WO2025149013A1 - Conjugué anticorps anti-nectine 4 hydrophile-médicament, son procédé de préparation et son utilisation - Google Patents

Conjugué anticorps anti-nectine 4 hydrophile-médicament, son procédé de préparation et son utilisation

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Publication number
WO2025149013A1
WO2025149013A1 PCT/CN2025/071654 CN2025071654W WO2025149013A1 WO 2025149013 A1 WO2025149013 A1 WO 2025149013A1 CN 2025071654 W CN2025071654 W CN 2025071654W WO 2025149013 A1 WO2025149013 A1 WO 2025149013A1
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mmol
gly
added
compound
antibody
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黄云生
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Hangzhou Adcoris Biopharma Co Ltd
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Hangzhou Adcoris Biopharma Co Ltd
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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
    • A61K47/6801—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K47/6889—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
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL

Definitions

  • the present invention relates to the field of medicine. Specifically, the present invention provides a series of camptothecin-7-ethylamine and its preparation of toxin-hydrophilic linker compounds formed by linkers, and the corresponding anti-nectin-4 antibodies are coupled to form antibody-coupled drugs and their application in the treatment of tumors.
  • Camptothecin and its derivatives have inhibitory activity against topoisomerase Top1, especially against the complex formed by Top1-DNA.
  • Camptothecin has significant therapeutic effects on gastric cancer, esophageal cancer, lung cancer, bladder cancer, etc., and is a broad-spectrum anti-tumor drug.
  • the camptothecin derivatives Irinotecan and Topotecan have been approved for the treatment of various cancers in many countries.
  • Another camptothecin derivative Belotecan has been approved in South Korea for the treatment of SCLC and ovarian cancer.
  • the main defects of camptothecin anti-tumor drugs are their toxicity, poor solubility and tumor cell resistance to them.
  • R 1 and R 2 are each independently selected from hydrogen, fluorine and C 1-3 alkyl, or R 1 , R 2 and the carbon atom to which they are connected together form an oxygen-containing heterocyclic group;
  • R 4 is selected from hydrogen or a heteroalkyl group comprising repeating units of -OCH 2 CH 2 -;
  • R 5 is selected from hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl
  • Lp is selected from a peptide residue comprising 1-5 amino acids
  • n is an integer selected from 1 to 8;
  • a, p are selected from 1, 2 or 3;
  • R 3 is selected from oxetanyl, oxolanyl or oxhexyl.
  • the linker used to couple the antibody or antigen-binding fragment with the other parts of the compound of formula (I) can be a single linker or a double linker, wherein the double linker refers to a structure that can simultaneously connect two chemical functional groups (specifically, an antibody and a toxin part).
  • the structure has a group connected to the antibody and a group connected to the toxin part.
  • Z is selected from in, The positions shown indicate attachment to antibodies. The indicated position indicates linkage to -NH-.
  • the heavy chain amino acid sequence of the anti-nectin-4 antibody is as shown in SEQ ID NO:1, and the light chain amino acid sequence is as shown in SEQ ID NO:2.
  • the present invention provides the following toxin-linker compounds, pharmaceutically acceptable salts or stereoisomers thereof:
  • the present invention provides the following compounds, pharmaceutically acceptable salts or stereoisomers thereof:
  • the cancer is selected from breast cancer, transitional cell carcinoma of the bladder, prostate cancer, and pancreatic adenocarcinoma.
  • FIG2 shows the RP-MS value test results of ADC2 in Example 2; wherein A and B are HPLC results, and C and D are MS results.
  • FIG3 shows the RP-MS value test results of ADC3 in Example 3; wherein A and B are HPLC results, and C and D are MS results.
  • Antibodies include full-length immunoglobulin molecules or immunologically active portions of full-length immunoglobulin molecules, i.e., molecules that contain antigen binding sites that immunospecifically bind to target antigens or portions thereof, and these targets include, but are not limited to, cancer cells or cells that produce autoimmune antibodies associated with autoimmune diseases.
  • the term "antibody” is an immunoglobulin molecule that can bind to a specific antigen. It includes two light chains with lighter molecular weight and two heavy chains with heavier molecular weight. The heavy chain (H chain) and the light chain (L chain) are connected by disulfide bonds to form a tetrapeptide chain molecule.
  • ADC antibody-drug conjugate
  • cytotoxic drug moiety or "small molecule drug”, which refers to a compound that has a killing effect on tumor cells.
  • cytotoxic drug moiety at least one of an anti-tubulin agent, a DNA intercalator, a DNA topoisomerase inhibitor, a DNA synthesis inhibitor, an RNA polymerase inhibitor, a splicesome inhibitor, a proteolysis-targeting chimera (PROTAC), and an immunomodulator can be cited.
  • the small molecule drugs used in the present application can be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, such as enantiomers and diastereomers.
  • the stereoisomers include geometric isomers (such as cis, trans structures) and optical isomers (such as enantiomers), and therapeutic substances composed of monomers, racemates, racemic mixtures and pharmaceutically acceptable salts thereof.
  • the compounds containing asymmetric carbon atoms of the present application can be separated in optically pure form or racemic form. Optically pure forms can be separated from racemic mixtures, or synthesized by using chiral raw materials or chiral reagents. Racemates, diastereomers, and enantiomers are all included in the scope of the present application.
  • any variable e.g., Rn
  • its definition at each occurrence is independent.
  • R e.g., 1-5 R
  • the group may be optionally substituted with up to 5 R, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • pharmaceutically acceptable salt refers to a salt formed by a corresponding amine compound and an inorganic acid or an organic acid, or a salt formed by a corresponding carboxylic acid compound and an alkali metal or alkaline earth metal, or a salt formed by an organic amine.
  • inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.
  • organic acids include but are not limited to acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, citric acid, succinic acid, gluconic acid, maleic acid, fumaric acid, tartaric acid, etc.
  • alkali metal or alkaline earth metal salts include but are not limited to sodium, potassium, calcium, magnesium salts, etc.
  • organic amine salts include but are not limited to salts composed of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine,
  • the active drug component can be mixed with non-toxic, pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, traga
  • the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc.
  • Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.
  • compositions of the present application containing compounds of formula I as active compounds can also introduce beads, microspheres or microcapsules, such as those constructed by polyglycolic acid/lactic acid (PGLA).
  • PGLA polyglycolic acid/lactic acid
  • Liquid preparations for oral administration can take the form of solutions, syrups, emulsions or suspensions, for example, or they can be presented as dry products reconstituted with water or other suitable adjuvants before use. Preparations for oral administration can be suitably formulated to release the active compound in a controlled or delayed manner.
  • inhibitor as used herein is used relative to a control.
  • One skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.
  • DAR value testing and calculation Based on the RP-HPLC-MS test results, the DAR value of ADC was analyzed using a Waters Acquity UPLC I-Class/Xevo G2-XS QTOF instrument.
  • the ADC prepared uses but is not limited to Nectin-4 antibody.
  • amino acid sequence of the heavy chain of the nectin-4 antibody is as follows (SEQ ID NO: 1):
  • amino acid sequence of the light chain of the nectin-4 antibody is as follows (SEQ ID NO: 2):
  • Nectin4 antibody (10.0 mg/mL, 10 mg, 0.066 mmol)
  • adjust the pH to 7.2 with 1 M Na2HPO4 solution then add 0.1 M disodium ethylenediaminetetraacetic acid solution (25 ⁇ L)
  • Example 2 Ab nectin-4- (S-7-(N-(acetamide-PEG 2 -propionyl-Gly-Lys-PABC)-N-((R)-3-tetrahydrofuran))aminoethylcamptothecin) 8 (ADC2)
  • the intermediate I-1 (18 g, 68.12 mmol) was added to IPA (180 mL), the reaction solution was stirred, and then DIEA (17.61 g, 136.24 mmol) and (R)-3-aminotetrahydrofuran hydrochloride (33.67 g, 272.48 mmol) were added, and the reaction was refluxed for 12 h.
  • the reaction solution was concentrated to about 20 mL of IPA remaining, 200 mL of water was added, and the mixture was stirred at room temperature for 2 hours.
  • Nectin4 antibody (10.0 mg/mL, 10 mg, 0.066 mmol)
  • adjust the pH to 7.2 with 1 M Na2HPO4 solution then add 0.1 M disodium ethylenediaminetetraacetic acid solution (25 ⁇ L)
  • Example 4 Ab nectin-4- (S-7-(N-(acetamide-PEG 2 -propionyl-Gly-Lys-PAB(3-bisPEG 4 -carbonyl)C)-N-(4-tetrahydropyranyl))amineethylcamptothecin) 8 (ADC4)
  • the intermediate I-1 (18 g, 68.12 mmol) was added to IPA (180 mL), the reaction solution was stirred, and then DIEA (17.61 g, 136.24 mmol) and 4-aminotetrahydropyran hydrochloride (37.50 g, 272.48 mmol) were added.
  • the reaction was refluxed for 12 h, and the reaction solution was concentrated to about 20 mL of IPA remaining. 200 mL of water was added and stirred for 2 hours. The solid was filtered and dried at 40 ° C to obtain the product D3-1 (20.2 g, yield 91.7%); LCMS: [M+1] + 320.98 (calculated value 320.10).
  • L3-D3-3 (87 mg, 0.045 mmol) and DCM (6 mL) were added in sequence, stirred to dissolve, DBU (4.9 mg) was added dropwise, and the reaction was stirred at room temperature for 30 min.
  • the mixture was poured into methyl tert-butyl ether (50 mL), centrifuged, the supernatant was discarded, and the mixture was purified by silica gel column chromatography to obtain L3-D3-4 (74 mg, yield 97%, HPLC 96%); LCMS: [M+1] + 1678.96 (calculated value 1678.82).
  • L4-D2-3 (0.41 g, 217.49 ⁇ mol), DMF (4 mL), piperidine (370.37 mg, 4.35 mmol, 429.66 ⁇ L) were added to a 10 mL single-mouth eggplant-shaped bottle in sequence, and the mixture was stirred at room temperature for 1 h.
  • L4-D2-5 80 mg, 44.85 ⁇ mol
  • DCM 1 mL
  • TFA 153.41 mg, 1.35 mmol, 102.96 ⁇ L
  • nectin-4 antibody (10.0 mg/mL, 10 mg, 0.066 mmol)
  • adjust the pH to 7.2 with 1 M Na 2 HPO 4 solution then add 0.1 M disodium ethylenediaminetetraacetic acid solution (25 ⁇ L)
  • Test example ADC anti-tumor activity experiment
  • Human breast cancer cells MDA-MB-468, human bladder transitional cell carcinoma SW-780, human breast cancer cells MCF-7, human prostate cancer cells LNCaP and human pancreatic adenocarcinoma cells BxPC-3 were cultured in DMEM (Cellmax), DMEM (Cellmax), MEM (Cellmax), RPMI1640 (Cellmax) and RPMI1640 (Cellmax) culture media containing 10% fetal bovine serum (Cellmax) until the exponential growth phase, and after trypsin digestion, the supernatant was discarded by centrifugation and diluted with culture medium to 6 ⁇ 10 4 cells/mL, 6 ⁇ 10 4 cells/mL, 2 ⁇ 10 4 cells/mL, 3 ⁇ 10 4 cells/mL and 7 ⁇ 10 4 cells/mL, respectively, and 100 ⁇ L per well was added to a 96-well cell culture plate and returned to a 37°C, 5% CO 2 incubator for overnight culture.
  • the cell culture plate was removed, the culture medium in the culture plate was discarded with a pipette, and 100 ⁇ L of culture medium containing 10% CCK-8 was added to each well, and incubated at 37°C for 3h. After the incubation was completed, the culture plate was removed, protected from light, placed in an ELISA reader, and 630nm was selected as the reference wavelength and 450nm was selected as the measurement wavelength to measure the absorbance. Based on the absorbance values, IC 50 was calculated using four-parameter regression in GraphPad (Table 1). ) is the positive control drug.
  • the ADC compounds provided in the embodiments of the present invention all have a good inhibitory effect on the growth of cancer cells and have significant anti-cancer activity.
  • Test Example 2 In vivo tumor growth inhibition activity of ADC
  • Human breast cancer cells MDA-MB-468, human bladder transitional cell carcinoma SW-780, human lung cancer cells NCI-H292, human bladder cancer cells HT-1376 and human pancreatic adenocarcinoma cells BxPC-3 were cultured in monolayer in vitro. When the cell saturation was 80%-90%, they were digested with trypsin-EDTA, centrifuged and the supernatant was discarded, and the cells were resuspended in PBS.
  • the cell suspension was adjusted to an appropriate concentration, and human breast cancer cells MDA-MB-468, human bladder transitional cell carcinoma SW-780, human lung cancer cells NCI-H292, human bladder cancer cells HT-1376 and human pancreatic adenocarcinoma cells BxPC-3 (2-10 ⁇ 10 6 cells/0.1 mL) were subcutaneously inoculated into BALB/c nude mice. The animals and the growth of the transplanted tumors were observed regularly. When the tumor volume grew to about 100-200 mm 3 , the mice were randomly divided into two groups according to the tumor volume and body weight, namely, a vehicle control group (normal saline) and an ADC administration group (dissolved in normal saline), with 6 animals in each group.
  • a vehicle control group normal saline
  • ADC administration group dissolved in normal saline
  • Intravenous injection was used for administration once (the time of the first administration was recorded as Day 0).
  • Statistical analysis was performed based on the data of tumor volume at the end of the experiment to obtain the tumor inhibition rate, which was expressed as: 100% * (average tumor volume of the blank control (solvent) group - average tumor volume of the test group) / average tumor volume of the blank control (solvent) group.
  • N4-Dxd represents the ADC formed by coupling Dxd (GGFG linker) and the anti-nectin-4 antibody of the present application example;

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Abstract

L'invention concerne un composé lieur hydrophile-toxine formé par la camptothécine-7-éthylamine et un lieur, un conjugué de celui-ci avec un anticorps anti-nectine 4, et son utilisation pharmaceutique. Le composé lieur hydrophile-toxine peut être conjugué à un anticorps monoclonal anti-nectine 4 pour former un conjugué anticorps-médicament (ADC), de façon à augmenter l'hydrophilie de l'ADC, à réduire son agrégation dans le système circulatoire, à améliorer l'efficacité et à réduire les effets indésirables.
PCT/CN2025/071654 2024-01-12 2025-01-10 Conjugué anticorps anti-nectine 4 hydrophile-médicament, son procédé de préparation et son utilisation Pending WO2025149013A1 (fr)

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CN202410051888.5A CN118001423A (zh) 2024-01-12 2024-01-12 亲水性抗Nectin-4抗体偶联药物及其制备方法和应用
CN202410051888.5 2024-01-12

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CN118001423A (zh) * 2024-01-12 2024-05-10 杭州爱科瑞思生物医药有限公司 亲水性抗Nectin-4抗体偶联药物及其制备方法和应用
WO2026037321A1 (fr) * 2024-08-13 2026-02-19 Lepu Biopharma Co., Ltd. Composés, compositions et méthodes

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WO2022228406A1 (fr) * 2021-04-26 2022-11-03 江苏恒瑞医药股份有限公司 Anticorps anti-nectine-4 et conjugué anticorps anti-nectine-4-médicament et utilisateur médicinal de ceux-ci
CN116712562A (zh) * 2022-12-29 2023-09-08 杭州爱科瑞思生物医药有限公司 N-叠氮烷基取代的喜树碱衍生物的抗体偶联药物
CN116712561A (zh) * 2022-12-29 2023-09-08 杭州爱科瑞思生物医药有限公司 含n-亚甲基酰胺连接子的抗体-药物偶联物
CN116712563A (zh) * 2022-12-29 2023-09-08 杭州爱科瑞思生物医药有限公司 N-卤代烷基取代的喜树碱衍生物的抗体偶联药物
CN116726192A (zh) * 2022-12-29 2023-09-12 杭州爱科瑞思生物医药有限公司 N-烷氧烷基取代的喜树碱衍生物的抗体偶联药物
CN116870187A (zh) * 2022-12-29 2023-10-13 杭州爱科瑞思生物医药有限公司 N-氧杂环烷基取代的喜树碱衍生物的抗体偶联药物
CN118001423A (zh) * 2024-01-12 2024-05-10 杭州爱科瑞思生物医药有限公司 亲水性抗Nectin-4抗体偶联药物及其制备方法和应用

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