WO2022228494A1 - 抗体偶联药物的制备方法及应用 - Google Patents

抗体偶联药物的制备方法及应用 Download PDF

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WO2022228494A1
WO2022228494A1 PCT/CN2022/089725 CN2022089725W WO2022228494A1 WO 2022228494 A1 WO2022228494 A1 WO 2022228494A1 CN 2022089725 W CN2022089725 W CN 2022089725W WO 2022228494 A1 WO2022228494 A1 WO 2022228494A1
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Prior art keywords
optionally substituted
compound
group
cancer
tautomer
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PCT/CN2022/089725
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English (en)
French (fr)
Chinese (zh)
Inventor
张惠
孟逊
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Shanghai Huilian Bio Pharm Co Ltd
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Shanghai Huilian Bio Pharm Co Ltd
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Priority to US18/557,448 priority Critical patent/US20240238440A1/en
Priority to CN202280030774.1A priority patent/CN117241834A/zh
Priority to CA3173511A priority patent/CA3173511A1/en
Priority to JP2023566659A priority patent/JP2024522388A/ja
Priority to EP22794964.1A priority patent/EP4331612A1/en
Publication of WO2022228494A1 publication Critical patent/WO2022228494A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic

Definitions

  • the present application relates to the field of biomedicine, in particular to a preparation method and application of an antibody conjugated drug.
  • ADC Antibody Drug Conjugate
  • Cytotoxics are essential for ADC drugs to play a role. Camptothecin drugs have great application prospects.
  • the marketed ADC drugs Trodelvy and Enhertu use camptothecin drugs SN38 and DX-8951f as warhead molecules respectively.
  • camptothecins finally prepared by camptothecins have greatly changed the properties of monoclonal antibodies, and the stability and half-life have been greatly attenuated.
  • the objective response rate (ORR) confirmed by Enhertu reached 79.7%
  • the objective response rate (ORR) confirmed by Enhertu was 37.0 for HER2-low expressing breast cancer %
  • the treatment efficiency was significantly lower than that of breast cancer with high or medium expression.
  • ADC drugs have new symptoms of toxic side effects, such as pneumonia and interstitial lung disease with the drug Enhertu.
  • WO2020233174A1 discloses a class of camptothecin compounds containing a valine-citrulline (Val-Cit)-PAB linker, however, this molecule cannot be coupled with an antibody to obtain a qualified ADC molecule (in qualified ADC products).
  • the aggregate content needs to be less than 5%). Therefore, there is an urgent need in the art to provide more suitable antibody-drug conjugates based on camptothecins (such as ixatecan, belotecan, etc.) to achieve efficient, simple and practical chemical preparation and conjugation, and Improve the pharmaceutical properties, metabolic properties, efficacy and safety of the existing antibody-conjugated drugs, such as improving the stability of ADC molecules, improving the therapeutic window, etc.
  • the present application provides an antibody conjugated drug, an intermediate thereof, a preparation method and an application thereof.
  • the antibody conjugated drug of the present application can realize the wide application of cytotoxic drugs in the field of ADC to treat tumor diseases.
  • the main technical effect of the present application is that the provided novel linker can combine highly hydrophobic anti-tumor drugs, such as topoisomerase inhibitors isanotecan, belotecan, etc., with antibodies through specific chemical methods. Conjugation, the obtained conjugate has high hydrophilicity and stability.
  • the antibody conjugate provided by the application is not easy to produce aggregates when the drug load is higher;
  • the toxin molecules released in the present application are the prototype molecules of topoisomerase inhibitor ixatecan and belotecan. Tests show that the drug molecules have better properties than the drug derivatives released by similar ADC drugs. Good biological activity, safety and other drug-related properties. Therefore, the present application can improve the half-life of the drug in vivo and the concentration of the drug in the tumor tissue, thereby referring to the anti-tumor activity of the drug and/or improving the overall drug treatment window.
  • the application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof
  • L 1a is selected from the group consisting of optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted alicyclic groups, optionally substituted alicyclic heterocyclyl groups, optionally substituted arylene groups, and optionally substituted heteroarylene groups;
  • L2 comprises optionally substituted polypeptide residues
  • L 3 comprises an optionally substituted spacer group
  • L 2 and/or L 3 comprise optionally substituted polysarcosine residues
  • T contains the drug unit
  • Ab is a ligand capable of binding HER2, and m is a number from 1 to 8.
  • the application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof
  • a pharmaceutically acceptable salt, prodrug or solvate
  • the compound comprises a structure selected from the group consisting of:
  • Ab is a ligand capable of binding HER2, and m is a number from 1 to 8.
  • the application provides a pharmaceutical composition, which contains the compound described in any one of the application, or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and optionally a pharmaceutically acceptable carrier.
  • the present application provides a compound containing any one of the present application, or its tautomer, meso, racemate, enantiomer, diastereomer, Use of the mixture form thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and/or the pharmaceutical composition described in this application in the preparation of a medicament for treating and/or preventing tumors.
  • the present application provides an antibody-drug conjugate, which is formed by coupling the compound of the present application with an antibody.
  • the conjugates of the present application are covalently attached to one or more drug components.
  • the antibody and drug of the present application are coupled covalently (eg, by covalent attachment to a linker, respectively).
  • the present application provides a method for preparing an antibody-drug conjugate, wherein a pair of cysteine residues is generated by reduction of the disulfide chain in the hinge region of the antibody or antibody fragment, and the cysteine
  • the sulfhydryl group in the acid residue undergoes a substitution reaction with the connecting group of the compound in the present application, such as maleimide group, and then the compound of the present application is connected to the cysteine sulfhydryl group of the antibody or antibody fragment to obtain an antibody -Drug conjugate
  • the drug-antibody conjugation rate DAR (for example, m in this application) is controlled according to the reaction conditions, for example, it is usually between 2 and 8.
  • m represents the molar ratio of cytotoxic drug molecules to Ab (also known as DAR, that is, drug-antibody coupling ratio), and m can be an integer or a decimal number, which can be understood as: a single monoclonal antibody molecule and cell
  • the average molar ratio of drug molecules to monoclonal antibody molecules in the antibody-drug conjugate obtained after toxic drug conjugation can generally be determined by hydrophobic chromatography (Hydrophobic-Interaction Chromatography, HIC), reversed-phase high-performance liquid chromatography (Reverse high-performance liquid chromatography) phase HPLC, RP-HPLC), polyacrylamide-SDS gel electrophoresis (SDS PAGE, electrophoresis), liquid chromatograph-mass spectrometer (LC-MS), ultraviolet/visible spectroscopy (UV/Vis), etc. measured.
  • the application provides a method for preparing the compound of the application, comprising the steps of:
  • an amino acid active ester with an amino protecting group N1 with an amino acid to obtain an intermediate M1; in the presence of a condensing agent such as EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline)
  • the intermediate M1 is contacted with substituted/unsubstituted p-aminobenzyl alcohol to obtain the intermediate M2; the N1 of the intermediate M2 is removed to obtain the intermediate M3; contacting a compound of an imide group to obtain an intermediate M4; contacting the intermediate M4 with bis(4-nitrophenyl) carbonate to obtain an intermediate M5; contacting the intermediate M5 with a drug unit .
  • the N1 comprises fluorenylmethoxycarbonyl.
  • the intermediate comprising the amino protecting group N2 is contacted with trifluoroacetic acid, followed by contact with acetyl polysarcosine contacts.
  • the N2 comprises tert-butoxycarbonyl.
  • the application provides a method of preparing a compound of the application comprising the steps of contacting the ligand with the compound of the application under conditions suitable for forming a bond between the ligand and the compound.
  • the ligand is contacted with the compound of the present application in a mixture of buffer and organic solvent.
  • the ligand is contacted with a compound of the present application at about 0 to about 37°C.
  • the following step is included before contacting the ligand with the compound of the present application: reacting the ligand with a reducing agent in a buffer to obtain the reduced ligand.
  • the step of removing the reducing agent is included.
  • the removing the reducing agent comprises subjecting the reaction product to a desalting column and/or ultrafiltration.
  • the reducing agent is selected from the group consisting of tris(2-carboxyethyl)phosphine hydrochloride (TCEP), beta-mercaptoethanol, beta-mercaptoethylamine hydrochloride, and dithiothreose Alcohol (DTT).
  • TCEP tris(2-carboxyethyl)phosphine hydrochloride
  • beta-mercaptoethanol beta-mercaptoethylamine hydrochloride
  • DTT dithiothreose Alcohol
  • the buffer is selected from the group consisting of potassium dihydrogen phosphate-sodium hydroxide (KH 2 PO 4 -NaOH)/sodium chloride (NaCl)/diethyltriaminepentaacetic acid (DTPA) Buffer, disodium hydrogen phosphate-citric acid/sodium chloride (NaCl)/diethyltriaminepentaacetic acid (DTPA), boric acid-borax/sodium chloride (NaCl)/diethyltriaminepentaacetic acid (DTPA) , histidine-sodium hydroxide/sodium chloride (NaCl)/diethyltriaminepentaacetic acid (DTPA) and PBS/diethyltriaminepentaacetic acid (DTPA).
  • KH 2 PO 4 -NaOH potassium dihydrogen phosphate-sodium hydroxide
  • DTPA diethyltriaminepentaacetic acid
  • Buffer dis
  • the organic solvent is selected from the group consisting of acetonitrile (ACN), dimethylformamide (DMF), dimethylacetamide (DMA) and dimethylsulfoxide (DMSO).
  • ACN acetonitrile
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • DMSO dimethylsulfoxide
  • the volume ratio of the organic solvent in the buffer solution and the organic solvent mixture does not exceed 30%.
  • This application finds that the antibody-drug conjugates in this application, compared with traditional antibody-drug conjugates, due to the large hydrophobicity of ixatecan and belotecan drugs, the introduction of polysarcosine can The hydrophilicity of the conjugate is greatly increased, thereby making the obtained antibody-drug conjugate more stable and less prone to polymerization as a whole.
  • the present application provides carbamate, which can undergo rapid 1,6-elimination after enzymatic cleavage to release the drug, and has better stability and biological activity in vitro and in vivo. Based on the above findings, the present application has been completed.
  • Figure 1 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 1 of the present application
  • Figure 2 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 2 of the present application
  • Figure 3 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 2 of the present application
  • Figure 4 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 3 of the present application
  • Figure 5 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 4 of the present application
  • Figure 6 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 4 of the present application
  • Figure 7 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 5 of the present application
  • Figure 8 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 5 of the present application
  • Figure 9 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 6 of the present application.
  • Figure 10 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 6 of the present application
  • Figure 11 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 7 of the present application
  • Figure 12 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 7 of the present application
  • Figure 13 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 8 of the present application
  • Figure 14 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 8 of the present application
  • Figure 15 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 9 of the present application
  • Figure 16 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 9 of the present application
  • Figure 17 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 10 of the present application
  • Figure 18 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 10 of the present application
  • Figure 19 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 11 of the present application
  • Figure 20 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 11 of the present application
  • Figure 21 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 12 of the present application
  • Figure 22 shows the hydrophobic interaction high performance liquid chromatogram (HIC-HPLC) of the antibody conjugate 12 of the present application
  • Figure 23 shows the concentration change diagram of the accelerated stability experiment of some antibody conjugates of the present application.
  • Figure 24 shows a graph showing the increase of aggregates in the accelerated stability experiment of some antibody conjugates of the present application.
  • Figure 25 shows the results of the in vitro NCI-N87 cell (human gastric cancer cell) proliferation inhibitory activity test results of some antibody conjugates of the present application;
  • Figure 26 shows the results of the in vitro OV-CAR3 cell (human ovarian adenocarcinoma cell) proliferation inhibitory activity test results of some of the antibody conjugates of the present application;
  • Figure 27 shows the results of the in vitro NCI-N87 cell (human gastric cancer cell) proliferation inhibitory activity test results of some antibody conjugates of the present application;
  • Figure 28 shows the results of the in vitro SK-BR-3 cell (human breast cancer cell) proliferation inhibitory activity test results of some of the antibody conjugates of the present application;
  • Figure 29 shows the efficacy results of some anti-HER2 antibody conjugates of the present application in COLO205 human colon cancer
  • Figure 30 shows the in vivo efficacy results of some anti-HER2 antibody conjugates of the present application in HCC1954 human breast cancer
  • Figure 31 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 13 of the present application
  • Figure 32 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 14 of the present application
  • Figure 33 shows the size exclusion chromatography (SEC-HPLC) chromatogram of the antibody conjugate 15 of the present application
  • Figure 34 shows the mass spectrum of Trastuzumab after reduction
  • Figure 35 shows the mass spectrogram corresponding to the light chain and the heavy chain after reduction of the antibody conjugate 5 of the present application
  • Figure 36 shows the mass spectrum corresponding to the light chain and the heavy chain after reduction of the antibody conjugate 6 of the present application.
  • the term "ligand” generally refers to a macromolecular compound capable of recognizing and binding to an antigen or receptor associated with a target cell.
  • the role of the ligand can be to present the drug to the target cell population that binds to the ligand, including but not limited to protein hormones, lectins, growth factors, antibodies, or others that can bind to cells, receptors and/or antigens molecule.
  • the ligand can be represented as Ab, and the ligand antigen forms a bond with the connecting unit through the heteroatom on the ligand, which can be an antibody or an antigen-binding fragment thereof, and the antibody can be selected from chimeric antibodies, human-derived antibody, fully human, or murine; the antibody may be a monoclonal antibody.
  • the antibody may be an antibody or antigen-binding fragment thereof targeting a target selected from the group consisting of: HER2.
  • alkyl generally refers to a residue derived from an alkane by removal of a hydrogen atom. Alkyl groups can be substituted or unsubstituted, substituted or unsubstituted.
  • alkyl generally refers to a saturated straight-chain or branched aliphatic hydrocarbon group having a residue derived by removing a hydrogen atom from the same carbon atom or two different carbon atoms of the parent alkane, which may be a group containing 1 to A straight or branched chain group of 20 carbon atoms, eg 1 to 12 carbon atoms, eg, an alkane alkyl group containing 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, propyl, butyl, and the like.
  • Alkyl groups may be substituted or unsubstituted, substituted or non-substituted, for example when substituted, substituents may be substituted at any available point of attachment, and the substituents may be independently optionally selected from alkyl groups , alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy , heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and one or more substituents in oxo, such as hydrogen, protium, deuterium, tritium, halogen, -NO 2 , - CN, -OH,
  • alkylene generally refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 hydrogen atoms derived from the same or two different carbon atoms of the parent alkane by removing two hydrogen atoms.
  • residue which may be a straight or branched chain group containing 1 to 20 carbon atoms, for example, the term “methylene” may refer to a residue derived from a group of 1 carbon atom by removing two hydrogen atoms base.
  • a methylene group may be substituted or unsubstituted, substituted or non-substituted; eg, an alkylene group containing from 1 to 12 carbon atoms, eg, an alkylene group containing from 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene ( -CH2CH2CH2- ), 1,4 - Butylene ( -CH2CH2CH2CH2- ) and 1,5 - Butylene ( -CH2CH2CH2CH2CH2- ) Wait.
  • Alkylene may be substituted or unsubstituted, substituted or non-substituted, for example, when substituted, substituents may be substituted at any available point of attachment, which may be independently optionally selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy substituted by one or more substituents in the group, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo, such as hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH
  • alkenyl generally refers to a straight or branched chain hydrocarbon group containing one or more double bonds.
  • alkenyl groups include allyl, homoallyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, and the like.
  • C2-6 alkenyl groups having more than one double bond include butadienyl, pentadienyl, hexadienyl, and hexatrienyl and branched forms thereof.
  • the position of the unsaturated bond (double bond) can be anywhere in the carbon chain.
  • Alkenyl groups can be substituted or unsubstituted.
  • alkenylene generally refers to residues having two hydrogen atoms removed from the carbon atoms of an olefin.
  • alkenylene groups can be substituted or unsubstituted.
  • alkynyl generally refers to unsaturated straight or branched chain alkynyl groups such as ethynyl, 1-propynyl, propargyl, butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
  • alkynylene generally refers to residues having two hydrogen atoms removed from the carbon atoms of an alkyne.
  • it can be ethynylene, propynylene, propargylene, butynylene and the like.
  • Alkynylene groups can be substituted or unsubstituted.
  • aryl generally refers to residues having an aromatic ring derived by removing one hydrogen atom.
  • aromatic ring may refer to a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring (ie, rings that share adjacent pairs of carbon atoms) having a conjugated pi-electron system, and may be 6 to 10 membered, such as benzene and Naphthalene.
  • the aromatic ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring.
  • Aryl may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , and heterocycloalkylthio.
  • Aryl groups can be substituted or unsubstituted.
  • arylene generally refers to a residue having two hydrogen atoms removed from a carbon atom of an aromatic ring.
  • phenylene and naphthylene may be mentioned.
  • Arylene groups can be substituted or unsubstituted.
  • heteroaryl generally refers to a residue having a hydrogen atom removed from a carbon atom of a heteroaromatic ring.
  • heteromatic ring refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur and nitrogen.
  • Heteroaryl can be 5 to 10 membered, 5 membered or 6 membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazole Base et al.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy group, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, and heterocycloalkylthio. Heteroaryl groups can be substituted or unsubstituted.
  • heteroarylene generally refers to a residue having two hydrogen atoms removed from a carbon atom of a heteroaromatic ring.
  • it may be a furanylene group, a thienylene group, a pyridylene group, a pyrrolidine group, a pyrimidinylene group, a pyrazinylene group, an imidazolylylene group, a tetrazolium group, and the like.
  • a heteroarylene group can be substituted or unsubstituted.
  • alicyclic group generally refers to a residue having a hydrogen atom removed from the same carbon atom or a plurality of different carbon atoms of an alicyclic ring.
  • cycloalkane generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the carbocyclic ring containing 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, may Contains 3 to 8 carbon atoms.
  • Non-limiting examples of alicyclic groups include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclopentyl Heptatrienyl, cyclooctyl, etc.; polycyclic carbocycles may include spiro, fused, and bridged carbocycles. Alicyclic groups can be substituted or unsubstituted.
  • the term "carbocyclyl" generally refers to a residue derived from a carbon atom having a carbocyclic ring by removing one hydrogen atom.
  • carbocycle generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the carbocycle contains 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, may Contains 3 to 8 carbon atoms.
  • Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane etc.; polycyclic carbocycles may include spiro, fused and bridged carbocycles. Carbocyclyl groups can be substituted or unsubstituted. Alicyclic and carbocyclic may be used interchangeably in some cases.
  • partially unsaturated generally refers to a cyclic structure containing at least one double or triple bond between the ring molecules.
  • the term “partially unsaturated” encompasses cyclic structures with multiple unsaturations, but is not intended to include aromatic or heteroaromatic rings as defined herein.
  • the term “unsaturated” means that the moiety has one or more degrees of unsaturation.
  • alicyclic group generally refers to a residue having two hydrogen atoms removed from a carbon atom of an alicyclic ring.
  • it can be cyclopropene, cyclobutane, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cyclohexadienylene, cycloheptane cycloheptatrienyl, cyclooctylene, etc.
  • polycyclic carbocycles may include spiro, fused, and bridged carbocycles.
  • Alicyclic groups can be substituted or unsubstituted.
  • alicyclic heterocyclyl generally refers to stable non-aromatic 3- to 7-membered monocyclic carbocyclic structures, fused 7- to 10-membered bicyclic heterocyclic structures or bridged 6-membered -10-membered bicyclic heterocyclic structures, these cyclic structures can be either saturated or partially saturated, in addition to carbon atoms, these cyclic structures also contain one or more heteroatoms, wherein the heteroatoms can be selected from The following groups: oxygen, sulfur and nitrogen. For example, it contains 1-4 heteroatoms as defined above.
  • nitrogen when used to refer to an atom on an alicyclic ring structure may include nitrogen that has undergone a substitution reaction.
  • a heteroalicyclic group may include "heterocycloalkyl", which may refer to a stable non-aromatic 3- to 7-membered monocycloalkane structure, a fused 7- to 10-membered bicyclic heterocyclic structure or Bridged 6- to 10-membered bicyclic heterocyclic structures containing, in addition to carbon atoms, one or more heteroatoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur and nitrogen. For example, it contains 1-4 heteroatoms as defined above.
  • Heterocycloalkyl can be substituted or unsubstituted.
  • Alicyclic groups may be substituted or unsubstituted.
  • alicyclic heterocyclyl generally refers to a residue having two hydrogen atoms removed from a carbon atom of an alicyclic ring. Aliphatic heterocyclyl groups can be substituted or unsubstituted.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the specification may include both instances where the heterocyclic group is substituted with an alkyl group and where the heterocyclic group is not substituted with an alkyl group. situation.
  • substituted generally means that one or more hydrogen atoms in a group, eg up to 5, eg 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents.
  • Substituents are only in their possible chemical positions, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • alkyl alkenyl
  • cycloalkyl alkyl
  • C 3 alkyl C 3 -C 7 cycloalkoxy, C 1 -C 4 alkylcarbonylamino, etc.
  • C followed by a subscript number indicates the number of atoms present in the group number of carbon atoms.
  • C3 alkyl refers to an alkyl group having three carbon atoms (eg, n-propyl, isopropyl); in C1-10 , the members of the group can have any number falling within the range of 1-10 of carbon atoms.
  • One or more hydrogen atoms in the group are substituted by the corresponding number of substituents.
  • Substituents are only in their possible chemical positions, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the term "compound” generally refers to a substance having two or more different elements.
  • the compound of the present application may be an organic compound.
  • the compound of the present application may be a compound with a molecular weight of 500 or less, a compound with a molecular weight of 1,000 or less, or a compound with a molecular weight of 1,000 or more, or a compound of 10,000 or more and 100,000 or more. compound.
  • a compound may also refer to a compound connected by chemical bonds, for example, it may be a compound in which one or more molecules with a molecular weight below 1000 are connected with a biological macromolecule by chemical bonds, and the biological macromolecule may be a high polysaccharide, a protein , nucleic acids, peptides, etc.
  • the compounds of the present application may include compounds in which proteins are linked to one or more molecules with a molecular weight of less than 1000; A compound with less than 100,000 molecules linked together.
  • the term "about” generally refers to a range of 0.5%-10% above or below the specified value, such as 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%.
  • the compounds of the present application include tautomers, mesomers, racemates, enantiomers, and/or diastereomers of the compounds.
  • the term “diastereomer” generally refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers can have different physical properties, eg, melting points, boiling points, spectral properties, and reactivities.
  • the terms “tautomer” or “tautomeric form” are used interchangeably and generally refer to structural isomers of different energies that can be interconverted through a low energy barrier.
  • protontautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include interconversions by recombination of some of the bonding electrons.
  • mesome generally refers to atoms that contain asymmetry in the molecule, but have a symmetry factor such that the total optical rotation in the molecule is zero.
  • racemate or “racemic mixture” refers to a composition consisting of two enantiomeric species in equimolar amounts.
  • certain atoms of the compounds of the present application may occur in more than one isotopic form.
  • hydrogen may exist as protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H), and carbon may exist naturally in three different isotopes ( 12 C, 13 C, and 14 C).
  • isotopes that can be incorporated into the compounds of the present application also include, but are not limited to, 15 N, 18 O, 17 O, 18 F, 32 P, 33 P, 129 I, 131 I, 123 I, 124 I, 125 I, or the like of isotopes.
  • the compounds of the present application may be enriched in one or more of these isotopes relative to their natural abundance.
  • Such isotopically enriched compounds can be used for a variety of purposes, as known to those skilled in the art.
  • substitution with heavy isotopes such as deuterium ( 2 H) may offer certain therapeutic advantages, which may be due to greater metabolic stability.
  • the natural abundance of deuterium ( 2 H) is about 0.015%. Therefore, for every 6,500 hydrogen atoms in nature, there is one deuterium atom. Accordingly, the deuterium-containing compounds of the present application have a deuterium abundance greater than 0.015% at one or more positions (as the case may be).
  • structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, except that the hydrogen atom is replaced by deuterium or tritium, or the carbon atom is replaced by carbon 13 or carbon 14, the compounds whose structure is consistent with the present application are all within the scope of the present application.
  • the term "pharmaceutical composition” generally refers to a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other Such as physiological/pharmaceutically acceptable carriers and excipients.
  • the pharmaceutical composition can facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the preparation of conventional pharmaceutical compositions can be found in the techniques commonly used in the art.
  • the term "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” generally refers to a salt of a compound or ligand-drug conjugate of the present application, or a salt of a compound described in the present application, Such salts can be safe and/or effective when used in mammals, and can have due biological activity, and the antibody-antibody drug conjugate compounds of the present application can form salts with acids, and the pharmaceutically acceptable salts are salts.
  • Non-limiting examples include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, pear Acid, hydrogen phosphate, dihydrogen phosphate, salicylate, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, mesylate, ethyl acetate Sulfonate, benzenesulfonate, or p-toluenesulfonate.
  • conjugate generally refers to a compound of the present application prepared by one or more chemical reactions, or by one such as a bridge, spacer, or linking moiety, etc. or multiple connecting structures are connected to each other.
  • a pharmaceutically acceptable carrier generally refers to a carrier for administration of therapeutic agents, such as antibodies or polypeptides, genes and other therapeutic agents.
  • the term refers to any pharmaceutical carrier that itself does not induce the production of antibodies detrimental to the individual receiving the composition and can be administered without undue toxicity.
  • a pharmaceutically acceptable carrier can be distinguished from a nucleic acid vector used in genetic engineering to contain a gene of interest. Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polyamino acids, amino acid copolymers, lipid aggregates, and inactivated viral particles. Those skilled in the art are familiar with these vectors.
  • Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol and ethanol. Auxiliary substances such as wetting or emulsifying agents, pH buffering substances and the like can also be present in these carriers.
  • Trop2 generally refer to a single-pass transmembrane type I cell membrane protein.
  • the term “Trop2” may also encompass homologues, variants and isoforms of Trop 2, including splice isoforms.
  • the term “Trop” also includes proteins having one or more sequences of Trop 2 homologues, variants and isoforms, as well as fragments of such sequences, so long as the variant protein (including isoforms).
  • Trop2 can be human Trop2.
  • Uniprot Accession No. P09758 provides a description of Trop2 and sequences.
  • HER2 generally refers to human epidermal growth factor receptor 2 (HER2).
  • HER2 refers to any native HER2 from any human source.
  • the term also encompasses "full-length” and unprocessed HER2 as well as any form of HER2 derived from processing in a cell (eg, the mature protein).
  • the term also encompasses naturally occurring variants and isoforms of HER2, such as splice variants or allelic variants.
  • Uniprot Accession No. P04626 provides a description of HER2 and sequences.
  • Nectin-4" generally refers to adhesion molecule 4.
  • Nectin-4" refers to any native Nectin-4 from any human source.
  • the term also encompasses "full-length” and unprocessed Nectin-4 as well as any form of Nectin-4 derived from processing in a cell (eg, mature protein).
  • the term also encompasses naturally occurring variants and isoforms of Nectin-4, such as splice variants or allelic variants.
  • Uniprot Accession No. Q96NY8 provides a description of Nectin-4 and sequences.
  • chimeric antibody generally refers to an antibody in which the variable region of a murine antibody is fused with the constant region of a human antibody, which can alleviate the immune response induced by the murine antibody.
  • a hybridoma that secretes a mouse-specific monoclonal antibody can be established, and then the variable region gene can be cloned from the mouse hybridoma cell, and the constant region gene of the human antibody can be cloned according to the needs.
  • the human constant region gene is connected into a chimeric gene and inserted into an expression vector, and the chimeric antibody molecule can be expressed in a eukaryotic system or a prokaryotic system.
  • humanized antibody also known as CDR-grafted antibody
  • CDR-grafted antibody generally refers to the grafting of murine CDR sequences into the framework of human antibody variable regions, i.e. different Types of human germline antibody framework sequences produced in antibodies.
  • the heterologous reaction induced by chimeric antibodies can be overcome because they carry a large amount of murine protein components.
  • framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • the germline DNA sequences of the human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database.
  • monoclonal antibodies has gone through four stages, namely: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies.
  • the antibodies or ligands described herein may be fully human monoclonal antibodies.
  • Related technologies for the preparation of fully human antibodies include: human hybridoma technology, EBV transformation of B lymphocytes, phage display technology, transgenic mouse antibody preparation technology, and single B cell antibody preparation technology.
  • CDR generally refers to one of the six hypervariable regions within the variable domain of an antibody that primarily contribute to antigen binding.
  • One of the most commonly used definitions of the 6 CDRs is provided by Kabat E.A. et al., Chothia et al. and MacCallum et al.
  • the Kabat definition of CDRs can be applied to CDR1, CDR2 and CDR3 (CDR L1, CDR L2, CDR L3 or L1, L2, L3) of the light chain variable domains, as well as the heavy chain variable domains of CDR1, CDR2 and CDR3 (CDR H1, CDR H2, CDR H3 or H1, H2, H3).
  • group capable of coupling with a thiol group generally means that the compound A has a thiol group, the compound B has a group capable of coupling with a thiol group, and the compound B has a group capable of coupling with a thiol group through a group capable of coupling with a thiol group.
  • the group reacts with the sulfhydryl group of compound A, which can realize the connection between compound A and compound B.
  • linker usually refers to a chemical structural fragment or bond with one end connected to one group and the other end connected to another group. It can also be connected to other linkers and then to drugs and/or ligands. connected.
  • the direct or indirect linking of the ligand may refer to that the group is directly linked to the ligand through a covalent bond, or may be linked to the ligand through a linker.
  • the linker can be the structure shown by Q 1 described in this application.
  • chemical fragments comprising acid-labile linker structures (eg, hydrazones), protease-sensitive (eg, peptidase-sensitive) linker structures, photolabile linker structures, dimethyl linker structures, or disulfide-containing linker structures may be used or bond as a linker.
  • acid-labile linker structures eg, hydrazones
  • protease-sensitive linker structures eg, peptidase-sensitive linker structures
  • photolabile linker structures eg, dimethyl linker structures
  • disulfide-containing linker structures may be used or bond as a linker.
  • linking group generally refers to a group that has the ability to attach to another group.
  • the linking of the compound with another group can be achieved through a coupling reaction between the linking group and another group.
  • a maleimide group can serve as the linking group.
  • drug unit generally refers to a chemical moiety that directly or indirectly conjugates an antibody or antigen-binding fragment to form an immunoconjugate.
  • a drug unit includes, but is not limited to, compounds described herein with anti-tumor activity.
  • the drug unit includes a topoisomerase inhibitor.
  • the term "compound with antitumor activity” generally refers to a compound having the ability to reduce the proliferation rate, viability or metastatic activity of tumor cells.
  • anti-tumor activity may be manifested by a reduction in the growth rate of abnormal cells or by stabilization or shrinkage of tumor size during treatment, or by longer survival due to treatment compared to a control in the absence of treatment.
  • Antitumor activity can be assessed using recognized in vitro or in vivo tumor models, such as xenograft models.
  • the biologically active molecule in the conjugate is a compound with specific anti-tumor activity, for example, a radioisotope, such as At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , or radioisotopes of Lu; metal complexes, such as metal platinum complexes (such as oxaliplatin) or metal gold complexes; glycopeptide antibiotics, such as bleomycin or pingyangmycin; topoisomerase inhibitors; drugs that interfere with DNA synthesis, such as methotrexate, 5-fluorouracil, cytarabine, gemcitabine, mercaptopurine, pentostatin, fludarabine, cladrix Drugs acting on structural proteins, such as tubulin inhibitors (such as vinca alkaloids, vincristine, vinblastine, paclitaxel
  • topoisomerase inhibitor generally refers to compounds or derivatives thereof that include topoisomerase I inhibitors and topoisomerase II inhibitors.
  • topoisomerase I inhibitors include, but are not limited to, camptothecin and its analogs; topoisomerase II inhibitors (such as actinomycin D, doxorubicin, doxorubicin, docarmycin, daunorubicin, mitoxantrone, podophyllotoxin or etoposide, etc.).
  • a topoisomerase may refer to an enzyme that corrects the number of concatenated chains of DNA by cleaving phosphodiester bonds in one or both strands of DNA, followed by rewinding and sealing.
  • camptothecin analog generally refers to compounds that are structurally similar to or derived from camptothecin.
  • structure of camptothecin can be described in CAS Accession No. 7689-03-4.
  • a camptothecin analog may refer to ixatecan (Exatecan, CAS Accession No. 171335-80-1) or Belotecan (Belotecan, CAS Accession No. 256411-32-2).
  • non-camptothecin-type topoisomerase I inhibitors generally refers to indolecarbazoles, indenoisoquinolinones, triphenanthridines, and dibenzonaphthyridinones with topoisomerases I heterocyclic molecules with inhibitory activity mainly refer to Genz-644282 (CAS accession number 529488-28-6).
  • the term "expression-related" disease of a target generally means that the occurrence and/or progression of the disease is associated with the expression level of the target.
  • the expression level of a target in cells from a disease area such as within a particular tissue or organ of a patient, is increased, ie, highly expressed, relative to the expression level of normal cells from the tissue or organ.
  • the expression level of a certain target in cells from a disease area such as a particular tissue or organ of a patient, is reduced, ie, underexpressed, relative to the expression level of normal cells from the tissue or organ.
  • cells from a disease area such as within a particular tissue or organ of a patient, express a certain target, ie, are positive.
  • cells from a disease area such as a particular tissue or organ of a patient, do not express a certain target, ie, are negative.
  • target expression can be characterized by standard assays known in the art.
  • the term "effective amount” generally refers to the amount of a therapeutic agent that treats, ameliorates, or prevents a target disease or condition, or an amount that exhibits a measurable therapeutic or prophylactic effect.
  • the precise effective amount for a subject depends on the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is useless to prespecify the exact effective amount. However, for a given situation, routine experimentation can be used to determine the effective amount, as is the judgment of the clinician.
  • each chiral carbon atom can optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • the term "compound of the present application” refers to a compound of the present application.
  • the term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of the present application.
  • the tradename is intended to include the tradename product formulation, its corresponding generic drug, and the active pharmaceutical ingredient of the tradename product.
  • antibody is used in its broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, dimers, multimers, multispecific antibodies (eg, bispecific antibodies), and antibody fragments, so long as they are exhibit the desired biological activity.
  • Antibodies can be murine, human, humanized, chimeric, or derived from other species.
  • Antibodies are proteins produced by the immune system capable of recognizing and binding specific antigens.
  • Target antigens generally have a large number of binding sites, also referred to as epitopes, recognized by the CDRs of various antibodies. Each antibody that specifically binds to a different epitope has a different structure. Thus, an antigen can have more than one corresponding antibody.
  • Antibodies include full-length immunoglobulin molecules or immunologically active portions of full-length immunoglobulin molecules, i.e., molecules that contain an antigen or portion thereof that specifically binds a target of interest, including, but not limited to, cancer cells or Cells with autoimmune antibodies associated with autoimmune diseases.
  • the immunoglobulins described herein can be of any class (eg, IgG, IgE, IgM, IgD, and IgA), class (eg, IgGl, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass of immunoglobulin molecules. Immunoglobulins can be derived from any species.
  • the immunoglobulin is derived from human, murine or rabbit.
  • An "antibody fragment” may comprise a portion of a full-length antibody, typically its antigen-binding or variable region.
  • antibody fragments include: Fab, Fab', F(ab')2 and Fv fragments; diabodies; linear antibodies; minibodies; Fab expression library prepared fragments; anti-idiotypic (anti-Id) antibodies ; CDRs (complementarity determining regions); and any of the above epitope-binding fragments that immunospecifically bind to cancer cell antigens, viral antigens, or microbial antigens; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • the antibody constituting the antibody-drug conjugate in the present application can maintain the antigen-binding ability of its original wild state.
  • the antibodies of the present application can, for example, specifically bind to an antigen.
  • Antigens involved include, for example, tumor-associated antigens (TAAs), cell surface receptor proteins and other cell surface molecules, regulators of cell survival, regulators of cell proliferation, molecules associated with tissue growth and differentiation (as known or predicted) functional), lymphokines, cytokines, molecules involved in the regulation of the cell cycle, molecules involved in angiogenesis, and molecules involved in angiogenesis (eg known antibodies can bind to antigens from one or a subset of the above categories) , while other subsets contain other molecules/antigens with specific properties (compared to the target antigen).
  • TAAs tumor-associated antigens
  • cell surface receptor proteins and other cell surface molecules regulators of cell survival, regulators of cell proliferation, molecules associated with tissue growth and differentiation (as known or predicted) functional
  • lymphokines cytokines
  • Antibodies used in antibody drug conjugates include, but are not limited to, targeting cell surface receptors and tumor-associated Antibodies to antigens.
  • tumor-associated antigens are well known in the industry, and can be prepared by well-known antibody preparation methods and information in the industry.
  • targets can be specifically expressed on the surface of one or more cancer cells, while in a or a variety of non-cancer cells that are expressed little or not on the surface.
  • tumor-associated polypeptides can be more overexpressed on the surface of cancer cells relative to the surface of non-cancer cells.
  • enrozumab generally refers to an antibody that targets Nectin-4.
  • Enfortumab can be described in WO2017042210A1.
  • ennozumab may refer to any antibody or antigen-binding fragment comprising the heavy chain variable region CDR1-3 and light chain variable region CDR1-3 of enrozumab.
  • ennozumab may refer to any antibody or antigen-binding fragment comprising the heavy chain variable region and light chain variable region of enrozumab.
  • Pertuzumab generally refers to an antibody that targets HER2.
  • Pertuzumab can be described in WO2014172371A2.
  • Pertuzumab may refer to any antibody or antigen-binding fragment comprising the heavy chain variable region CDR1-3 and the light chain variable region CDR1-3 of Pertuzumab.
  • Pertuzumab may refer to any antibody or antigen-binding fragment comprising the variable region of the heavy chain and the variable region of the light chain of Pertuzumab.
  • trastuzumab generally refers to an antibody that targets HER2.
  • Trastuzumab can be described in US20060275305A1.
  • trastuzumab may refer to any antibody or antigen-binding fragment comprising the heavy chain variable region CDR1-3 and light chain variable region CDR1-3 of trastuzumab.
  • trastuzumab may refer to any antibody or antigen-binding fragment comprising the heavy and light chain variable regions of trastuzumab.
  • certolizumab generally refers to an antibody that targets TROP2.
  • Sacituzumab hRS7
  • certolizumab may refer to any antibody or antigen-binding fragment comprising the heavy chain variable region CDR1-3 and light chain variable region CDR1-3 of certolizumab.
  • certolizumab may refer to any antibody or antigen-binding fragment comprising the heavy and light chain variable regions of certolizumab.
  • Patritumab generally refers to an antibody that targets HER3.
  • Patritumab can be described in CN102174105B.
  • Patritumab monoclonal antibody may refer to any antibody or antigen-binding fragment comprising the heavy chain variable region CDR1-3 and light chain variable region CDR1-3 of Patritumab.
  • Patritumab may refer to any antibody or antigen-binding fragment comprising the variable region of the heavy chain and the variable region of the light chain of Patritumab.
  • the term "antibody H01L02" generally refers to an antibody targeting CDH6.
  • the monoclonal antibody H01L02 can be described in WO2018212136, US20200171163A1.
  • the H01L02 mAb can be the mAb used by the drug DS6000.
  • the H01L02 monoclonal antibody may refer to any antibody or antigen-binding fragment comprising the heavy chain variable region CDR1-3 and the light chain variable region CDR1-3 of the H01L02 monoclonal antibody.
  • the H01L02 mAb can refer to any antibody or antigen-binding fragment comprising the heavy chain variable region and the light chain variable region of the H01L02 mAb.
  • polypeptide residue generally refers to a residue comprising one or more amino acid residues linked together.
  • one or more amino acids in a polypeptide residue may be optionally substituted.
  • the polypeptide residues of the present application may be selected from the group consisting of phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val) -Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine-lysine ( Val-Lys), Alanine-Alanine-Alanine (Ala-Ala-Ala), Alanine-Alanine-Asparagine (Ala-Ala-Asn), and Glycine-Glycine-Phenylalanine Acid-glycine (Gly-Gly-Phe-Gly).
  • polyethylene glycol generally refers to a residue comprising one or more ethylene glycol residues linked together.
  • a polyethylene glycol group may comprise - ( CH2CH2O ) p- , where p is a number of at least one.
  • polyethylene glycol groups in this application may be optionally substituted.
  • glycol group generally refers to a polyethylene glycol group.
  • glycol groups in this application may be optionally substituted.
  • a number preceding a glycol group may indicate the number of ethylene glycol units of a glycol group, eg, a diethylene glycol group may refer to the polymerized residue of two glycols.
  • polysarcosine residue generally refers to a residue comprising one or more sarcosine residues linked together.
  • a polysarcosine residue may comprise -(COCH2N( CH3 ) ) q- , where q is a number of at least one.
  • polysarcosine residues in the present application may be optionally substituted.
  • a structure containing polysarcosine residues can be where n2 is a number from 4 to 18.
  • sodium dodecyl sulfate polyacrylamide gel electrophoresis generally refers to an analytical characterization technique for substances.
  • sodium dodecyl sulfate polyacrylamide gel electrophoresis SDS-PAGE
  • SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis
  • hydrophobic chromatography generally refers to an analytical technique based on differences in the hydrophobicity of substances.
  • liquid phase mass spectrometry generally refers to an analytical method for identifying constituents of matter.
  • liquid chromatography-mass spectrometry can analyze the molecular weight of the substance to be tested by liquid chromatography-mass spectrometry.
  • tumor generally refers to any new pathological tissue proliferation.
  • angiogenesis is part of the tumor profile.
  • Tumors can be benign or malignant.
  • the term “tumor” is generally used to refer to benign or malignant tumors, while the term “cancer” is generally used to refer to malignant tumors, which may be metastatic or non-metastatic.
  • Tumors diagnosable by the methods of the present application are selected from the group consisting of breast cancer, ovarian cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, anaplastic large cell lymphoma, multiple myeloma, Prostate cancer, non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, pancreatic cancer, prostate cancer, rectal colon, gastric cancer, glial tumor and mesothelioma.
  • these tissues can be isolated from readily available sources by methods well known to those skilled in the art.
  • the application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable compound thereof.
  • Q can be a linking group
  • L 1a can be selected from the following group: optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted idene cyclyl, optionally substituted alicyclic heterocyclyl, optionally substituted arylene, and optionally substituted heteroarylene;
  • L2 may comprise optionally substituted polypeptide residues
  • L 3 may contain an optionally substituted spacer group, for example, the spacer group of the present application may be self-degradable.
  • the spacer groups of the present application may comprise optionally substituted or optionally substituted
  • L2 and/or L3 may comprise optionally substituted polysarcosine residues
  • T may contain drug units
  • Ab is a ligand capable of binding HER2, and m is a number from 1 to 8.
  • the present application also provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof A pharmaceutically acceptable salt, prodrug or solvate, wherein the compound may comprise a structure represented by formula (C-M-HER2):
  • Q 1 may contain a linker
  • L 1a can be selected from the following group: optionally substituted alkylene, optionally substituted polyethylene glycol, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted idene cyclyl, optionally substituted alicyclic heterocyclyl, optionally substituted arylene, and optionally substituted heteroarylene;
  • L2 may comprise optionally substituted polypeptide residues
  • L 3 may contain an optionally substituted spacer group, for example, the spacer group of the present application may be self-degradable.
  • the spacer groups of the present application may comprise optionally substituted or optionally substituted
  • L 2 and/or L 3 may comprise optionally substituted structural unit-X
  • T may contain drug units
  • Ab is a ligand capable of binding HER2, and m can be a number from 1 to 8.
  • L is selected from the group of: optionally substituted and optionally substituted
  • the benzene ring of L 3 may be substituted by the optionally substituted structural unit -X.
  • the structural unit -X can be selected from the group of: optionally substituted wherein X 1 is selected from the group consisting of carbonyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, straight chain heteroalkyl containing 1-8 atoms, and Linear-cyclic heteroalkyl groups containing 1-8 atoms containing 1-3 atoms selected from N, O or S ; wherein X is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, linear heteroalkyl containing 1-8 atoms, and linear-cyclic heteroalkane containing 1-8 atoms group, the heteroalkyl group contains 1-3 atoms selected from N, O or S; wherein X 3 is
  • the benzene ring of L 3 may be substituted by the optionally substituted structural unit -X.
  • the building block -X may contain an optionally substituted wherein X 1 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, straight chain heteroalkyl containing 1-8 atoms, and containing 1 -8-atom straight-chain-cyclic heteroalkyl, said heteroalkyl containing 1-3 atoms selected from N, O or S, said C 1 -C 8 alkyl, C 1 -C 8 Alkoxy, C1 - C6cycloalkyl, linear heteroalkyl containing 1-8 atoms, and linear-cyclic heteroalkyl containing 1-8 atoms are each independently optionally selected from Substituted with one or more substituents of deuterated, halogen, cyano, nitro, amino, alkyl, carboxyl, al
  • the present application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Accepted salts, prodrugs or solvates, wherein the compound may comprise the structure of formula (C-M2):
  • L can contain an optionally substituted alkylene group, an optionally substituted polyethylene glycol group and an optionally substituted alicyclic group;
  • R 1 can be an optionally substituted isopropyl group or an optionally substituted benzyl group ;
  • R 2 can be optionally substituted methyl, optionally substituted or optionally substituted
  • R 3 can be hydrogen or R 5 ; wherein R 5 can be optionally substituted T may comprise ixatecan (Exatecan, CAS accession number 171335-80-1) and/or belonotecan (Belotecan, CAS accession number 256411-32-2) and/or Genz-644282 (CAS accession number 529488- 28-6).
  • Q 1 may comprise a linker coupled with a thiol group.
  • Q 1 can be selected from the group of: optionally substituted optionally substituted optionally substituted and optionally substituted
  • L 1a may be selected from the group consisting of optionally substituted C 1 -C 7 alkylene, optionally substituted diethylene glycol to octaethylene glycol, optionally substituted C 3 -C 6 alkylene Alicyclic, optionally substituted arylene, and optionally substituted heteroarylene.
  • L 1a may be selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, optionally substituted propylene, optionally substituted butylene, optionally substituted pentylene , optionally substituted diethylene glycol, optionally substituted tetraethylene glycol, optionally substituted hexaethylene glycol, optionally substituted octaethylene glycol, and optionally substituted cyclohexylene.
  • L 1a can be selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, optionally substituted propylene, optionally substituted butylene, and optionally substituted pentylene base.
  • L 1a can be selected from the group of: optionally substituted diethylene glycol, optionally substituted triethylene glycol, optionally substituted tetraethylene glycol, optionally substituted pentaethylene glycol, optionally substituted Substituted hexaethylene glycol, optionally substituted heptaethylene glycol, and optionally substituted octaethylene glycol.
  • L 1a may be selected from the group consisting of optionally substituted cyclopropylene, optionally substituted cyclobutylene, and optionally substituted cyclohexylene.
  • L2 may comprise optionally substituted polypeptide residues consisting of amino acids selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine , tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartate acid and glycine.
  • amino acids selected from the group consisting of phenylalanine, isoleucine, leucine, tryptophan, valine, methionine , tyrosine, alanine, threonine, histidine, serine, glutamine, arginine, lysine, asparagine, glutamic acid, proline, citrulline, aspartate acid and glycine.
  • L 2 may comprise optionally substituted polypeptide residues consisting of amino acids selected from the group consisting of glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartate acid, asparagine and lysine.
  • L 2 may comprise an optionally substituted polypeptide residue selected from the group consisting of: phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine Acid-citrulline (Val-Cit), glutamic acid-valine-alanine (Glu-Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), valine Amino-Lysine (Val-Lys), Alanine-Alanine-Alanine (Ala-Ala-Ala), Alanine-Alanine-Asparagine (Ala-Ala-Asn) and Glycine-Glycine-Phenylalanine-Glycine (Gly-Gly-Phe-Gly).
  • Phe-Lys phenylalanine-lysine
  • Val-Ala valine-alanine
  • Val-Cit valine Acid-citrulline
  • Glu-Val-Ala glutamic acid-
  • L 2 may comprise an optionally substituted polypeptide residue selected from the group consisting of: phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine Acid-citrulline (Val-Cit) and valine-lysine (Val-Lys).
  • L2 comprises a lysine residue
  • the lysine residue can be substituted by a structure R1 comprising a polysarcosine residue.
  • any H contained in L 2 may be substituted by R 1 .
  • the R 1 can be optionally substituted wherein n1 is a number from 4 to 18, and R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, and C 1 -C 6 alkoxy.
  • n1 can be 4 to 18, 8 to 18, 4 to 12, or 8 to 12.
  • n1 can be 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.
  • L is selected from the group of: optionally substituted and optionally substituted
  • the benzene ring of L3 can be substituted with a structure R2 comprising a polysarcosine residue.
  • any H contained in the benzene ring of L 3 may be substituted by R 2 .
  • the structural unit -X- is selected from the group consisting of: optionally substituted wherein X 1 is selected from the group consisting of carbonyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, straight chain heteroalkyl containing 1-8 atoms, and Linear-cyclic heteroalkyl groups containing 1-8 atoms containing 1-3 atoms selected from N, O or S ; wherein X is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, linear heteroalkyl containing 1-8 atoms, and linear-cyclic heteroalkane containing 1-8 atoms group, the heteroalkyl group contains 1-3 atoms selected from N, O or S;
  • the benzene ring of L 3 is connected to the optionally substituted polysarcosine residue through a structural unit -X-, which is selected from, but is not limited to: wherein X 1 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, straight chain heteroalkyl containing 1-8 atoms, and containing 1 -8-atom straight-chain-cyclic heteroalkyl, said heteroalkyl containing 1-3 atoms selected from N, O or S, said C 1 -C 8 alkyl, C 1 -C 8 Alkoxy, C1 - C6cycloalkyl, linear heteroalkyl containing 1-8 atoms, and linear-cyclic heteroalkyl containing 1-8 atoms are each independently optionally selected from Substituted with one or more substituents of deuterated, halogen, cyano, nitro, amino, alkyl, carboxyl,
  • the optionally substituted polysarcosine residue comprises wherein n2 is a number from 4 to 18, and R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, and C 1 -C 6 alkoxy.
  • the structural unit -X- is selected from the group consisting of optionally substituted wherein X 1 is selected from the group consisting of carbonyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, straight chain heteroalkyl containing 1-8 atoms, and Linear-cyclic heteroalkyl groups containing 1-8 atoms containing 1-3 atoms selected from N, O or S ; wherein X is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, linear heteroalkyl containing 1-8 atoms, and linear-cyclic heteroalkane containing 1-8 atoms group, the heteroalkyl group contains 1-3 atoms selected from N, O or S; wherein X 3 is a covalent bond or is selected from the following group: hydrogen, C 1 -C 8 alkyl, C 1 -
  • the optionally substituted polysarcosine residue comprises wherein n2 is a number from 4 to 18, and R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, and C 1 -C 6 alkoxy.
  • the structural unit -X- is selected from the group consisting of optionally substituted wherein X 1 is selected from the group consisting of carbonyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, straight chain heteroalkyl containing 1-8 atoms, and Linear-cyclic heteroalkyl groups containing 1-8 atoms containing 1-3 atoms selected from N, O or S ; wherein X is selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 6 cycloalkyl, linear heteroalkyl containing 1-8 atoms, and linear-cyclic heteroalkane containing 1-8 atoms group, the heteroalkyl group contains 1-3 atoms selected from N, O or S; wherein X 3 is a covalent bond or is selected from the following group: hydrogen, C 1 -C 8 alkyl, C 1 -
  • n2 can be 4 to 18, 8 to 18, 4 to 12, or 8 to 12.
  • n2 can be 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.
  • T may comprise a compound having antitumor activity.
  • T can comprise a topoisomerase inhibitor
  • T can include camptothecin-based and non-camptothecin-based topoisomerase I inhibitors.
  • T may comprise ixatecan (Exatecan, CAS accession number 171335-80-1) and/or belotecan (Belotecan, CAS accession number 256411-32-2) and/or Genz-644282 (CAS accession number 256411-32-2) Accession No. 529488-28-6).
  • T can be selected from the following group:
  • the present application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Accepted salts, prodrugs or solvates, wherein the compound may comprise the structure of formula (C-HER2):
  • Q 1 may comprise a linker coupled with a thiol group
  • L2 may comprise optionally substituted polypeptide residues consisting of amino acids selected from the group consisting of glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, aspartic acid amide and lysine,
  • L 3 may contain optionally substituted
  • L 2 may comprise a polysarcosine residue
  • T may contain a topoisomerase inhibitor.
  • the present application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Accepted salts, prodrugs or solvates, wherein the compound may comprise the structure of formula (C-HER2):
  • Q 1 may comprise a linker coupled with a thiol group
  • L2 may comprise optionally substituted polypeptide residues consisting of amino acids selected from the group consisting of glycine, phenylalanine, valine, alanine, arginine, citrulline, aspartic acid, aspartic acid amide and lysine,
  • L 3 may contain optionally substituted
  • L3 may comprise a polysarcosine residue
  • T may contain a topoisomerase inhibitor.
  • the present application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Accepted salts, prodrugs or solvates, wherein the compound may comprise the structure of formula (C-HER2):
  • Q 1 may contain optionally substituted
  • L 2 may comprise a structure selected from the group consisting of phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit) and valine-lysine (Val-Lys),
  • L 3 may contain optionally substituted
  • L2 may comprise a lysine residue, and the lysine residue may be optionally substituted Substitution, where n1 is a number from 4 to 18,
  • T may comprise ixatecan (Exatecan, CAS accession number 171335-80-1) and/or belonotecan (Belotecan, CAS accession number 256411-32-2) and/or Genz-644282 (CAS accession number 529488- 28-6).
  • the present application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Accepted salts, prodrugs or solvates, wherein the compound may comprise the structure of formula (C-HER2):
  • Q 1 can be selected from the following group: optionally substituted optionally substituted optionally substituted and optionally substituted
  • L 2 may comprise a structure selected from the group consisting of phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), valine-citrulline (Val-Cit) and valine-lysine (Val-Lys),
  • L 3 may contain optionally substituted
  • L can be optionally substituted Substitution, wherein L can be optionally substituted Substitution, wherein n2 is a number from 4 to 18,
  • T may comprise ixatecan (Exatecan, CAS accession number 171335-80-1) and/or belonotecan (Belotecan, CAS accession number 256411-32-2) and/or Genz-644282 (CAS accession number 529488- 28-6).
  • the present application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Accepted salts, prodrugs or solvates, wherein the compound may comprise the structure of formula (C2-HER2):
  • L can contain an optionally substituted alkylene group, an optionally substituted polyethylene glycol group and an optionally substituted alicyclic group;
  • R 1 can be an optionally substituted isopropyl group or an optionally substituted benzyl group ;
  • R 2 can be optionally substituted methyl, optionally substituted or optionally substituted R 3 can be hydrogen or optionally substituted methyl;
  • R 2 can be optionally substituted Substitute, where n1 is a number from 4 to 18, and T may comprise ixatecan (Exatecan, CAS Accession No. 171335-80-1) and/or Belotecan (Belotecan, CAS Accession No. 256411-32-2) and /or Genz-644282 (CAS Accession No. 529488-28-6).
  • the present application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Accepted salts, prodrugs or solvates, wherein the compound may comprise the structure of formula (C2-HER2):
  • L can contain an optionally substituted alkylene group, an optionally substituted polyethylene glycol group and an optionally substituted alicyclic group;
  • R 1 can be an optionally substituted isopropyl group or an optionally substituted benzyl group ;
  • R 2 can be optionally substituted methyl, optionally substituted or optionally substituted R 3 can be hydrogen or optionally substituted methyl;
  • R 2 can be optionally substituted Substitute, where n2 is a number from 4 to 18, and T may comprise ixatecan (Exatecan, CAS Accession No. 171335-80-1) and/or Belotecan (Belotecan, CAS Accession No. 256411-32-2) and /or Genz-644282 (CAS Accession No. 529488-28-6).
  • the present application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Accepted salts, prodrugs or solvates, wherein the compound may comprise the structure of formula (C2-HER2):
  • L can contain an optionally substituted alkylene group, an optionally substituted polyethylene glycol group and an optionally substituted alicyclic group;
  • R 1 can be an optionally substituted isopropyl group or an optionally substituted benzyl group ;
  • R 2 can be optionally substituted R 3 can be hydrogen or optionally substituted methyl;
  • R 4 can be optionally substituted where n1 is a number from 4 to 18, and T may contain ixatecan (Exatecan, CAS accession number 171335-80-1) and/or belotecan (Belotecan, CAS accession number 256411-32-2) and/or Genz-644282 (CAS Accession No. 529488-28-6).
  • the present application provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Accepted salts, prodrugs or solvates, wherein the compound may comprise the structure of formula (C2-HER2):
  • L can contain an optionally substituted alkylene group, an optionally substituted polyethylene glycol group and an optionally substituted alicyclic group;
  • R 1 can be an optionally substituted isopropyl group or an optionally substituted benzyl group ;
  • R 2 can be optionally substituted methyl, optionally substituted or optionally substituted
  • R 3 can be hydrogen or R 5 ; wherein R 5 can be optionally substituted where n2 is a number from 4 to 18, and T may comprise ixatecan (Exatecan, CAS accession number 171335-80-1) and/or belotecan (Belotecan, CAS accession number 256411-32-2) and/or Genz-644282 (CAS Accession No. 529488-28-6).
  • the Ab can comprise an anti-HER2 antibody or antigen-binding fragment thereof.
  • the antibody may be selected from the group consisting of murine antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies.
  • the antibody may comprise a monoclonal antibody.
  • the antibody may comprise a bispecific antibody.
  • the antigen-binding fragment may be selected from the group consisting of Fab, Fab', Fv fragments, F(ab') 2 , F(ab) 2 , scFv, di-scFv, VHH and dAb.
  • the heavy chains HCDR1, HCDR2 and HCDR3 and light chains LCDR1, LCDR2 and LCDR3 of the Ab comprise heavy chains HCDR1, HCDR2 and HCDR3 and light chains LCDR1, LCDR2 and LCDR3, respectively, of an anti-HER2 antibody.
  • the heavy chain variable region VH and light chain variable region VL of the Ab comprise the heavy chain variable region VH and light chain variable region VL, respectively, of an anti-HER2 antibody.
  • the heavy and light chains of the Ab comprise the heavy and light chains of an anti-HER2 antibody, respectively.
  • the Ab may comprise Trastuzumab or Pertuzumab.
  • m can be determined by a method selected from the group consisting of hydrophobic chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, and liquid phase mass spectrometry.
  • m is the average value of the molar ratio of drug molecules to monoclonal antibody molecules in the antibody-conjugated drug obtained by coupling a single monoclonal antibody molecule with a cytotoxic drug, and m can be an integer or decimal from 1 to 8, such as , m can be about 1 to about 2, about 1 to about 3, about 1 to about 4, about 1 to about 5, about 1 to about 6, about 1 to about 7, or about 1 to about 8; for example, m can be about 2 to about 8, about 3 to about 8, about 4 to about 8, about 5 to about 8, about 6 to about 8, about 7 to about 8, or about 1, about 2, about 3, about 4, About 5, about 6, about 7 or about 8.
  • the present application also provides a compound, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof
  • a pharmaceutically acceptable salt, prodrug or solvate
  • the compound may comprise a structure selected from the group consisting of:
  • Ab is a ligand capable of binding HER2, and m is a number from 1 to 8.
  • the ligands described herein may be protein hormones, lectins, growth factors, antibodies, or other molecules capable of binding to cells, receptors and/or antigens.
  • the ligand of the present application can be an anti-Her2 antibody or an antigen-binding fragment thereof.
  • the ligand comprises at least one CDR in the variable region VL of the antibody light chain.
  • the CDRs described in the present application may be defined according to Kabat; or may be defined according to Chothia, and the CDR sequences defined in various ways are all included within the protection scope of the present application.
  • the antigen-binding protein of the present application may comprise CDR1-3 of the heavy chain variable region and CDR1-3 of the light chain variable region, wherein CDR1-3 of the heavy chain variable region and CDR1-3 of the light chain variable region 3 may be CDR1-3 of the heavy chain variable region and CDR1-3 of the light chain variable region of Trastuzumab and Pertuzumab, respectively.
  • the antigen-binding protein of the present application may have the binding ability to bind to HER2.
  • the antigen-binding protein of the present application may comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region may be Trastuzumab, Pertuzumab, respectively The heavy and light chain variable regions of the monoclonal antibody (Pertuzumab).
  • the antigen-binding protein of the present application may have the binding ability to bind to HER2.
  • the antigen binding proteins of the present application may be comprised of heavy and light chains, wherein the heavy and light chains may be the heavy and light chains of Trastuzumab, Pertuzumab, respectively .
  • the heavy chain amino acid sequence of Trastuzumab can be shown in SEQ ID NO:3
  • the light chain amino acid sequence of Trastuzumab can be shown in SEQ ID NO:4.
  • the ligands of the present application can be: for example, the heavy chain amino acid sequence of Sacituzumab can be as shown in SEQ ID NO: 1, ) light chain amino acid sequence can be as shown in SEQ ID NO:2.
  • the heavy chain amino acid sequence of Trastuzumab can be shown in SEQ ID NO:3, and the light chain amino acid sequence of Trastuzumab can be shown in SEQ ID NO:4.
  • the heavy chain amino acid sequence of Pertuzumab can be shown in SEQ ID NO:5, and the light chain amino acid sequence of Pertuzumab can be shown in SEQ ID NO:6.
  • the heavy chain amino acid sequence of Enfortumab can be shown in SEQ ID NO:7, and the light chain amino acid sequence of Enfortumab can be shown in SEQ ID NO:8.
  • the heavy chain amino acid sequence of Patritumab can be set forth in SEQ ID NO:9, and the light chain amino acid sequence of Patritumab can be set forth in SEQ ID NO:10.
  • the heavy chain amino acid sequence of antibody H01L02 can be set forth in SEQ ID NO:11, and the light chain amino acid sequence of antibody H01L02 can be set forth in SEQ ID NO:12.
  • Antibodies of the present application can be prepared using techniques well known in the art, such as hybridoma methods, recombinant DNA techniques, phage display techniques, synthetic techniques, or a combination of these techniques, or other techniques known in the art.
  • Variants may refer to amino acid sequence mutants of antibodies, as well as covalent derivatives of the native polypeptide, provided that biological activity comparable to the native polypeptide is retained.
  • Amino acid sequence mutants generally differ from the native amino acid sequence by the substitution of one or more amino acids in the native amino acid sequence or the deletion and/or insertion of one or more amino acids in the polypeptide sequence.
  • Deletion mutants include fragments of the native polypeptide and N-terminal and/or C-terminal truncation mutants. Typically the amino acid sequence mutants have at least 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% or more homology compared to the native sequence.
  • the drugs can be released into cells in an active form through the endocytosis of the conjugates or drug infiltration.
  • the antibody-drug conjugate of the present application can be used to treat the target disease, and the antibody-drug conjugate of the present application can be administered to a subject (eg, human) in a therapeutically effective amount through a suitable route.
  • a subject in need of treatment may be a patient at risk, or suspected of having a disorder associated with the activity or level of expression of a particular antigen. Such patients can be identified by routine physical examination.
  • delivery can be performed by methods routine in the art. For example, it can be introduced into cells by using liposomes, hydrogels, cyclodextrins, biodegradable nanocapsules, or bioadhesive microspheres.
  • the nucleic acid or vector can be delivered locally by direct injection or by using an infusion pump.
  • Other methods may include the use of various transport and carrier systems through the use of conjugates and biodegradable polymers.
  • the application provides a pharmaceutical composition, which may contain the compound described in any one of the application, or a tautomer, meso, racemate, enantiomer, The diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, prodrugs or solvates thereof, and may optionally contain a pharmaceutically acceptable carrier.
  • the pharmaceutical composition described in the application may contain one or more excipients, which may be selected from the following group of ingredients: fillers (diluents), binders, wetting agents, disintegrating agents and excipients, etc.
  • the composition may contain from 0.1 to 99% by weight of active compound.
  • compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups.
  • Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, which may contain binders, fillers, lubricants, disintegrants or pharmaceutically acceptable wetting agents, etc.
  • the composition may also contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives.
  • Aqueous suspensions may contain the active materials in admixture with excipients suitable for the preparation of aqueous suspensions.
  • the aqueous suspensions may also contain one or more preservatives, such as one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable oils.
  • the oily suspensions may contain thickening agents. The above-mentioned sweetening and flavoring agents may also be added.
  • the pharmaceutical compositions may also provide the active ingredient as dispersible powders and granules for preparation of aqueous suspensions by admixing with water one or more of a dispersing agent, wetting agent, suspending agent or preservative. Other excipients such as sweetening, flavouring and colouring agents may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the present application may also be in the form of oil-in-water emulsions.
  • the pharmaceutical compositions may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution can then be processed to form a microemulsion by adding it to a mixture of water and glycerol. Injections or microemulsions can be injected into a patient's bloodstream by local bolus injection.
  • solutions and microemulsions can be administered in a manner that maintains a constant circulating concentration of the compounds of the application.
  • a continuous intravenous drug delivery device can be used.
  • the device may be an intravenous pump.
  • compositions may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Alternatively, sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • the compounds of the present application may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient , the patient's diet, administration time, administration mode, excretion rate, combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the compound or its tautomer, meso isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and/or compounds or tautomers, mesoisomers,
  • the daily amount of racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or the species of pharmaceutically acceptable salts can be verified according to conventional therapeutic regimens.
  • the pharmaceutical composition of the present application may contain a safe and effective amount of the antibody-drug conjugate of the present application and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier can include, but are not limited to, saline, buffers, dextrose, water, glycerol, ethanol, and combinations thereof.
  • the pharmaceutical preparation should match the mode of administration, and the pharmaceutical composition of the present application can be prepared in the form of a solution, for example, prepared by a conventional method with a physiological saline or an aqueous solution containing glucose and other adjuvants.
  • the pharmaceutical composition can be manufactured under sterile conditions.
  • the active ingredient may be administered in a therapeutically effective amount.
  • the effective amount of the antibody-drug conjugates described herein may vary with the mode of administration, the severity of the disease to be treated, and the like. Selection of an effective amount can be determined by one of ordinary skill in the art based on various factors (eg, through clinical trials). The factors may include, but are not limited to: the pharmacokinetic parameters of the diabody conjugate such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated by the patient, the weight of the patient, the immune status, route of administration, etc. Generally, when the antibody-drug conjugates of the present application are administered in an appropriate dose per day, satisfactory results can be obtained. For example, several divided doses may be administered daily or the dose may be proportionally reduced as dictated by the exigencies of the therapeutic situation.
  • the compounds of the present application may be administered alone, or may be administered in combination with other pharmaceutically acceptable therapeutic agents.
  • a safe and effective amount of the compound of the present application can be applied to a mammal (such as a human) in need of treatment, and the dose can be a pharmaceutically effective dose when administered, and the specific dose can also be considered. factors such as route, patient's health status, etc.
  • the present application provides a compound of the present application, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof
  • the tumor can be selected from tumors associated with expression of the following group of targets: HER2.
  • the tumor associated with the expression of the target includes a tumor with high expression of the target and/or a tumor positive for the target.
  • the tumor comprises a solid tumor and/or a hematological tumor.
  • the tumor is selected from the group consisting of breast cancer, ovarian cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, Non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, pancreatic cancer, prostate cancer, rectal cancer, gastric cancer, glioma and skin tumor.
  • the present application provides a compound of the present application, or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof Acceptable salts, prodrugs or solvates, and/or pharmaceutical compositions of the present application, which can be used for use in medicaments for the treatment and/or prevention of tumors.
  • the tumor can be selected from tumors associated with expression of the following group of targets: HER2.
  • the tumor associated with the expression of the target includes a tumor with high expression of the target and/or a tumor positive for the target.
  • the tumor comprises a solid tumor and/or a hematological tumor.
  • the tumor is selected from the group consisting of breast cancer, ovarian cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, Non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, pancreatic cancer, prostate cancer, rectal cancer, gastric cancer, glioma and skin tumor.
  • the present application provides a method of preventing and/or treating tumors, which may include administering to a subject a compound of the present application, or a tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, and/or the pharmaceutical composition of the present application.
  • the tumor can be selected from tumors associated with expression of the following group of targets: HER2.
  • the tumor associated with the expression of the target includes a tumor with high expression of the target and/or a tumor positive for the target.
  • the tumor comprises a solid tumor and/or a hematological tumor.
  • the tumor is selected from the group consisting of breast cancer, ovarian cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphoblastic leukemia, anaplastic large cell lymphoma, multiple myeloma, prostate cancer, Non-small cell lung cancer, small cell lung cancer, malignant melanoma, squamous cell carcinoma, glioblastoma, renal cell carcinoma, gastrointestinal tumors, pancreatic cancer, prostate cancer, rectal cancer, gastric cancer, glioma and skin tumor.
  • Fmoc is 9-fluorenylmethoxycarbonyl protecting group (9-fluorenylmethyloxycarbonyl)
  • Boc is tert-butoxycarbonyl protecting group (tert-butoxycarbonyl)
  • TBDMS/TBS is tert-butyldimethylsilyl protecting group ( tert-butyldimethylsilyl).
  • Fmoc-Val-OSu 100g, 229mmol was dissolved in 500ml of tetrahydrofuran, N ⁇ -(tert-butoxycarbonyl)-L-lysine (59.3g, 241mmol) and sodium bicarbonate (20.21g, 241mmol) were added respectively in 500 ml of aqueous solution.
  • the reaction solution was stirred at room temperature for 48 hours, and the detection reaction was completed.
  • the pH of the reaction solution was adjusted to about 6 with 1N dilute hydrochloric acid, and 500 ml of ethyl acetate was added for extraction.
  • the organic phase was separated, washed once with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness.
  • compound (A-5) is the same as that of compound (A-4), except that the acetylated-10-polysarcosine (Ac-Sar10-COOH) in the last step is replaced by acetylated-4-polysarcosine Amino acid (Ac-Sar4-COOH), the product (A-5) is a beige amorphous powder after several steps of reaction.
  • LC-MS (ESI, m/z) theoretical: 1330.60, found: 1331.61 (M+H).
  • the intermediate compound 15-5 (150 mg, 0.131 mmol) was dissolved in 1 ml of anhydrous DMF, and acetylated-10 polysarcosine (Ac-Sar10-COOH) (101 mg, 0.131 mmol), DIPEA (114 ⁇ l, 0.654 mmol) and HATU (74.6 mg, 0.196 mmol), stirred at room temperature overnight, the solvent was removed under reduced pressure to obtain the final product, which was then prepared and purified by reverse-phase HPLC to obtain compound A-15 (107 mg, 0.059 mmol, yield 45.4%).
  • LC-MS (ESI, m/z) theoretical: 1799.74, found: 1800.77 (M+H).
  • the intermediate compound 15-5 (300 mg, 0.268 mmol) was dissolved in 5 ml of anhydrous DMF, and acetylated-10 polysarcosine (Ac-Sar10-COOH) (206 mg, 0.268 mmol), DIPEA (94 ⁇ l, 0.536 mmol) and HATU (122 mg, 0.321 mmol), stirred overnight at room temperature, and removed the solvent under reduced pressure to obtain the final product, which was then prepared and purified by reverse-phase HPLC to obtain compound A-18 (170 mg, 36% yield).
  • LC-MS (ESI, m/z) theoretical: 1757.78, found: 1758.82 (M+H).
  • Mc-Val-Cit-OH (purchased from Shanghai Haoyuan Chemical) reacts with bis(4-nitrophenyl) carbonate to obtain activated nitroester and further reacts with ixatecan methanesulfonic acid Salt (purchased from Shanghai Haoyuan) was reacted to obtain the reference compound MC-Val-Cit-PAB-DX8951.
  • the antibody or antigen-binding fragment eg, a stock solution of Trastuzumab targeting HER2 (heavy chain sequence is shown in SEQ ID NO: 3, light chain sequence is shown in SEQ ID NO: 4) and/or, for example, targeting Trop-2.
  • hRS7 mAb (Sacituzumab) in 50 mM potassium dihydrogen phosphate-sodium hydroxide (KH 2 PO4-NaOH)/150 mM sodium chloride (NaCl)/1 mM diethyltriaminepentaacetic acid (DTPA), pH 7 reaction buffer Dilute to 2 mg/mL, add tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in an excess molar ratio of 6.0 times, and stir the reaction solution at 35° C. for 2.5 hours.
  • KH 2 PO4-NaOH potassium dihydrogen phosphate-sodium hydroxide
  • NaCl sodium chloride
  • DTPA diethyltriaminepentaacetic acid
  • pH 7 reaction buffer Dilute to 2 mg/mL, add tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in an excess molar ratio of 6.0 times, and stir the reaction solution at 35°
  • the above reaction solution was cooled to 8°C, an appropriate amount of dimethylacetamide (DMA) was added without purification, and then 6-15 times excess molar ratio of reference substance drug molecules or drug linker conjugates A1 to A29 ( 10 mg/ml pre-dissolved in DMA) to ensure that the volume ratio of DMA in the reaction system does not exceed 20%, and the coupling was performed by stirring at 37° C. for 3 hours.
  • DMA dimethylacetamide
  • the coupling reaction mixture was purified by gel filtration of pH 6.0 histidine-acetic acid/sucrose using a desalting column, and the peak samples were collected according to the UV280 absorption value. It was then sterilized through a 0.15 micron pore size filter and stored at -60°C.
  • a 12-fold excess of compound (A-4) was conjugated with the reduced Trastuzumab monoclonal antibody to obtain antibody conjugate 4 with a drug loading (DAR) of about 7 to 8.
  • DAR drug loading
  • Size exclusion chromatography ( SEC-HPLC) to analyze the content of the polymer, and the analytical spectrum is shown in Figure 5.
  • the proportion of aggregate 1 is about 0.3%.
  • the drug loading (DAR) was about 7-8 by hydrophobic interaction high performance liquid chromatography (HIC-HPLC) analysis, and the analytical spectrum is shown in Figure 6.
  • the hRS7 single-antigen solution targeting Trop-2 was dialyzed to 50mM sodium dihydrogen phosphate-disodium hydrogen phosphate (NaH 2 PO 4 -Na 2 HPO 4 )/50mM sodium chloride (NaCl), pH7.0 buffer middle. After measuring the concentration of mAb in the solution, dilute the antibody to 5 mg/mL with the above buffer. The reaction tube was placed in an ice bath to cool down for 10 minutes. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) was added in a molar ratio of 2.5 times, and the reaction solution was stirred at 4°C overnight.
  • TCEP Tris(2-carboxyethyl)phosphine hydrochloride
  • DMA dimethylacetamide
  • a 6.0-fold excess molar ratio of the reference substance drug molecule or drug linker conjugate A-11 (10mM pre-dissolved in DMA) ensure that the volume ratio of DMA in the reaction system does not exceed 10%, and stir at 4 °C for 2 hours for coupling.
  • a 4.0-fold molar ratio of Cysteine (Cysteine) small molecule was added to the reaction solution to consume the excess drug linker conjugate A-11, and the reaction was stirred at 4°C for 30 minutes for quenching.
  • the coupling reaction mixture was purified by filtration with histidine-acetic acid/sodium chloride pH 5.5 using a desalting column, and the filtrated sample was collected.
  • One-tenth volume of activated carbon-histidine-acetic acid/sodium chloride suspension (300 mg/mL) was added to the sample, and stirred at room temperature for 2 hours to fully absorb free small drug molecules. It was then sterilized through a 0.22 micron pore size filter and stored at -80°C.
  • the content of the polymer was analyzed by size exclusion chromatography (SEC-HPLC), and the analysis pattern was shown in Figure 31.
  • the purity of the antibody conjugate 13 monomer was 98.95%.
  • the conjugated drug concentration in the antibody-drug conjugate can be calculated by measuring the UV absorbance of the antibody-drug conjugate aqueous solution at two wavelengths of 280 nm and 370 nm, and then calculated as follows.
  • the total absorbance at any given wavelength is equal to the sum of the absorbances of all light-absorbing chemicals in the system (absorption additivity). Therefore, based on the assumption that the molar absorption coefficient of the antibody and the drug does not change before and after conjugation of the antibody and the drug, the antibody concentration and the drug concentration in the antibody-drug conjugate are represented by the following formula.
  • a 280 represents the absorbance of the antibody-drug conjugate solution at 280 nm
  • a 370 represents the absorbance of the antibody-drug conjugate solution at 370 nm
  • AD,280 represents the absorbance of the drug-linker conjugate at 280 nm
  • AD,370 represents the absorbance of the drug-linker conjugate at 370 nm
  • a A,280 represents the absorbance of the antibody at 280 nm
  • a A,370 represents the absorbance of the antibody at 370 nm.
  • ⁇ D,280 represents the molar absorption coefficient of the drug-linker conjugate at 280 nm
  • ⁇ D,370 represents the molar absorption coefficient of the drug-linker conjugate at 370 nm
  • ⁇ A,280 represents the molar absorption of the antibody at 280 nm
  • the coefficient, ⁇ A, 370 represents the molar absorption coefficient of the antibody at 370 nm.
  • CD represents the concentration of the drug linker conjugate in the antibody-drug conjugate solution
  • CA represents the concentration of the antibody in the antibody-drug conjugate solution.
  • ⁇ A,280 can be estimated from the amino acid sequence of the antibody by known computational methods (Protein Science, 1995, vol. 4, 2411-2423), and ⁇ A,370 is generally zero.
  • ⁇ D,280 and ⁇ D,370 are obtained according to the Lambert-Beer law by the absorbance of the solution of the drug-linker conjugate at a certain molar concentration.
  • the values of A 280 and A 370 are measured by a microplate reader or UV spectrophotometer, and the values of the above 4 molar absorption coefficients are put into the simultaneous equations (1) and (2), and C A and C can be calculated value of D.
  • the average number of conjugated drug molecules in each antibody molecule DAR C D /C A .
  • the hRS7 single-antigen solution targeting Trop-2 was dialyzed to 50mM sodium dihydrogen phosphate-disodium hydrogen phosphate (NaH 2 PO 4 -Na 2 HPO 4 )/50mM sodium chloride (NaCl), pH7.0 buffer middle. After measuring the concentration of mAb in the solution, dilute the antibody to 5 mg/mL with the above buffer. The reaction tube was placed in an ice bath to cool down for 10 minutes. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) was added in a molar ratio of 2.5 times, and the reaction solution was stirred at 4°C overnight.
  • TCEP Tris(2-carboxyethyl)phosphine hydrochloride
  • DMA dimethylacetamide
  • the coupling reaction mixture was purified by filtration with histidine-acetic acid/sodium chloride pH 5.5 using a desalting column, and the filtrated sample was collected.
  • One-tenth volume of activated carbon-histidine-acetic acid/sodium chloride suspension 300 mg/mL was added to the sample, and stirred at room temperature for 2 hours to fully absorb free small drug molecules. It was then sterilized through a 0.22 micron pore size filter and stored at -80°C.
  • the content of the polymer was analyzed by size exclusion chromatography (SEC-HPLC), and the analysis pattern was shown in Figure 32.
  • the purity of the antibody conjugate 14 monomer was 98.20%.
  • the hRS7 single-antigen solution targeting Trop-2 was dialyzed to 50mM sodium dihydrogen phosphate-disodium hydrogen phosphate (NaH 2 PO 4 -Na 2 HPO 4 )/50mM sodium chloride (NaCl), pH7.0 buffer middle. After measuring the concentration of mAb in the solution, dilute the antibody to 5 mg/mL with the above buffer. The reaction tube was placed in an ice bath to cool down for 10 minutes. Tris(2-carboxyethyl)phosphine hydrochloride (TCEP) was added in a molar ratio of 2.5 times, and the reaction solution was stirred at 4°C overnight.
  • TCEP Tris(2-carboxyethyl)phosphine hydrochloride
  • DMA dimethylacetamide
  • the coupling reaction mixture was purified by filtration with histidine-acetic acid/sodium chloride pH 5.5 using a desalting column, and the filtrated sample was collected.
  • One-tenth volume of activated carbon-histidine-acetic acid/sodium chloride suspension 300 mg/mL was added to the sample, and stirred at room temperature for 2 hours to fully absorb free small drug molecules. It was then sterilized through a 0.22 micron pore size filter and stored at -80°C.
  • the content of the polymer was analyzed by size exclusion chromatography (SEC-HPLC), and the analysis pattern was shown in Figure 33.
  • the purity of the antibody conjugate 15 monomer was 96.36%.
  • ADC drugs based on camptothecin-like topoisomerase inhibitors such as Sacituzumab govitecan (Trodelvy) and Trastuzumab Deruxtecan (Enhertu) usually have a higher drug-to-antibody loading ratio (DAR), due to the aromatic concentration of camptothecin-like molecules.
  • DAR drug-to-antibody loading ratio
  • the ring-like structure has strong hydrophobicity, and the stability of such ADC molecules must be affected to a certain extent.
  • the ADC prepared by the present invention introduces a polysarcosine peptide chain at a specific position, which has better "barrier effect" and may have better stability. We designed an antibody stability accelerated test to verify this hypothesis.
  • Molecules compared include:
  • the mobile phase of HPLC was 200 mM phosphate buffer (pH 7.0) + 150 mM KCl + 15% IPA, the column temperature was 25 °C, the injection volume was 7 ⁇ L, the flow rate was 0.75 ml/min, and the UV detection wavelengths were 280 nm and 370 nm.
  • NCI-N87 human gastric cancer cells were selected as the cell line for in vitro activity detection in this experiment, and the dose-effect of antibody conjugate 2, antibody conjugate 5, antibody conjugate 6, Trastuzumab monoclonal antibody, and IgG-deruxtecan on cell killing was observed.
  • the final concentration of the antibody-drug conjugate prepared in Example 2 was set to 500 nM as the initial concentration after sample addition, and a series of 9 concentrations (5-fold dilution) were designed from 500 to 0.1 nM, and the changes in killing (or inhibition) were observed for 120 hours.
  • Chemiluminescent staining Luminescent Cell Viability Assay
  • NCI-N87 cells with high expression of Her2 were treated with antibody conjugate 2, antibody conjugate 4, antibody conjugate 5, and antibody conjugate 6 with Trastuzumab monoclonal antibody and IgG-deruxtecan, and the antibody conjugated Compound 2, Antibody Conjugate 4, Antibody Conjugate 5, and Antibody Conjugate 6 can significantly inhibit tumor cell proliferation, significantly stronger than Trastuzumab mAb and IgG-deruxtecan.
  • antibody conjugate 5 As shown in Figure 26, antibody conjugate 5, antibody conjugate 11 and DS8201a (antibody conjugate 2) treated OV-CAR3 human ovarian adenocarcinoma cells with low Her2 expression, and all three antibody conjugates could significantly inhibit the Tumor cell proliferation, antibody conjugate 5 and antibody conjugate 11 are better than DS8201a (antibody conjugate 2).
  • antibody conjugate 12 and Belotecan small molecules treated NCI-N87 cells and SK-BR-3 cells with high expression of Her2, and antibody conjugate 12 could significantly inhibit tumor cell proliferation, which was significantly stronger than The loaded small molecule drug Belotecan.
  • the ADCs prepared from the compounds of the present application all show good in vitro anti-tumor activity, especially for tumor cells with low expression of related antigens.
  • the antibody conjugates of the present application have more obvious advantages.
  • the efficacy of the combinations of the invention can be measured in vivo, ie in rodents implanted with cancer cell allografts or xenografts, and treated with the combination.
  • Test mice are treated with drug or control and monitored for several weeks or longer to measure time to tumor doubling, log cell killing, and tumor inhibition.
  • COLO205 human colon cancer cells which are HER2-low-expressing cells, were suspended in physiological saline, and 4 ⁇ 10 7 cells were subcutaneously transplanted into the right flank of female nude mice, and grouping was performed at random on the sixth day. Taking the grouping day as the 0th day, on the 0th day, antibody conjugate 2 (DS8201), antibody conjugate 5, 10 mg/kg Kadcyla (T -DM1). As a control group, a PBS buffer-administered group was set.
  • HER2 in tumors based on the results obtained by immunohistochemical staining, those with a score of 3+ were classified as highly expressed, those with a score of 2+ were classified as moderately expressed, and those with a score of 2+ were classified as moderately expressed. 1+ is classified as low expression.
  • the score was 0 in this measurement method, the results obtained by other measurement methods such as a flow cytometer-based measurement method were positive, and were classified as low expression.
  • HCC1954 human breast cancer cells (ATCC) expressing HER2 were suspended in physiological saline, 4 ⁇ 10 7 cells were subcutaneously transplanted into the right flank of female nude mice, and grouping was performed at random on the sixth day.
  • the grouping day was regarded as day 0, and on day 0, antibody conjugate 2 (DS8201) and antibody conjugate 5 were administered into the tail vein at doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg, respectively.
  • IgG was set and the corresponding toxin linker was coupled to the IgG-deruxtecan conjugate and IgG-A11 conjugate-administered groups, respectively.
  • the ADCs prepared from the compounds of the present application all showed a certain anti-tumor activity in vivo, and could show significantly stronger anti-tumor activity compared with the control sample.
  • the tumor-bearing mice tolerated the above drugs well, and no symptoms such as weight loss occurred.
  • the pharmacokinetic properties of antibody conjugate 5, antibody conjugate 6 and the control drug DS8201a in rats were evaluated. Specifically, in this example, 3 mg/kg of Antibody Conjugate 5, Antibody Conjugate 6 and DS8201 were administered to rats by tail injection. The average toxicity parameters of the conjugated antibodies in each dose group are shown in the following table. The order of the half-life of the binding antibody is antibody conjugate 5 ⁇ antibody conjugate 6>DS8201a.

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