
  • the anti-HER2 antibody is selected from the group consisting of Trastuzumab, Pertuzumab, Margetuximab, Initux Monoclonal antibody (Inetetamab), HLX-22, GB-235, HK001, SSGJ-612, ZW25 (Zanidatamab), KN026 (Anbenitamab), BCD-147, MBS-301 or KM257.
  • the anti-HER2 antibody is trastuzumab.
  • the anti-HER2 antibody or antigen-binding fragment thereof is selected from monoclonal antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)'2 fragments, Fd fragments, Fv fragments, dAb fragments , isolated CDR regions, scFv, Nanobody or fusion protein.
  • the antibody-drug conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof has the general formula Ab-(LU) n , wherein Ab can be modified, for example, to include one or more Amino acid sequence changes, additions or subtractions.
  • Ab can be modified, for example, to include one or more Amino acid sequence changes, additions or subtractions.
  • the modified Ab still retains the activity of specifically binding to its corresponding antigen.
  • the antibody drug conjugate provided by the present invention or a pharmaceutically acceptable salt or solvate thereof has the structure shown below:
  • the n is 2-4.5, 2.2-4.5, 2.2-2.7, 2.5-4.5, 2.7-4.5, 3.3-4.5, 3.4-4.5, 3.5-4.5, 3.9-4.5, 3.3- 4, 3.3-3.9, 3.4-3.9, 7-8, 7-7.5, 7-7.8, 7.1-7.5, 7.1-7.8, 7.5-7.8, or 7.5-8.
  • the n is about 2.2, about 2.7, about 3.3, about 3.4, about 3.9, about 4, about 7, about 7.1, about 7.5, about 7.8 or about 8.
  • the antibody-drug conjugate having the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof provided by the present invention exhibits a combination of one or more of the following properties:
  • the antibody drug conjugate, or a pharmaceutically acceptable salt or solvate thereof binds human HER2.
  • the antibody-drug conjugates provided by the present invention or pharmaceutically acceptable salts or solvates thereof show strong endocytosis in cells with different HER2 expression levels, and at the same time, they can increase with endocytosis time. Increases the amount of ADC that is accumulatively endocytosed.
  • the present invention provides a pharmaceutical composition comprising the antibody drug conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a pharmaceutical composition, which comprises the antibody drug conjugate according to the present invention or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include, for example, excipients, diluents, encapsulating materials, fillers, buffers or other agents.
  • the present invention provides the use of the antibody drug conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating cancer.
  • the present invention provides the use of a pharmaceutical composition comprising the antibody drug conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier in the preparation of a drug for treating cancer.
  • the present invention provides the use of the pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment of cancer.
  • the present invention provides an antibody-drug conjugate for treating cancer or a pharmaceutically acceptable salt or solvate thereof, or the above-mentioned pharmaceutical composition.
  • the present invention provides a method of treating cancer, the method comprising administering a therapeutically effective amount of the antibody drug conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof or comprising the present invention to a patient in need thereof.
  • the present invention provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention.
  • the method comprises contacting tumor cells with the antibody drug conjugate or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, thereby killing tumor cells or inhibiting tumor cell growth .
  • administering a therapeutically effective amount of the antibody drug conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the present invention to a patient can kill tumor cells or inhibit the growth of tumor cells .
  • the present invention provides the use of the antibody drug conjugate of the present application or a pharmaceutically acceptable salt or solvate thereof to treat cancer.
  • the present invention provides the application of the pharmaceutical composition comprising the antibody drug conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier for treating cancer.
  • the present invention also provides the use of the pharmaceutical composition of the present invention for treating cancer.
  • the cancer in the above method or use, is a HER2 positive cancer.
  • administering a therapeutically effective amount of the antibody-drug conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the present invention to a patient can kill HER2-expressing tumor cells or inhibit HER2 express tumor cell growth.
  • cancers include, but are not limited to: biliary tract cancer, carcinosarcoma, esophageal cancer, gastroesophageal junction cancer, breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, colorectal cancer, kidney cancer, cervical cancer, ovarian cancer, endometrial cancer Carcinoma, Uterine Cancer, Melanoma, Pharyngeal Cancer, Oral Cancer, Skin Cancer, Lung Cancer, Urethral Cancer, Prostate Cancer, Bladder Cancer, Gastrointestinal Stromal Tumor, Squamous Cell Carcinoma, Peritoneal Cancer, Liver Cancer, Uterine Cancer, Salivary Gland Cancer , vulvar, thyroid, penile, leukemia, malignant lymphoma, plasmacytoma, or myeloma.
  • the antibody drug conjugates of the present invention or pharmaceutically acceptable salts or solvates thereof can be used to treat HER2-positive cancers, HER2-negative cancers (including triple-negative breast cancer) and immunohistochemical detection methods Cancers that test for HER2 expression as IHC2+.
  • the present invention provides a linker-drug intermediate compound of the structure shown in the following formula III:
  • R a is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R b is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R a and R b form an optionally substituted 5- to 8-membered heterocyclic group together with the atoms they are connected to.
  • the linker-drug intermediate compound of the structure shown in formula III wherein, R a and R b are each independently selected from a hydrogen atom, methyl, ethyl, propyl or isopropyl.
  • the present invention provides a linker-drug intermediate compound having the structure shown in the following formula III-1,
  • the linker structure adopted in the present invention connects the anti-tumor compound eribulin or its derivatives with the antibody or its antigen-binding fragment, and the provided antibody-drug conjugate achieves excellent anti-tumor effect and/or safety.
  • the antitumor effect and/or safety of the antibody drug conjugate is better than that of eribulin.
  • the provided anti-HER2 antibody drug conjugate exhibits good killing activity on tumor cells, and is effective against various tumor cells and/or cells with different expression levels of HER2 (high and/or medium and/or low) exhibited good killing activity.
  • the provided anti-HER2 antibody drug conjugate exhibits good killing activity on trastuzumab drug-resistant tumor cells.
  • provided anti-HER2 antibody drug conjugates have excellent safety profile. In some embodiments, provided antibody drug conjugates, such as anti-HER2 antibody drug conjugates, are not prone to aggregation. In some experiments, it was found that using the linker structure of the present invention to link the anti-tumor compound eribulin or its derivatives with the antibody or its antigen-binding fragment can improve the anti-aggregation property of the antibody-drug conjugate.
  • Figures 1A-1F are the binding activities of trastuzumab-eribulin conjugates, DS-8201a and trastuzumab with different DAR values to cells with different HER2 expression levels;
  • Figure 2A-2D shows the endocytosis of trastuzumab-eribulin conjugates, DS-8201a and trastuzumab with different DAR values in cells with different HER2 expression levels;
  • Figure 3A-3G shows the cell killing rate of trastuzumab-eribulin conjugates with different DAR values and DS-8201a on cells with different HER2 expression levels
  • Figure 4 shows the bystander effect of trastuzumab-eribulin conjugates, DS-8201a and T-DM1 with different DAR values
  • Figure 5 is the effect of trastuzumab-eribulin conjugates with different DAR values and vehicle control on the change of mouse tumor volume in the nude mouse subcutaneous xenograft tumor model of JIMT-1 human breast cancer cells;
  • Figure 6 shows the effect of trastuzumab-eribulin conjugates with different DAR values and vehicle controls on the tumor weight in mice in the subcutaneous xenograft tumor model of JIMT-1 human breast cancer cells;
  • Figure 7 shows the effect of trastuzumab-eribulin conjugates with different DAR values and vehicle control on the change of mouse body weight in nude mice subcutaneously transplanted tumor model of JIMT-1 human breast cancer cells.
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • optionally substituted means substituted or unsubstituted, for example, the ethyl group is "optionally” substituted by halogen, meaning that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (eg CHFCH 2 F, CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • C mn herein, is that the moiety has an integer or fractional number of carbon atoms in the given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • variable e.g, R
  • R any variable
  • its definition is independent at each occurrence. So, for example, if a group is substituted by 2 R's, each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to a -OH group.
  • cyano refers to a -CN group.
  • mercapto refers to a -SH group.
  • amino refers to a -NH2 group.
  • nitro refers to a -NO2 group.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 .
  • the alkyl group may be linear or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n - propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl portion (ie, alkyl group) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.
  • alkoxy refers to -O-alkyl
  • alkylamino refers to -NH-alkyl
  • dialkylamino refers to -N(alkyl) 2 .
  • alkylsulfonyl refers to -SO2 -alkyl.
  • alkylthio refers to -S-alkyl.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C- CH3 ), 2-propynyl (-CH2 - C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH), etc.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl Alkyl etc.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring which is not fully saturated and which may exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the carbocycle is typically a 5 to 8 membered ring.
  • Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.
  • heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and that can exist as a monocyclic, bridged, or spiro ring.
  • the heterocycle is typically a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl , pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethyl, cycloazaethyl
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetyl, Cyclic, thiabutanyl
  • 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine , imidazolidinyl, tetrahydropyrazolyl
  • 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazin
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, tetralin, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O or S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or multiple fused rings comprising 6 to 14, especially 6 to 10 ring atoms.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolyl , tetrazolyl, triazolyl, triazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, etc.
  • Derivative A compound formed by replacing atoms or atomic groups in the molecule of the parent compound with other atoms or atomic groups is called a derivative of the parent compound.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some of the bonding electrons.
  • Compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • Any atom of the synthesized compound labeled in the present invention may represent any stable isotope of the atom unless otherwise specified. Unless otherwise stated, when a position in a structure is defined as H, hydrogen (H-1), that position contains only the naturally occurring isotope.
  • a position in a structure is defined as D, or deuterium (H-2)
  • the position contains an isotope at least 3340 times greater than the naturally occurring isotope (0.015%) (i.e., at least 50.1% deuterium isotope)
  • the content of the compound shown in the structure can be at least 52.5%, at least 60%, At least 67.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98.5%, at least 99%, at least 99.5%.
  • the deuterium rate of the labeled synthetic compound in the present invention refers to the ratio of the labeled synthetic isotope content to the naturally occurring isotope amount.
  • the deuterium rate of each specified deuterium atom of the compound marked and synthesized in the present invention can be at least 3500 times (52.5%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times (75%), at least 5500 times (82.5%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), At least 6600 times (99%), at least 6633.3 times (99.5%).
  • Isotopologues in the present invention refer to compounds that differ only in isotopic composition in terms of chemical structure.
  • the compounds labeled and synthesized in the present invention have the same chemical structure, only the isotopic changes in the atomic composition of the molecule. Therefore, the deuterium-containing compound at a specific position synthesized by marking in the present invention will also contain very little hydrogen isotope at this position, and the amount of hydrogen isotope at a certain position in the compound marked and synthesized in the present invention depends on many factors , which includes the deuterium isotope purity of deuterium reagents (D 2 O, D 2 , NaBD 4 , LiAlD 4 , etc.) and the effectiveness of the introduction of deuterium isotope synthesis methods.
  • the amount of such hydrogen isotopologues at a certain position would total less than 49.9% as previously stated.
  • the total amount of hydrogen isotope at a certain position in the compound marked in the present invention will be less than 47.5%, 40%, 32.5%, 25%, 17.5%, 10%, 5%, 3%, 1% or 0.5% %.
  • any atom not designated as deuterium is present in its natural isotopic abundance.
  • bystander effect refers to the effect in which a cytotoxic drug coupled to an antibody or antigen-binding fragment thereof via a cleavable or non-cleavable linker Released has the ability to diffuse across cell membranes and thereby cause killing of adjacent cells.
  • the ability to diffuse across the cell membrane is related to the hydrophobicity of the cytotoxic drug or combination of cytotoxic drug and linker.
  • cytotoxic drugs may eg be eribulin or MMAE.
  • the bystander effect may be desirable.
  • treating means administering the compound or pharmaceutical composition described herein to prevent, improve or eliminate a disease or one or more symptoms associated with the disease, and includes but is not limited to:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound or pharmaceutical composition of the present application that constitutes a "therapeutically effective amount” may vary according to factors such as the compound or pharmaceutical composition and its ability to elicit a desired response in an individual, the disease state and its severity , the mode of administration and the age, sex and weight of the mammal to be treated.
  • the effective amount can also be routinely determined by those skilled in the art based on their own knowledge and the content of the present invention.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. .
  • solvate refers to a substance formed by the association of a compound with solvent molecules.
  • antibody is used in its broadest sense and encompasses in particular intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies (e.g. bispecific antibodies), multifunctional antibodies and antibody fragments, as long as they have the desired biological activity.
  • humanized antibody refers to an antibody comprising CDR regions derived from a non-human antibody and the remainder of the antibody molecule derived from one or more human antibodies.
  • mutant is used to refer to a peptide comprising an amino acid sequence derived from that of the peptide by substitution of one or two or more amino acids, deletion of one or two or more Wild-type amino acid, insertion of one or two or more amino acids not present in the wild-type, and/or addition of amino acids not present in the wild-type to the amino-terminal (N-terminal) and/or carboxy-terminal of the wild-type (C-terminus) (collectively referred to as “mutations").
  • insertion may also be included in “addition”.
  • CDR complementarity determining region
  • hypervariable region refers to each region of an antibody variable domain that is highly variable in sequence and/or forms structurally defined loops.
  • Native four-chain antibodies typically contain six CDRs, three in the heavy chain variable region and three in the light chain variable region.
  • variable region refers to the domain of about 100 to 110 or more amino acids defined by the N-terminal domain of the light or heavy chain of an antibody primarily responsible for antigen recognition.
  • VL light chain variable region
  • VH heavy chain variable region
  • Fab refers to the constant domain (CL) containing the light chain and the first constant domain (CH1) of the heavy chain together with the variable domain VL (light chain variable region) on the light chain and the heavy chain respectively and VH (heavy chain variable region).
  • the variable domains comprise complementarity determining regions (CDRs) involved in antigen binding.
  • scFv includes the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain.
  • the scFv further comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the structure required for antigen binding.
  • ECD extracellular domain.
  • the extracellular domain of HER2 includes four domains, namely ECD1, ECD2, ECD3 and ECD4.
  • antibody moiety refers to the antibody moiety in the antibody drug conjugate. In some specific schemes, it is connected to the intermediate linker part through a specific functional group, and the antibody part can specifically bind to the antigen.
  • linker part refers to the part of the antibody drug conjugate that connects the antibody part to the cytotoxic drug part, which can be cleavable or non-cleavable.
  • the cleavable linker can be broken in the target cell, thereby releasing the cytotoxic drug drug.
  • cytotoxic drug moiety refers to the cytotoxic drug moiety in the antibody drug conjugate. In some specific schemes, it is connected with the intermediate linker part through a functional group, and the cytotoxic drug molecule will be released in the tumor cells, thereby exerting the anti-tumor effect.
  • Trastuzumab with the common name Trastuzumab is a recombinant humanized monoclonal antibody that selectively acts on the ECD4 of human epidermal growth factor receptor-2 (HER2), and can be used to treat HER2-positive Cancer, an example of which is under the trade name Marketed therapeutic monoclonal antibody products.
  • HER2 human epidermal growth factor receptor-2
  • HER2 is the second member of the EGFR family with tyrosine kinase activity, where the expression level of HER2 can be detected by immunohistochemical assay, HER2 positive means IHC3+, HER2 negative means IHC1+/0, for IHC2+ Additional ISH testing should be performed for further clarification.
  • triple negative breast cancer refers to breast cancers that are negative for the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2.
  • EC50 refers to the effective concentration which elicits 50% of the maximal response of the antigen binding construct. EC50 can be measured by ELISA or FACS analysis or any other method known in the art.
  • identity also called consistency.
  • Percent identity (%) of an amino acid sequence refers to the alignment of the sequences to be compared with the specific amino acid sequences shown herein and after introducing gaps, if necessary, to achieve the maximum percent sequence identity, and without regard to Where any conservative substitutions are considered as part of the sequence identity, the percentage of amino acid residues in the aligned sequences that are identical to the amino acid residues of the particular amino acid sequence shown herein. Alignment of amino acid sequences for identity can be performed by various means within the skill in the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • the term “subject”, “patient” or “subject” is used interchangeably herein.
  • the term “subject”, “patient” or “subject” is a mammal.
  • the subject, patient or subject is a mouse.
  • the subject, patient or subject is a human.
  • “about” means within a range of acceptable error for a particular value, as judged by one of ordinary skill in the art, which depends in part on how the value is measured or determined, ie, the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean up to ⁇ 5%, for example within ⁇ 2%, within ⁇ 1%, or within ⁇ 0.5% of the particular numerical range given. When a specific value is given in the present application or the patent scope of the invention, unless otherwise stated, the meaning of "about” should be considered as being within the acceptable error range of the specific value.
  • values of step parameters or conditions are modified by "about” by default.
  • the present invention also provides the following specific embodiments, but protection scope of the present invention is not limited thereto:
  • Embodiment 1 An antibody drug conjugate having the general formula Ab-(LU) n or a pharmaceutically acceptable salt or solvate thereof, wherein Ab represents an antibody moiety, L represents a linker moiety, and U represents a cytotoxic drug moiety , n is an integer or decimal selected from 1 to 10, wherein the antibody drug conjugate comprises the structure shown in the following formula IIa:
  • R a is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R b is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R a and R b together with the atoms to which they are attached form an optionally substituted 5- to 8-membered heterocyclic group.
  • Embodiment 2 The antibody-drug conjugate according to embodiment 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody-drug conjugate comprises the structure shown in the following formula IIIa:
  • Embodiment 3 The antibody-drug conjugate according to embodiment 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody-drug conjugate has the structure shown in the following formula IV:
  • n is an integer or decimal selected from 1-10.
  • Embodiment 4 The antibody drug conjugate according to any one of embodiments 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R a and R b are each independently selected from a hydrogen atom, a radical, ethyl, propyl or isopropyl.
  • Embodiment 5 The antibody-drug conjugate according to embodiment 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody-drug conjugate comprises the structure shown in the following formula IIIa-1:
  • Embodiment 6 The antibody-drug conjugate according to embodiment 3 or a pharmaceutically acceptable salt or solvate thereof, wherein the antibody-drug conjugate has the structure shown in the following formula IV-1:
  • Embodiment 7 The antibody drug conjugate according to any one of embodiments 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2-4.5, 2.2-4.5, 2.2- 2.7, 2.5-4.5, 2.7-4.5, 3.3-4.5, 3.4-4.5, 3.5-4.5, 3.9-4.5, 3.3-4, 3.3-3.9, 3.4-3.9, 7-8, 7-7.5, 7-7.8, 7.1-7.5, 7.1-7.8, 7.5-7.8, or 7.5-8.
  • Embodiment 8 The antibody drug conjugate according to embodiment 7 or a pharmaceutically acceptable salt or solvate thereof, wherein said n is about 2.2, about 2.7, about 3.3, about 3.4, about 3.9, about 4. About 7, about 7.1, about 7.5, about 7.8 or about 8.
  • Embodiment 9 The antibody drug conjugate according to any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein the Ab is an anti-HER2 antibody or an antigen-binding fragment thereof.
  • Embodiment 10 The antibody drug conjugate according to embodiment 9 or a pharmaceutically acceptable salt or solvate thereof, wherein the anti-HER2 antibody or antigen-binding fragment thereof comprises the amino acid sequence shown in SEQ ID NO:1
  • the HCDR1 comprising the HCDR2 of the amino acid sequence shown in SEQ ID NO:2, the HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, the LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, comprising the amino acid sequence shown in SEQ ID NO:5 LCDR2 of amino acid sequence and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.
  • Embodiment 11 The antibody drug conjugate according to embodiment 10 or a pharmaceutically acceptable salt or solvate thereof, wherein the anti-HER2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region A variable region, the heavy chain variable region comprising an amino acid sequence having at least 80% identity with the amino acid sequence shown in SEQ ID NO:7, and the light chain variable region comprising an amino acid sequence having at least 80% identity with the amino acid sequence shown in SEQ ID NO:8 Amino acid sequences of at least 80% identity; or the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 8.
  • Embodiment 12 The antibody drug conjugate according to embodiment 10 or 11, or a pharmaceutically acceptable salt or solvate thereof, wherein the anti-HER2 antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, so
  • the heavy chain comprises an amino acid sequence having at least 80% identity to the amino acid sequence shown in SEQ ID NO:9
  • the light chain comprises an amino acid sequence having at least 80% identity to the amino acid sequence shown in SEQ ID NO:10.
  • Embodiment 13 The antibody drug conjugate according to embodiment 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the anti-HER2 antibody is trastuzumab.
  • Embodiment 14 The antibody drug conjugate or a pharmaceutically acceptable salt or solvate thereof according to any one of embodiments 9-13, wherein the antibody drug conjugate or a pharmaceutically acceptable A salt or solvate exhibits one or a combination of the following properties:
  • Embodiment 15 A pharmaceutical composition comprising the antibody drug conjugate of any one of embodiments 1-14 or a pharmaceutically acceptable salt or solvate thereof; optionally, the pharmaceutical composition Also included are pharmaceutically acceptable carriers.
  • Embodiment 16 The antibody drug conjugate described in any one of embodiments 1-14 or a pharmaceutically acceptable salt or solvate thereof or the pharmaceutical composition described in embodiment 15 in the preparation of a medicament for treating cancer
  • the cancer is HER2-positive cancer
  • the cancer is biliary tract cancer, carcinosarcoma, esophageal cancer, gastroesophageal junction cancer, breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, colorectal cancer , kidney cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, melanoma, pharyngeal cancer, oral cancer, skin cancer, lung cancer, urethral cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, squamous Cell carcinoma, peritoneal cancer, liver cancer, uterine cancer, salivary gland cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, or myeloma.
  • Embodiment 17 A method of treating cancer, comprising administering to a patient in need a therapeutically effective amount of the antibody drug conjugate of any one of embodiments 1-14 or a pharmaceutically acceptable salt or solvate thereof Or the pharmaceutical composition of embodiment 15; preferably, the cancer is a HER2-positive cancer.
  • Embodiment 18 The method according to embodiment 17, comprising contacting tumor cells with the antibody drug conjugate or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, thereby killing tumor cells or inhibit tumor cell growth.
  • Embodiment 19 The method according to embodiment 17 or 18, wherein the cancer is biliary tract cancer, carcinosarcoma, esophageal cancer, gastroesophageal junction cancer, breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, colorectal cancer, Kidney cancer, cervical cancer, ovarian cancer, endometrial cancer, uterine cancer, melanoma, pharyngeal cancer, oral cancer, skin cancer, lung cancer, urethral cancer, prostate cancer, bladder cancer, gastrointestinal stromal tumor, squamous cell cancer, peritoneal cancer, liver cancer, uterine cancer, salivary gland cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma or myeloma.
  • the cancer is biliary tract cancer, carcinosarcoma, esophageal cancer, gastroesophageal junction cancer, breast cancer, gastric cancer, pancreatic cancer, head and neck cancer, colore
  • Embodiment 20 A linker-drug intermediate compound having the structure shown in formula III:
  • R a is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R b is selected from hydrogen atom, deuterium atom, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 3-7 heterocyclyl, optionally Substituted C 6-10 aryl, optionally substituted C 5-12 heteroaryl;
  • R a and R b form an optionally substituted 5- to 8-membered heterocyclic group together with the atoms they are connected to.
  • Embodiment 21 The linker-drug intermediate compound according to embodiment 20, wherein R a and R b are each independently selected from a hydrogen atom, methyl, ethyl, propyl or isopropyl.
  • the trastuzumab (Trastuzumab) used in the examples of the present application was prepared according to the conventional method for antibodies, and the expression vector (including, for example, the pcDNA3.1 vector disclosed in CN107001463A, the pCHO1.0 vector disclosed in CN109422811A, etc.) was constructed first, and then transformed into Expressed after transfection in CHO host cells, and purified by multi-step chromatography; the amino acid sequences of the heavy chain and light chain of trastuzumab are shown in SEQ ID NO: 9 and 10, respectively.
  • DS-8201a is the active ingredient of Enhertu, an ADC drug commercially available from Daiichi Sankyo Co., Ltd.
  • T-DM1 is Trastuzumab-Matansine Union, product name
  • Solution A pH 7.4 PBS buffer
  • Solution B 10mM TCEP (tris(2-carboxyethyl)phosphine hydrochloride) aqueous solution
  • Solution D Histidine buffer (containing L-histidine 0.89mg/mL and L-histidine hydrochloride monohydrate 4.04mg/mL)
  • Solution E 700mg/mL sucrose solution (prepared with solution D)
  • Solution F 20mg/mL Tween 80 (prepared with solution D)
  • the DAR value was determined by LC-MS method. Take 50 ⁇ g of ADC sample, add 1 ⁇ L of glycosidase PNGase F (Ruian Biology, China), and incubate at 37°C for 20 hours.
  • the mass spectrometer used in the experiment is a high-resolution Xevo G2-XS (Waters, USA).
  • the sample concentration was adjusted to 5 ⁇ M, and the mass spectrometry data in positive ion mode was collected by direct injection method.
  • the collected non-denaturing mass spectrometry data were analyzed and processed using the software UNIFI 1.8.2.169 (Waters, USA).
  • the protein concentration was detected by the Lowry method. Measure the absorbance value of the sample at OD 650 wavelength with a microplate reader, fit the standard curve, bring the absorbance value of the sample into the standard curve, and calculate the protein concentration.
  • Antibody-drug conjugates of formula IV-1 (including IV-1 (Trastuzumab)) and other antibody-drug conjugates of formula IV series are prepared by the above method:
  • the small molecule cytotoxic compound was diluted to 35000ng/mL-0.0896ng/mL with culture medium, a total of 9 concentrations. Tumor cells in the logarithmic growth phase were collected, adjusted to a density of 1 ⁇ 10 5 cells/mL for plating, 100 ⁇ L was added to each well, and a cell-free blank well was set as a control. Add the above-mentioned serially diluted samples, 50 ⁇ L per well. Cultivate for 5 days in a 37°C, 5% CO 2 carbon dioxide incubator.
  • the antibody-drug conjugate was diluted to 5000ng/mL-0.0128ng/mL with culture medium, a total of 9 concentrations. Take tumor cells in logarithmic growth phase, adjust the density to 2 ⁇ 10 4 cells/mL for plating, add 100 ⁇ L to each well, and set a cell-free blank well as a control. Add the above-mentioned serially diluted samples, 50 ⁇ L per well. Cultured in a 37°C, 5% CO 2 carbon dioxide incubator.
  • Solution G histidine/histidine hydrochloride buffer (L-histidine 1.43mg/mL, L-histidine hydrochloride monohydrate 2.27mg/mL);
  • Solution H 10mM TCEP (tris(2-carboxyethyl)phosphine hydrochloride) aqueous solution;
  • Solution I DMSO (dimethyl sulfoxide);
  • Solution J 500mg/mL sucrose solution (prepared with solution G);
  • Solution K 30mg/mL Tween 80 (prepared with solution G);
  • Solution L Solution G in 10% DMSO
  • Solution M 0.3M Na 2 HPO 4 ;
  • Antibody trastuzumab
  • Linker-payload (linker-drug intermediate compound): the compound MC-GGFG-eribulin with the structure shown in Formula III-1 in Example 1.
  • trastuzumab-eribulin conjugates with a DAR of 2.2-2.7 or 7.1-7.5 according to the following experimental procedure, named trastuzumab-eribulin-D2 and trastuzumab respectively Zizumab-eribulin-D8:
  • trastuzumab-eribulin conjugate with a DAR of 3.4-3.9 according to the following experimental procedure, and name it trastuzumab-eribulin-D4:
  • linker-payload Take an appropriate amount of linker-payload and dissolve it with 50% acetone aqueous solution to a final concentration of 10 mg/mL; add an appropriate amount of the above-mentioned linker-payload solution dissolved in acetone aqueous solution to the reaction solution 3, so that the molar weight of linker-payload is N3; The mixture was reacted at 5-10° C. in the dark for 40 min to obtain a reaction solution 4 .
  • ADC Antibody linker-payload N1:N2 N1:N3 Trastuzumab-eribulin-D4 Trastuzumab MC-GGFG-eribulin 1:2.58 1:5.1
  • the components of the trastuzumab-eribulin conjugate prepared in the above example 4 were separated by using a non-porous polystyrene/divinylbenzene (PS/DVB) filler bonded to butyl, and neutral
  • PS/DVB polystyrene/divinylbenzene
  • the high-salt mobile phase improves the hydrophobicity of the protein molecule, thereby combining with the hydrophobic bonded phase in the chromatographic column, and then by gradually reducing the salt concentration and gradually increasing the proportion of isopropanol to elute the substance, the components with low hydrophobicity are first Elution, the most hydrophobic components elute later.
  • the column specifications are Sepax HIC-Butyl, 4.6 ⁇ 100mm, 5 ⁇ m, and the column temperature is 25°C.
  • Mobile phase A is 10mM phosphate buffer-1.5M ammonium sulfate, pH 7.0 (Weigh 1.42g of anhydrous disodium hydrogen phosphate and 198.21g of ammonium sulfate, add about 800mL of ultrapure water, stir until fully dissolved, adjust with phosphoric acid to pH 7.0 ⁇ 0.1, dilute to 1L, mix well and filter through a 0.22 ⁇ m filter membrane).
  • Mobile phase B is 10mM phosphate buffer, pH 7.0 (Weigh 1.42g of anhydrous disodium hydrogen phosphate, add about 800mL ultrapure water, stir until fully dissolved, adjust to pH 7.0 ⁇ 0.1 with phosphoric acid, and dilute to 1L , and filtered through a 0.22 ⁇ m membrane filter).
  • Mobile phase C was 100% isopropanol. Flow rate is 0.5mL/min, gradient elution is 30min, mobile phase parameters are: 0-15min from 75% mobile phase A plus 25% mobile phase B to 75% mobile phase B plus 25% mobile phase C, 15-20min is 75% mobile phase B plus 25% mobile phase C, 20-30min is 75% mobile phase A plus 25% mobile phase B).
  • DAR value (the percentage of ADC peak area containing 0 cytotoxic drugs ⁇ 0 + the percentage of ADC peak area containing 1 cytotoxic drug ⁇ 1 + the percentage of ADC peak area containing 2 cytotoxic drugs ⁇ 2+ ADC peak area percentage with 3 cytotoxic drugs ⁇ 3 + ADC peak area percentage with 4 cytotoxic drugs ⁇ 4 + ADC peak area percentage with 5 cytotoxic drugs ⁇ 5 + ADC with 6 cytotoxic drugs Peak area percentage ⁇ 6+ADC peak area percentage containing 7 cytotoxic drugs ⁇ 7+ADC peak area percentage containing 8 cytotoxic drugs ⁇ 8)/100%.
  • the measured DAR value of trastuzumab-eribulin-D2 is 2.2-2.7; the measured DAR value of trastuzumab-eribulin-D4 is 3.4-3.9; For trastuzumab-eribulin-D8, the measured DAR value is 7.1-7.5.
  • the components of the trastuzumab-eribulin conjugate prepared in Example 4 above were separated by using a gel chromatography column.
  • the neutral pH buffer solution added with 10% isopropanol was used as the mobile phase for elution, and each component was eluted sequentially in descending order of molecular weight.
  • the column is ACQUITY UPLC Protein BEH SEC Column 1.7 ⁇ m, 4.6 ⁇ 300mm gel chromatographic column, the column temperature is 25°C.
  • the mobile phase is 50mM phosphate buffer-200mM sodium chloride-10% isopropanol, pH 7.0 (weigh 12.53g of disodium hydrogen phosphate dodecahydrate, 2.33g of sodium dihydrogen phosphate dihydrate, and 11.69g of sodium chloride, Add about 800mL of ultrapure water, stir until fully dissolved, add ultrapure water to 1000mL for later use, take 100mL of isopropanol and add the above solution to 1000mL, mix well and filter through a 0.22 ⁇ m membrane). Precisely take 20 ⁇ g of trastuzumab-eribulin conjugate and inject it into a liquid chromatograph, and detect it at a wavelength of 280 nm. The flow rate is 0.3mL/min, isocratic elution is 15min.
  • trastuzumab-eribulin conjugate was diluted 5 times with 9 concentration gradients at an initial concentration of 135.14 nM, and diluted in Incubate in FACS buffer (Miltenyi Biotec, product number: 130-091-221) at 4°C for 60 minutes, centrifuge at 1000 rpm for 5 minutes, discard the supernatant, wash with pre-cooled PBS (pH 7.4) for 3 times, add 1:200 (v /v) Diluted goat anti-human IgG Fc ⁇ -PE secondary antibody (Jackson immunoresearch, catalog number: 109-116-170), 100 ⁇ L/well, incubated at 4°C for 30 min.
  • the endocytosis of the trastuzumab-eribulin conjugate prepared in Example 4 above in cells with different HER2 expression levels was analyzed, Including SKBR3 and BT474 cells with high expression level of HER2, JIMT-1 cells with high expression level of HER2 and MCF-7 cells with low expression level of HER2.
  • Sample preparation pre-dilute the trastuzumab-eribulin conjugate to a concentration of 20 ⁇ g/mL, mark it as S1, and then dilute it in a 3-fold concentration gradient to obtain 9 samples S1-S9; Add the sample solution to the cell culture plate, add 50 ⁇ L to each well, and incubate at 4°C for 30 min. After the incubation, the 96-well cell culture plate was taken out, placed at 4°C, centrifuged at 400g for 4min, and the supernatant was discarded.
  • Dilute pHrodo TM Green Maleimide green maleimide; Invitrogen, catalog number: P35370 labeled AffiniPure Goat Anti-Human IgG, Fc ⁇ fragment specific (goat anti-human IgG, Fc fragment specific antibody) according to 1:200 (v/v) ; Jackson Immuno; Cat. No.: 109-005-190), add 50 ⁇ L to each well and incubate at 4°C. After 30 minutes of washing, 50 ⁇ L of cell culture medium was added to each well, mixed well, placed at 37° C. for 2 hours, placed in a flow cytometer (Sartorius, iQUE), and the fluorescence reading value of the BL1 channel was measured.
  • DS-8201a was used as a control, and cells with different expression levels of HER2 were used to detect the killing activity, including NCI-N87, BT474, and SK-OV3 cells with high expression levels of HER2, JIMT-1 and Capan1 cells with high expression levels of HER2, and MCF-7 and KYSE410 cells with low expression levels of HER2.
  • the cells in the logarithmic growth phase were added to a 96-well plate, 100 ⁇ L/well, and the cell density was 1 ⁇ 10 4 cells/mL or 2 ⁇ 10 4 cells/mL. 37°C, 5% CO 2 for overnight culture.
  • Sample preparation The trastuzumab-eribulin conjugate was prepared into a test sample (starting at 5 ⁇ g/mL, 5-fold serial dilution, nine gradients) in basal medium containing 10% FBS.
  • Killing rate (%) (1-luminescence value of experimental group/luminescence value of control group) ⁇ 100%.
  • the processed data was analyzed with Graphpad Prism5, the results are shown in Figures 3A-3G, and the calculated EC50 is shown in Table 5 below.
  • the results showed that the larger the DAR value, the stronger the killing activity of the trastuzumab-eribulin conjugate on cells with high, medium and low expression levels of HER2, and the trastuzumab-eribulin conjugates of each DAR value
  • the killing activity of Bollinger conjugates is better than DS-8201a.
  • Table 5 The killing activity of trastuzumab-eribulin conjugates on cells with different expression levels of HER2
  • T-DM1 and DS-8201a were used as controls, and a blank control group was set up.
  • NCI-N87 was used as positive cells and MDA-MB-468 was used as negative cells.
  • the method based on FACS Tested. Take the NCI-N87 and MDA-MB-468 cells in the logarithmic growth phase, adjust the living cell density of the two kinds of cells to 2 ⁇ 105 cells/mL, add 1mL of the two kinds of cells to each well of the 6-well cell culture plate, Culture overnight in a 37°C, 5% CO 2 cell incubator.
  • the trastuzumab-eribulin conjugate prepared in Example 4 above was pre-diluted to 0.5 ⁇ g/mL (final concentration), and added to the cell plate in sequence. After incubation for 5 days, cells were taken from the 6-well cell culture plate, trypsinized and counted, and the cells in different loading wells were collected, and the cell density was adjusted to 1 ⁇ 10 6 cells/mL with Running buffer (Miltenyi Biotec, catalog number: 130-091-221) , 100 ⁇ L/well was added to a 96-well V-bottom plate.
  • Running buffer Miltenyi Biotec, catalog number: 130-091-221
  • the in vivo efficacy of the trastuzumab-eribulin conjugate prepared in Example 4 was evaluated by using the trastuzumab drug-resistant cell line JIMT-1 human breast cancer cell subcutaneous xenograft model in nude mice.
  • JIMT-1 cells were inoculated subcutaneously in the right axilla of SPF female nude mice (source: Changzhou Cavens Experimental Animal Co., Ltd.), 2 ⁇ 10 6 cells/mouse. When the average volume of the tumor reached 100-300 mm 3 , the animals were divided into 8 groups, 6 animals in each group.
  • the day of grouping was d0 day, and the tail vein was administered on d1 day after grouping.
  • the tumor volume was measured 2-3 times a week, and the mice were weighed at the same time, and the data was recorded; the general performance of the mice was observed and recorded daily. After the experiment, the tumors were stripped, weighed, and photographed.
  • Detection indicators include:
  • Tumor volume TV (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ); wherein, a is the long axis and b is the short axis.
  • Relative tumor volume RTV TV t /TV 0 ; wherein, TV 0 is the tumor volume on day d0, and TV t is the tumor volume at each measurement.
  • T/C (%) T RTV /C RTV ⁇ 100%; wherein, T RTV is the RTV of the treatment group, and C RTV is the RTV of the control group.
  • Tumor growth inhibition rate 1-T/C.
  • Tumor inhibition rate TGI(%) (1-TW/TW 0 ) ⁇ 100%; wherein, TW is the tumor weight of the treatment group, and TW 0 is the tumor weight of the control group.

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WO2024235135A1 (zh) * 2023-05-12 2024-11-21 四川科伦博泰生物医药股份有限公司 大环化合物及其制备方法和用途
WO2025092965A1 (zh) * 2023-11-03 2025-05-08 正大天晴药业集团股份有限公司 抗体药物偶联物的制备方法

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2024263367A1 (en) * 2023-04-27 2025-11-13 CSPC Megalith Biopharmaceutical Co., Ltd. Antibody-drug conjugate
JPWO2024248123A1 (enExample) 2023-06-02 2024-12-05
EP4725969A1 (en) * 2023-06-09 2026-04-15 Latticon (Suzhou) Biopharmaceuticals Co., Ltd. Anti-her2 complementary bispecific antibody-drug conjugate, preparation method therefor and use thereof
CN116444672B (zh) * 2023-06-13 2023-11-03 上海偌妥生物科技有限公司 人表皮生长因子3的抗体、其制备方法及其应用
CN119925630A (zh) * 2023-11-03 2025-05-06 正大天晴药业集团南京顺欣制药有限公司 抗体药物偶联物的制备方法
CN117257977A (zh) * 2023-11-07 2023-12-22 正大天晴药业集团南京顺欣制药有限公司 用于制备抗体药物偶联物的方法
WO2026114362A1 (zh) * 2024-11-29 2026-06-04 正大天晴药业集团股份有限公司 抗体-偶联物、其制备方法及应用

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108883198A (zh) * 2016-03-02 2018-11-23 卫材研究发展管理有限公司 基于艾日布林的抗体-药物偶联物和使用方法
WO2019200322A1 (en) * 2018-04-13 2019-10-17 Genentech, Inc. Stable anti-cd79b immunoconjugate formulations
CN110997010A (zh) * 2019-08-07 2020-04-10 烟台迈百瑞国际生物医药有限公司 一种抗体药物偶联物及其应用
CN111116745A (zh) * 2018-11-01 2020-05-08 上海新理念生物医药科技有限公司 抗CD79b抗体、其药物偶联物及其应用
WO2021132166A1 (ja) * 2019-12-23 2021-07-01 エーザイ・アール・アンド・ディー・マネジメント株式会社 エリブリンをベースとする抗体－薬物コンジュゲートの製造方法
WO2021148003A1 (zh) * 2020-01-22 2021-07-29 上海森辉医药有限公司 艾日布林衍生物的药物偶联物、其制备方法及其在医药上的应用
WO2022022508A1 (zh) * 2020-07-27 2022-02-03 上海拓界生物医药科技有限公司 抗cd79b抗体药物偶联物、其制备方法及其医药用途
WO2022104697A1 (en) * 2020-11-20 2022-05-27 Bliss Biopharmaceutical (Hangzhou) Co., Ltd. Modified egfr antibody with reduced affinity
WO2022105878A1 (en) * 2020-11-20 2022-05-27 Bliss Biopharmaceutical (Hangzhou) Co., Ltd. Modified egfr antibody with reduced affinity, drug conjugate, and use thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG10201901057UA (en) 2014-08-05 2019-03-28 Cb Therapeutics Inc Anti-pd-l1 antibodies
CN109422811A (zh) 2017-08-29 2019-03-05 信达生物制药(苏州)有限公司 抗cd47抗体及其用途
WO2020059772A1 (ja) * 2018-09-20 2020-03-26 第一三共株式会社 抗ｈｅｒ３抗体－薬物コンジュゲート投与によるｈｅｒ３変異がんの治療
WO2021090062A1 (en) * 2019-11-07 2021-05-14 Eisai R&D Management Co., Ltd. Anti-mesothelin eribulin antibody-drug conjugates and methods of use
EP4768463A2 (en) 2020-08-13 2026-07-01 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Antibody drug conjugate

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108883198A (zh) * 2016-03-02 2018-11-23 卫材研究发展管理有限公司 基于艾日布林的抗体-药物偶联物和使用方法
WO2019200322A1 (en) * 2018-04-13 2019-10-17 Genentech, Inc. Stable anti-cd79b immunoconjugate formulations
CN111116745A (zh) * 2018-11-01 2020-05-08 上海新理念生物医药科技有限公司 抗CD79b抗体、其药物偶联物及其应用
CN110997010A (zh) * 2019-08-07 2020-04-10 烟台迈百瑞国际生物医药有限公司 一种抗体药物偶联物及其应用
WO2021132166A1 (ja) * 2019-12-23 2021-07-01 エーザイ・アール・アンド・ディー・マネジメント株式会社 エリブリンをベースとする抗体－薬物コンジュゲートの製造方法
WO2021148003A1 (zh) * 2020-01-22 2021-07-29 上海森辉医药有限公司 艾日布林衍生物的药物偶联物、其制备方法及其在医药上的应用
WO2022022508A1 (zh) * 2020-07-27 2022-02-03 上海拓界生物医药科技有限公司 抗cd79b抗体药物偶联物、其制备方法及其医药用途
WO2022104697A1 (en) * 2020-11-20 2022-05-27 Bliss Biopharmaceutical (Hangzhou) Co., Ltd. Modified egfr antibody with reduced affinity
WO2022105878A1 (en) * 2020-11-20 2022-05-27 Bliss Biopharmaceutical (Hangzhou) Co., Ltd. Modified egfr antibody with reduced affinity, drug conjugate, and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAKADA, T. ET AL.: "Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 26, no. 6, 8 February 2016 (2016-02-08), XP029436554, DOI: 10.1016/j.bmcl.2016.02.020 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024235131A1 (zh) * 2023-05-12 2024-11-21 四川科伦博泰生物医药股份有限公司 大环类药物偶联物及其制备方法和用途
WO2024235135A1 (zh) * 2023-05-12 2024-11-21 四川科伦博泰生物医药股份有限公司 大环化合物及其制备方法和用途
WO2025092965A1 (zh) * 2023-11-03 2025-05-08 正大天晴药业集团股份有限公司 抗体药物偶联物的制备方法

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