WO2023061472A1 - 抗her2抗体药物偶联物和酪氨酸激酶抑制剂联合在制备治疗肿瘤的药物中的用途 - Google Patents

抗her2抗体药物偶联物和酪氨酸激酶抑制剂联合在制备治疗肿瘤的药物中的用途 Download PDF

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WO2023061472A1
WO2023061472A1 PCT/CN2022/125321 CN2022125321W WO2023061472A1 WO 2023061472 A1 WO2023061472 A1 WO 2023061472A1 CN 2022125321 W CN2022125321 W CN 2022125321W WO 2023061472 A1 WO2023061472 A1 WO 2023061472A1
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drug
antibody
formula
her2 antibody
antigen
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French (fr)
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傅强
林侃
施松
廖成
朱晓宇
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江苏恒瑞医药股份有限公司
上海盛迪医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the disclosure belongs to the field of medicine, and relates to the use of an anti-HER2 antibody-drug conjugate (antibody-drug conjugate, ADC) combined with a tyrosine kinase inhibitor in the preparation of a drug for treating tumors.
  • ADC antibody-drug conjugate
  • HER2 is a member of the type I transmembrane tyrosine kinase receptor family, which is basically inactive in the monomeric state, but can aggregate with the other three transmembrane tyrosine kinase members HER1, HER3, and HER4 in the family. Lead to the phosphorylation of receptor tyrosine residues, start a variety of signaling pathways (such as MAPK, PI3K/Akt, etc.), thereby promoting cell proliferation and tumor development.
  • signaling pathways such as MAPK, PI3K/Akt, etc.
  • the antibody in the ADC specifically recognizes and binds to the HER2 receptor on the surface of the target cell, and then enters the target cell through endocytosis, where it is decomposed to release the cytotoxic drug
  • cytotoxic drugs can induce cell apoptosis by destroying DNA or acting on tubulin, thereby exerting anti-tumor effects. If the cytotoxic drug has high membrane permeability, it may penetrate into the extracellular space after being released in the target cell and kill the surrounding HER2-negative cells. This effect is called bypass killing effect. This effect may also occur if the cytotoxic drug is released before ADC endocytosis occurs.
  • WO2020063676A discloses a class of ADCs targeting HER2.
  • TDM-1 Trastuzumab emtansine
  • DS-8201 Trastuzumab Deruxtecan
  • the present disclosure provides an anti-HER2 antibody-drug conjugate combined with a tyrosine kinase inhibitor in the preparation of a drug for treating tumors.
  • the structure of the antibody-drug conjugate is shown in formula (I):
  • n 3 to 8, and n is a decimal or an integer
  • Pc is an anti-HER2 antibody or an antigen-binding fragment thereof.
  • the anti-HER2 antibody or antigen-binding fragment thereof is selected from Trastuzumab, or an antigen-binding fragment thereof, Pertuzumab, or an antigen-binding fragment thereof.
  • the anti-HER2 antibody or antigen-binding fragment thereof is Trastuzumab or an antigen-binding fragment thereof.
  • the antibody drug conjugate has a structure as shown in the following formula:
  • n is 3 to 8, and n is a decimal or an integer.
  • n 6 in the antibody drug conjugate.
  • the tyrosine kinase inhibitor is selected from neratinib, lapatinib, afatinib, dacomitinib, tucatinib or a compound represented by formula (III) or its pharmaceutically acceptable salt,
  • the tyrosine kinase inhibitor is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.
  • the tyrosine kinase inhibitor is the dimaleate of the compound represented by formula (III).
  • the antibody drug conjugate has a structure as shown in the following formula:
  • n 3 to 8
  • n is a decimal or an integer
  • the tyrosine kinase inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • the single administration dose of the anti-HER2 antibody drug conjugate is 1.0 mg/kg-10.0 mg/kg, and the administration frequency is once a week, once every two weeks, and once every three weeks Once or every four weeks.
  • the single dose of the anti-HER2 antibody drug conjugate can be selected from 1.0 mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg, 5.8mg/kg, 6.0mg/kg, 6.2mg/kg, 6.4mg/kg, 6.6mg/kg, 6.8mg/kg, 7.0mg/kg, 7.2mg/kg, 7.4mg/kg, 7.6mg/kg, 7.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 1.0 mg/kg, and the administration frequency is once every three weeks.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 2.0 mg/kg, and the administration frequency is once every three weeks.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 3.2 mg/kg, and the administration frequency is once every three weeks.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 4.8 mg/kg, and the administration frequency is once every three weeks.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 6.4 mg/kg, and the administration frequency is once every three weeks.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 8.0 mg/kg, and the administration frequency is once every three weeks.
  • the dosage of the tyrosine kinase inhibitor is 100-1000 mg, and the frequency of administration is once a day or twice a day.
  • the dosage of the tyrosine kinase inhibitor is selected from 100mg, 120mg, 140mg, 160mg, 180mg, 200mg, 220mg, 240mg, 260mg, 280mg, 300mg, 320mg, 340mg, 360mg, 380mg, 400mg, 420mg, 440mg, 460mg, 480mg, 500mg, 520mg, 540mg, 560mg, 580mg, 600mg, 620mg, 640mg, 660mg, 680mg, 700mg, 720mg, 740mg, 760mg, 780mg, 800mg, 820mg, 840mg, 860mg, 880mg, 900mg, 920mg, 940mg, 960mg, 980mg or 1000mg, the administration frequency is once a day.
  • the dosage of the tyrosine kinase inhibitor is selected from 160 mg, 240 mg, 320 mg or 400 mg, and the dosage is once a day.
  • the dosage of the tyrosine kinase inhibitor is 400 mg, and the frequency of administration is once a day.
  • the single administration dose of the anti-HER2 antibody drug conjugate is
  • the administration frequency is once every three weeks; the administration dose of the tyrosine kinase inhibitor is 400 mg, and the administration frequency is once a day.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 2.0 mg/kg, and the administration frequency is once every three weeks; the administration of the tyrosine kinase inhibitor The dose is 400mg, and the administration frequency is once a day.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 3.2 mg/kg, and the administration frequency is once every three weeks; the administration of the tyrosine kinase inhibitor The dose is 400mg, and the administration frequency is once a day.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 4.8 mg/kg, and the administration frequency is once every three weeks; the administration of the tyrosine kinase inhibitor The dose is 400mg, and the administration frequency is once a day.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 6.4 mg/kg, and the administration frequency is once every three weeks; the administration of the tyrosine kinase inhibitor The dose is 400mg, and the administration frequency is once a day.
  • the single administration dose of the anti-HER2 antibody drug conjugate is 8.0 mg/kg, and the administration frequency is once every three weeks; the administration of the tyrosine kinase inhibitor The dose is 400mg, and the administration frequency is once a day.
  • the present disclosure also provides an anti-HER2 antibody-drug conjugate for treating tumors, the anti-HER2 antibody-drug conjugate is used in combination with a tyrosine kinase inhibitor, and the antibody-drug conjugate is represented by formula (I) as shown,
  • n 3 to 8, and n is a decimal or an integer
  • Pc is an anti-HER2 antibody or an antigen-binding fragment thereof.
  • the present disclosure also provides a tyrosine kinase inhibitor for treating tumors.
  • the tyrosine kinase inhibitor is used in combination with an anti-HER2 antibody-drug conjugate, and the antibody-drug conjugate is represented by formula (I),
  • n 3 to 8, and n is a decimal or an integer
  • Pc is an anti-HER2 antibody or an antigen-binding fragment thereof.
  • Another aspect of the present disclosure provides an anti-HER2 antibody-drug conjugate for the preparation of a drug for treating drug-resistant or refractory HER-2-expressing tumors, the antibody-drug conjugate is represented by formula (I) as shown,
  • n 3 to 8, and n is a decimal or an integer
  • Pc is an anti-HER2 antibody or an antigen-binding fragment thereof.
  • the anti-HER2 antibody or its antigen-binding fragment is selected from Trastuzumab or its antigen-binding fragment, Pertuzumab or its antigen-binding fragment.
  • the anti-HER2 antibody or antigen-binding fragment thereof is Trastuzumab or an antigen-binding fragment thereof.
  • Another aspect of the present disclosure provides a method for treating tumors by administering the anti-HER2 antibody-drug conjugate and the tyrosine kinase inhibitor to the patient.
  • the tumor described in the present disclosure is breast cancer.
  • the tumor described in the present disclosure is gastric cancer.
  • the tumor described in the present disclosure is esophagogastric junction adenocarcinoma.
  • the tumor described in the present disclosure is colorectal cancer.
  • the breast cancer described in the present disclosure is HER-2 positive breast cancer.
  • the breast cancer described in the present disclosure is advanced or metastatic HER-2 positive breast cancer.
  • the breast cancer described in the present disclosure is a breast cancer that cannot be completely removed by surgery.
  • the tumor described in the present disclosure is a drug-resistant tumor treated with an anti-HER-2 drug
  • the anti-HER-2 drug is selected from Trastuzumab, Pertuzumab , Trastuzumab emtansine (TDM-1), Trastuzumab Deruxtecan (DS-8201), neratinib, lapatinib, afatinib, dacomitinib, tucatinib, compounds represented by formula (I) or A compound represented by formula (III) or a pharmaceutically acceptable salt thereof.
  • the breast cancer described in this disclosure is drug-resistant breast cancer treated with anti-HER-2 drugs
  • the anti-HER-2 drugs are selected from Trastuzumab, Pertuzumab Monoclonal antibody, Trastuzumab emtansine (TDM-1), Trastuzumab Deruxtecan (DS-8201), neratinib, lapatinib, afatinib, dacomitinib, tucatinib, represented by formula (I)
  • the antibody drug conjugate and the tyrosine kinase inhibitor are contained as active ingredients in different formulations and administered simultaneously or at different times.
  • the combined administration route is selected from oral administration, parenteral administration, and transdermal administration, and the parenteral administration includes but not limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • the present disclosure incorporates the compound structure and preparation method in WO2020063676A in its entirety, especially related to ADC-32.
  • Antibody drug conjugate is to link an antibody or antibody fragment with a biologically active cytotoxin or a small molecule drug with cell killing activity through a stable chemical linker compound, making full use of the antibody's ability to inhibit tumors. Cell-specific or highly expressed antigen-binding specificity and high efficiency of cytotoxicity, avoiding toxic and side effects on normal cells. Compared with traditional chemotherapy drugs in the past, antibody drug conjugates can precisely bind tumor cells and reduce the impact on normal cells.
  • An antibody "retains its chemical stability" in a drug formulation if the antibody drug conjugate exhibits no significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that often alter protein chemical structure include hydrolysis or truncation (evaluated by methods such as size exclusion chromatography and CE-SDS), oxidation (by methods such as peptide mapping combined with mass spectrometry or MALDI/TOF/MS, etc. method), deamidation (evaluated by methods such as ion-exchange chromatography, capillary isoelectric focusing, peptide mapping, isoaspartic acid measurement, etc.) and isomerization (by measuring isoaspartic acid content, Peptide mapping, etc. to evaluate).
  • hydrolysis or truncation evaluationated by methods such as size exclusion chromatography and CE-SDS
  • oxidation by methods such as peptide mapping combined with mass spectrometry or MALDI/TOF/MS, etc.
  • An Antibody Drug Conjugate "retains its biological activity" in a pharmaceutical formulation if the biological activity of the Antibody Drug Conjugate at a given time is within a predetermined range of the biological activity exhibited when the pharmaceutical formulation was prepared.
  • immunoglobulin is a tetrapeptide chain structure of a complete antibody consisting of two identical heavy chains and two identical light chains connected by interchain disulfide bonds.
  • the amino acid composition and sequence of the constant region of the immunoglobulin heavy chain are different, so their antigenicity is also different.
  • immunoglobulins can be divided into five classes, or isotypes, of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE, and their corresponding heavy chains are mu, delta, and gamma chains, respectively , ⁇ chain, and ⁇ chain.
  • IgG can be divided into different subclasses according to the amino acid composition of its hinge region and the number and position of heavy chain disulfide bonds.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are classified as either kappa chains or lambda chains by difference in the constant region.
  • Each of the five Ig classes can have either a kappa chain or a lambda chain.
  • the "antibody or its antigen-binding" or “functional fragment” in the present disclosure refers to Fab fragments, Fab' fragments, F(ab')2 fragments, and antibody-binding Fv fragments scFv fragments with antigen-binding activity.
  • the Fv fragment contains the antibody heavy chain variable region and the light chain variable region, but has no constant region, and has the smallest antibody fragment with all antigen-binding sites.
  • Fv antibodies also contain a polypeptide linker between the VH and VL domains and are capable of forming the structures required for antigen binding. Different linkers can also be used to connect the variable regions of two antibodies into one polypeptide chain, called single chain antibody (single chain antibody) or single chain Fv (sFv).
  • linker unit or "connecting fragment” or “linking unit” refers to a chemical structural fragment or bond that is connected to an antibody or its antigen-binding fragment at one end and to a drug at the other end, and can also be connected to other linkers before being connected to a drug.
  • the preferred scheme of the present disclosure is expressed as L and L 1 to L 4 , wherein the end of L 1 is connected to the antibody, and the end of L 4 is connected to the structural unit Y and then connected to the compound or toxin.
  • Linkers including stretchers, spacers and amino acid units, can be synthesized by methods known in the art, such as described in US2005-0238649A1.
  • the linker can be a "cleavable linker" that facilitates release of the drug in the cell.
  • acid-labile e.g., hydrazone
  • protease-sensitive e.g., peptidase-sensitive
  • photolabile dimethyl, or disulfide-containing linkers
  • drug loading refers to the average amount of cytotoxic drugs loaded on each antibody or antigen-binding fragment thereof in the molecule of formula (I), and can also be expressed as the ratio of the amount of drug to the amount of antibody, and the range of drug loading can be
  • Each antibody or its antigen-binding fragment (Pc) is linked with 0-12, preferably 1-10, more preferably 3-8, most preferably 5.3-6.1 cytotoxic drugs (D).
  • the drug loading amount is expressed as n, which may be an exemplary average value of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • the average amount of drug product per ADC molecule after the conjugation reaction can be characterized by conventional methods such as UV/visible spectroscopy, mass spectrometry, ELISA experiments and HPLC.
  • the cytotoxic drug is coupled to the N-terminal amino group of the antibody or its antigen-binding fragment, the ⁇ -amino group of the lysine residue and/or the sulfhydryl group through the linking unit.
  • the number of drug molecules that can be conjugated to the antibody will be less than the theoretical maximum.
  • cytotoxic drugs can be controlled by the following non-limiting methods, including:
  • administering and “treating” when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid refer to the interaction of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, or subject. contact with subjects, cells, tissues, organs or biological fluids.
  • administering can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research and experimental methods.
  • Treatment of cells includes contacting the reagents with the cells, and contacting the reagents with a fluid, wherein the fluid contacts the cells.
  • administeristering” and “treating” also mean in vitro and ex vivo treatment of, for example, a cell by a reagent, diagnostic, binding composition or by another cell.
  • Treatment when applied to human, veterinary or research subjects means therapeutic treatment, prophylactic or preventive measures, research and diagnostic applications.
  • Treating means administering a therapeutic agent, internally or externally, such as a composition comprising any of the conjugated compounds of the present disclosure, to a patient having one or more symptoms of a disease for which the therapeutic agent is known to have an effect.
  • a therapeutic agent is administered in a patient or population to be treated in an amount effective to alleviate one or more symptoms of a disease, to induce regression of such symptoms or to inhibit the progression of such symptoms to any clinically measurable extent.
  • the amount of a therapeutic agent effective to alleviate the symptoms of any particular disease (also referred to as a "therapeutically effective amount”) will vary depending on factors such as the patient's disease state, age and weight, and the ability of the drug to produce the desired effect in the patient.
  • Whether disease symptoms have been alleviated can be assessed by any of the clinical tests commonly used by a physician or other professional health care practitioner to assess the severity or progression of such symptoms.
  • embodiments of the present disclosure e.g., methods of treatment or articles of manufacture
  • any statistical test known in the art such as Student's t-test, chi-square test, Mann and Whitney's The U test, Kruskal-Wallis test (H test), Jonckheere-Terpstra test and Wilcoxon test determined that it should reduce the target disease symptoms in a statistically significant number of patients.
  • an "effective amount” includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical disease.
  • An effective amount also means an amount sufficient to permit or facilitate diagnosis.
  • Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the route and dosage of administration and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • the "combination" in this disclosure is a mode of administration, which refers to the administration of at least one dose of anti-HER2 antibody drug conjugate and at least one dose of tyrosine kinase inhibitor within a certain period of time, wherein both Both drugs show pharmacological effects.
  • the time period can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours.
  • the anti-HER2 antibody drug conjugate or a pharmaceutically acceptable salt thereof and the tyrosine kinase inhibitor can be administered simultaneously or sequentially.
  • This term includes treatments wherein the anti-HER2 antibody drug conjugate and the tyrosine kinase inhibitor are administered by the same route of administration or by different routes of administration.
  • the mode of administration of the combinations described in the present disclosure is selected from simultaneous administration, separate formulation and co-administration or separate formulation and sequential administration.
  • n in the anti-HER2 antibody-drug conjugate of the present disclosure refers to the average number of cytotoxic drugs loaded on each antibody or its antigen-binding fragment in the antibody-drug conjugate molecule, and can also be expressed as the ratio of the amount of drug to the amount of antibody , is the average amount of drug per ADC molecule after conjugation reaction identified by hydrophobic chromatography (HIC) mass spectrometry.
  • HIC hydrophobic chromatography
  • the HER2-positive tumors described in the present disclosure are selected from tumors with high expression of HER2, medium expression of HER2 or low expression of HER2.
  • FIG. 3 The tumor growth curve of DS8201 in the JIMT1 model before and after DS8201 drug resistance (note: the arrow indicates the time point of DS8201 administration);
  • Trastuzumab anti-HER2 antibody
  • trastuzumab The following is the sequence of trastuzumab:
  • mice BALB/C-nude mice, SPF, 7-8 weeks old, female, were purchased from Beijing Weitong Lihua Animal Technology Co., Ltd., license number: SCXK (Beijing) 2016-0006. Animal certificate number: 1100111911040944. The mice were adapted to the laboratory environment for 10 days.
  • Human HER2-positive breast cancer PDX model BC#197 was provided by Jingdi Biomedical Technology Co., Ltd. The tumors used were passage 6 of this model.
  • TDM-1 provided by Jiangsu Hengrui Medicine Co., Ltd.
  • ADC-32 batch number P1919, provided by Jiangsu Hengrui Medicine Co., Ltd.
  • V tumor volume
  • T/C (%) (TT 0 )/(CC 0 ) ⁇ 100, wherein T, C are the tumor volumes of the treatment group and the control group at the end of the experiment; T 0 , C 0 are the tumor volumes at the beginning of the experiment tumor volume.
  • Tumor inhibition rate TGI(%) 100-T/C(%).
  • mice BALB/C-nude mice, SPF, 6-7 weeks old, female, were purchased from the Experimental Animal Management Department of Shanghai Institute of Family Planning.
  • Human breast cancer cell JIMT-1 was provided by Shanghai Hengrui. After Balb/c-nude mice were subcutaneously inoculated into tumors, 10 mg/kg DS8201 was intravenously injected every 2 to 3 weeks, and the tumor volume grew to 2000-2500 mm 3 before being transferred to a new batch of mice. After continuous administration in this way for about 6 months, spread to the third batch of mice. After the tumor inhibition rate of 10 mg/kg DS8201 was ⁇ 25%, it was considered that the tumor model had become resistant to DS8201.
  • the drug effect of 10mg/kg DS8201 in the JIMT1 model before drug resistance (first generation) and after drug resistance (third generation) is shown in Figure 3.
  • ADC-32 was provided by Jiangsu Hengrui Medicine Co., Ltd.
  • ADC-32 was diluted with PBS to 20mg/mL mother solution, subpackaged and stored in a -80°C refrigerator, diluted with PBS to 0.3mg/mL solution before administration, and the dosage was 3mg/kg, once every three weeks, intraperitoneal injection Volume 10mL/kg.
  • Pyrotinib is configured into a 2.5mg/ml clear solution with pure water, and the dosage is 25mg/kg, administered every day, and the oral gavage volume is 10ml/kg.
  • Vehicle is PBS, once every three weeks, intraperitoneal injection volume 10mL/kg.
  • the JIMT1 tumor tissue that had been previously inoculated into Balb/c-nude mice was inoculated subcutaneously in the right flank of 122 Balb/c-nude mice at a volume of about 40 mm3. After the tumor volume grew to about 120-170 mm3 , excess body weight Mice with heavy or light tumors, too large or too small tumors were randomly divided into 4 groups with similar average volumes according to tumor volume, the first batch had 3 mice in each group, and the second batch had 4 mice in each group, as shown in Table 1. Show. On the day of grouping, the administration started on day0. The tumor volume and body weight of the mice were measured twice a week, and the data were recorded. The grouping and drug administration are shown in Table 3.
  • V tumor volume
  • T/C (%) (TT 0 )/(CC 0 ) ⁇ 100, wherein T, C are the tumor volumes of the treatment group and the control group at the end of the experiment; T 0 , C 0 are the tumor volumes at the beginning of the experiment tumor volume.
  • Tumor inhibition rate TGI(%) 100-T/C(%).
  • Example 4 An open, multi-center phase Ib/II clinical study of ADC-32 combined with pyrotinib in the treatment of HER2-positive unresectable or metastatic breast cancer.
  • This study is a multi-center, open-label, dose-finding and efficacy-expanding phase Ib/II study.
  • the first stage is the dose exploration stage, using a 3+3 method of climbing; the second stage is the efficacy expansion stage, using random grouping.
  • the dose exploration phase aims to evaluate the safety, tolerability, pharmacokinetic characteristics and immunogenicity of ADC-32 combined with pyrotinib, and to initially observe its anti-tumor efficacy.
  • the dosage of ADC-32 is 2.0mg/kg, 3.2mg/kg, 4.8mg/kg, intravenous infusion, once every 3 weeks, every 3 weeks (21 days) as a cycle; the administration of pyrotinib
  • the dosage is 240mg, 320mg, 400mg, orally, once a day, every 3 weeks as a cycle.
  • a 3+3 dose-finding approach will be used for tolerance observation until dose-limiting toxicity (DLT) occurs in ⁇ 2 subjects among 3-6 subjects.
  • DLT dose-limiting toxicity
  • the second stage (curative effect expansion stage)
  • the efficacy expansion stage aims to observe and evaluate the preliminary efficacy, safety, pharmacokinetic characteristics and immunogenicity of ADC-32 combined with pyrotinib.
  • ADC-32 combined with pyrotinib completed the first phase of dose exploration, 2 to 3 dose groups were selected for efficacy expansion. The qualified subjects were randomly divided into ADC-32 combined with pyrotinib (dose group A), ADC-32 combined with pyrotinib (dose group B), ADC-32 combined with pyrotinib (dose group C) and ADC-32 combined with pyrotinib (dose group C). 32 single drugs (4.8mg/kg).
  • HER2-positive (IHC3+ or ISH+) unresectable or metastatic breast cancer confirmed by histology or cytology.
  • ⁇ Phase I dose-finding: patients who have received trastuzumab and at least one line of chemotherapy in the relapse/metastasis stage.

Abstract

抗HER2抗体药物偶联物和酪氨酸激酶抑制剂联合在制备治疗肿瘤的药物中的用途。具体而言，抗HER2抗体药物偶联物的结构如式(I)所示。

Description

抗HER2抗体药物偶联物和酪氨酸激酶抑制剂联合在制备治疗肿瘤的药物中的用途 技术领域
本公开属于医药领域，涉及抗HER2抗体抗体药物偶联物(antibody-drug conjugate，ADC)联合酪氨酸激酶抑制剂在制备治疗肿瘤的药物中的用途。
背景技术
HER2是I型跨膜酪氨酸激酶受体家族的一员，其在单体状态下基本无活性，但可与家族其他3个跨膜酪氨酸激酶成员HER1、HER3、HER4发生聚合作用，导致受体酪氨酸残基的磷酸化、启动多种信号通路(如MAPK、PI3K/Akt等)，从而促进细胞增殖和肿瘤发生发展。
以HER2为靶点的ADCs通过以下方式发挥作用，首先，ADC中的抗体特异性识别并结合靶细胞表面的HER2受体，然后通过内吞作用进入靶细胞，在胞内经分解释放出细胞毒药物，最后细胞毒药物通过破坏DNA或者作用于微管蛋白，诱导细胞的凋亡，从而发挥抗肿瘤作用。若细胞毒药物具有高透膜性，其在靶细胞内被释放后或可穿透至细胞外间隙，杀伤周围的HER2阴性细胞，该作用即被称为旁路杀伤效应。若细胞毒药物在ADC内吞发生之前被释放，也可能产生该效应。WO2020063676A公开了一类以HER2为靶点的ADCs，鉴于已经获批上市的HER-2ADC药物Trastuzumab emtansine(TDM-1)及Trastuzumab Deruxtecan(DS-8201)在乳腺癌、胃癌治疗方面的优异效果，对WO2020063676A中的抗体药物偶联物进行适应症方面的研究具有重大意义。
发明内容
本公开提供一种抗HER2抗体药物偶联物和酪氨酸激酶抑制剂联合在制备治疗肿瘤的药物中的用途，所述抗体药物偶联物的结构如式(I)所示：
Figure PCTCN2022125321-appb-000001
其中：
n为3至8，n是小数或整数；
Pc为抗HER2抗体或其抗原结合片段。
一些实施方案中，所述抗HER2抗体或其抗原结合片段选自Trastuzumab，或其抗原结合片段，Pertuzumab或其抗原结合片段。
一些实施方案中，所述抗HER2抗体或其抗原结合片段为Trastuzumab或其抗原结合片段。
一些实施方案中，所述的抗体药物偶联物具有如下式所示的结构：
Figure PCTCN2022125321-appb-000002
其中，n为3至8，n是小数或整数。
可选的实施方案中，所述的抗体药物偶联物中n为6。
可选的实施方案中，所述酪氨酸激酶抑制剂选自奈拉替尼、拉帕替尼、阿法替尼、达可替尼、图卡替尼或式(III)所示化合物或其药学上可接受的盐，
Figure PCTCN2022125321-appb-000003
可选的实施方案中，所述酪氨酸激酶抑制剂为式(III)所示化合物或其药学上可接受的盐。
可选的实施方案中，所述酪氨酸激酶抑制剂为式(III)所示化合物的二马来酸盐。
可选的实施方案中，本公开提供的用途中，所述的抗体药物偶联物具有如下式所示的结构：
Figure PCTCN2022125321-appb-000004
其中，n为3至8，n是小数或整数；所述的酪氨酸激酶抑制剂为式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2022125321-appb-000005
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为1.0mg/kg-10.0mg/kg，给药频次为每一周一次，每二周一次，每三周一次或每四周一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量可选1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg或10.0mg/kg，给药频次为每三周一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为1.0mg/kg，给药频次为每三周一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为2.0mg/kg，给药频次为每三周一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为3.2mg/kg，给药频次为每三周一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为4.8mg/kg，给药频次为每三周一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为6.4mg/kg，给药频次为每三周一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为8.0mg/kg，给药频次为每三周一次。
可选的实施方案中，所述的酪氨酸激酶抑制剂的给药剂量为100-1000mg给药频次为一日一次或一日二次。
可选的实施方案中，所述的酪氨酸激酶抑制剂的给药剂量选自100mg、120mg、140mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、320mg、340mg、360mg、380mg、400mg、420mg、440mg、460mg、480mg、500mg、520mg、540mg、560mg、580mg、600mg、620mg、640mg、660mg、680mg、700mg、720mg、740mg、760mg、780mg、800mg、820mg、840mg、860mg、880mg、900mg、920mg、940mg、960mg、980mg或1000mg，给药频次为一日一次。
可选的实施方案中，所述的酪氨酸激酶抑制剂的给药剂量选自160mg、240mg、320mg或400mg，给药频次为一日一次。
可选的实施方案中，所述的酪氨酸激酶抑制剂的给药剂量为400mg，给药频次为一日一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为
1.0mg/kg，给药频次为每三周一次；所述的酪氨酸激酶抑制剂的给药剂量为400mg，给药频次为一日一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为2.0mg/kg，给药频次为每三周一次；所述的酪氨酸激酶抑制剂的给药剂量为400mg，给药频次为一日一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为3.2mg/kg，给药频次为每三周一次；所述的酪氨酸激酶抑制剂的给药剂量为400mg，给药频次为一日一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为4.8mg/kg，给药频次为每三周一次；所述的酪氨酸激酶抑制剂的给药剂量为400mg，给药频次为一日一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为6.4mg/kg，给药频次为每三周一次；所述的酪氨酸激酶抑制剂的给药剂量为400mg，给药频次为一日一次。
可选的实施方案中，所述的抗HER2抗体药物偶联物的单次给药剂量为8.0mg/kg，给药频次为每三周一次；所述的酪氨酸激酶抑制剂的给药剂量为400mg，给药频次为一日一次。
本公开还提供一种用于治疗肿瘤的抗HER2抗体药物偶联物，所述抗HER2抗体药物偶联物与酪氨酸激酶抑制剂联合使用，所述抗体药物偶联物如式(I) 所示，
Figure PCTCN2022125321-appb-000006
其中：
n为3至8，n是小数或整数；
Pc为抗HER2抗体或其抗原结合片段。
本公开还提供一种用于治疗肿瘤的酪氨酸激酶抑制，所述酪氨酸激酶抑制与抗HER2抗体药物偶联物联合使用，所述抗体药物偶联物如式(I)所示，
Figure PCTCN2022125321-appb-000007
其中：
n为3至8，n是小数或整数；
Pc为抗HER2抗体或其抗原结合片段。
本公开另一方面提供一种抗HER2抗体药物偶联物用于制备治疗耐药或难治性的HER-2表达的肿瘤的药物中的用途，所述抗体药物偶联物如式(I)所示，
Figure PCTCN2022125321-appb-000008
其中：
n为3至8，n是小数或整数；
Pc为抗HER2抗体或其抗原结合片段。
可选的实施方案中，所述的抗HER2抗体或其抗原结合片段选自Trastuzumab或其抗原结合片段、Pertuzumab或其抗原结合片段。
可选的实施方案中，所述的抗HER2抗体或其抗原结合片段为Trastuzumab或其抗原结合片段。
本公开另一方面提供一种治疗肿瘤的方法，给与患者上述抗HER2抗体药物偶联物及酪氨酸激酶抑制剂。
可选的实施方案中，本公开中所述的肿瘤为乳腺癌。
可选的实施方案中，本公开中所述的肿瘤为胃癌。
可选的实施方案中，本公开中所述的肿瘤为食管胃交界腺癌。
可选的实施方案中，本公开中所述的肿瘤为结直肠癌。
可选的实施方案中，本公开中所述的乳腺癌为HER-2阳性的乳腺癌。
可选的实施方案中，本公开中所述的乳腺癌为为晚期或者转移性HER-2阳性乳腺癌。
可选的实施方案中，本公开中所述的乳腺癌为无法无法通过手术完全切除的乳腺癌。
可选的实施方案中，本公开中所述的肿瘤为经抗HER-2的药物治疗后耐药的肿瘤，所述抗HER-2的药物选自曲妥珠单抗、帕妥珠单抗、Trastuzumab emtansine(TDM-1)、Trastuzumab Deruxtecan(DS-8201)、奈拉替尼、拉帕替尼、阿法替尼、达可替尼、图卡替尼、式(I)所示化合物或式(III)所示化合物或其药学上可接受的盐。
可选的实施方案中，本公开中所述的乳腺癌为经抗HER-2的药物治疗后耐药的乳腺癌，所述抗HER-2的药物选自曲妥珠单抗、帕妥珠单抗、Trastuzumab emtansine(TDM-1)、Trastuzumab Deruxtecan(DS-8201)、奈拉替尼、拉帕替尼、阿法替尼、达可替尼、图卡替尼、式(I)所示化合物或式(III)所示化合物或其药学上可接受的盐。
一些实施方案中，所述抗体药物偶联物和酪氨酸激酶抑制剂作为活性成分包含在不同制剂中，并且同时或在不同时间施用。
一些实施方案中，所述联合的给药途径选自经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
本公开全文引入WO2020063676A中化合物结构和制备方法，特别是ADC-32相关的。
如本领域技术人员所熟知的，本公开中所述各个实施方案的一项、一些或所有特性可以进一步组合以形成本公开的其它实施方案。本公开的以上实施方案和 通过组合得到的其他实施方案通过下面的详述进一步说明。
术语
为了更容易理解本公开，以下具体定义了某些技术和科学术语。除非在本文中另有明确定义，本文使用的所有其它技术和科学术语都具有本公开所属领域的一般技术人员通常理解的含义。
本公开将申请WO2020063676A中的全部内容引入本申请。
“抗体药物偶联物(antibody drug conjugate，ADC)”是把抗体或者抗体片段通过稳定的化学接头化合物与具有生物活性的细胞毒素或具有细胞杀伤活性的小分子药物相连，充分利用了抗体对肿瘤细胞特异或高表达抗原结合的特异性和细胞毒素的高效性，避免对正常细胞的毒副作用。与以往传统的化疗药物相比，抗体药物偶联物能精准地结合肿瘤细胞并降低将对正常细胞的影响。
如果抗体药物偶联物没有显示出显著的化学改变，那么所述抗体在药物制剂中“保留它的化学稳定性”。通过检测和定量化学上改变的形式的蛋白，可以评估化学稳定性。经常改变蛋白化学结构的降解过程包括水解或截短(通过诸如尺寸排阻色谱法和CE-SDS等方法来评价)、氧化(通过诸如与质谱法或MALDI/TOF/MS结合的肽谱法等方法来评价)、脱酰胺作用(通过诸如离子交换色谱法、毛细管等电聚焦、肽谱法、异天冬氨酸测量等方法来评价)和异构化(通过测量异天冬氨酸含量、肽谱法等来评价)。
如果抗体药物偶联物在给定时间的生物活性是在制备药物制剂时表现出的生物活性的预定范围内，那么所述抗体药物偶联物在药物制剂中“保留它的生物活性”。
本公开所述的“抗体”指免疫球蛋白，是完整抗体由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同，故其抗原性也不同。据此，可将免疫球蛋白分为五类，或称为免疫球蛋白的同种型，即IgM、IgD、IgG、IgA和IgE，其相应的重链分别为μ链、δ链、γ链、α链、和ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别，又可分为不同的亚类，如IgG可分为IgG1、IgG2、IgG3、IgG4。轻链通过恒定区的不同分为κ链或λ链。五类Ig中每类Ig都可以有κ链或λ链。
本公开中所述的“抗体或其抗原结合”或“功能片段”，指具有抗原结合活性的Fab片段，Fab’片段，F(ab’)2片段，以及与抗体结合的Fv片段scFv片段。Fv片段含有抗体重链可变区和轻链可变区，但没有恒定区，并具有全部抗原结合位点的最小抗体片段。一般地，Fv抗体还包含在VH和VL结构域之间的多肽接头，且能够形成抗原结合所需的结构。也可以用不同的连接物将两个抗体可变区连接成一条多肽链，称为单链抗体(single chain antibody)或单链Fv (sFv)。
术语“接头单元”或“连接片段”或“连接单元”是指一端与抗体或其抗原结合片段连接而另一端与药物相连的化学结构片段或键，也可以连接其他接头后再与药物相连。本公开的优选方案表示为L和L 1至L 4，其中L 1端与抗体相连，L 4端与结构单元Y相连后与化合物或毒素相连。
接头，包括延伸物、间隔物和氨基酸单元，可以通过本领域已知方法合成，诸如US2005-0238649A1中所记载的。接头可以是便于在细胞中释放药物的“可切割接头”。例如，可使用酸不稳定接头(例如腙)、蛋白酶敏感(例如肽酶敏感)接头、光不稳定接头、二甲基接头、或含二硫化物接头(Chari等,Cancer Research 52:127-131(1992)；美国专利No.5,208,020)。
术语“载药量”是指式(I)分子中每个抗体或其抗原结合片段上加载的细胞毒性药物平均数量，也可以表示为药物量和抗体量的比值，药物载量的范围可以是每个抗体或其抗原结合片段(Pc)连接0-12个，优选1-10个，更优选3-8个，最优选5.3-6.1个细胞毒性药物(D)。在本公开的实施方式中，载药量表示为n，示例性的可以为1，2，3，4，5，6，7，8，9，10的均值。可用常规方法如UV/可见光光谱法，质谱，ELISA实验和HPLC特征鉴定偶联反应后每个ADC分子的药物品均数量。
本公开的一个实施方式中，细胞毒性药物通过连接单元偶联在抗体或其抗原结合片段的N端氨基、赖氨酸残基的ε-氨基和/或巯基上，一般地，偶联反应中能与抗体偶联的药物分子数将小于理论上的最大值。
可以用以下非限制性方法控制细胞毒性药物的载量，包括：
(1)控制连接试剂和单抗的摩尔比，
(2)控制反应时间和温度，
(3)选择不同的反应试剂。
常规的药物组合物的制备见中国药典。
“给予”和“处理”当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时，是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。“给予”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触，以及试剂与流体的接触，其中所述流体与细胞接触。“给予”和“处理”还意指通过试剂、诊断、结合组合物或通过另一种细胞体外和离体处理例如细胞。“处理”当应用于人、兽医学或研究受试者时，是指治疗处理、预防或预防性措施，研究和诊断应用。
“治疗”意指给予患者内用或外用治疗剂，例如包含本公开的任一种结合化合物的组合物，所述患者具有一种或多种疾病症状，而已知所述治疗剂对这些症 状具有治疗作用。通常，在受治疗患者或群体中以有效缓解一种或多种疾病症状的量给予治疗剂，以诱导这类症状退化或抑制这类症状发展到任何临床可测量的程度。有效缓解任何具体疾病症状的治疗剂的量(也称作“治疗有效量”)可根据多种因素变化，例如患者的疾病状态、年龄和体重，以及药物在患者产生需要疗效的能力。通过医生或其它专业卫生保健人士通常用于评价该症状的严重性或进展状况的任何临床检测方法，可评价疾病症状是否已被减轻。尽管本公开的实施方案(例如治疗方法或制品)在缓解每个目标疾病症状方面可能无效，但是根据本领域已知的任何统计学检验方法如Student t检验、卡方检验、依据Mann和Whitney的U检验、Kruskal-Wallis检验(H检验)、Jonckheere-Terpstra检验和Wilcoxon检验确定，其在统计学显著数目的患者中应当减轻目标疾病症状。
“有效量”包含足以改善或预防医学疾病的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：例如，待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
本公开所述的“联合”是一种给药方式，是指一定时间期限内给予至少一种剂量的抗HER2抗体药物偶联物，以及至少一种剂量的酪氨酸激酶抑制剂，其中两种药物都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内，更优选12小时以内。可以同时或依次给予抗HER2抗体药物偶联物或其可药用盐和酪氨酸激酶抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予抗HER2抗体药物偶联物和酪氨酸激酶抑制剂。本公开所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
本公开抗HER2抗体药物偶联物中“n”是指抗体药物偶联物分子中每个抗体或其抗原结合片段上加载的细胞毒性药物平均数量，也可以表示为药物量和抗体量的比值，为经疏水色谱法(HIC)质谱鉴定偶联反应后每个ADC分子的药物平均数量。
本公开中所述HER2阳性的肿瘤选自HER2高表达、HER2中表达或HER2低表达肿瘤。
附图说明
图1.各组鼠在BC#197模型中的肿瘤生长曲线
图2.各组小鼠在BC#197模型中的肿瘤生长曲线
图3.DS8201在DS8201耐药前及耐药后JIMT1模型中的肿瘤生长曲线(注：箭头指示为DS8201给药时间点)；
图4.各组小鼠在JIMT1模型中的肿瘤生长曲线；
图5.各组小鼠在JIMT1模型中的体重变化曲线。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非是对本公开范围的限制。本公开实施例中未注明具体条件的实验方法，通常按照常规条件，如参照冷泉港实验室出版的《抗体技术实验手册》，《分子克隆手册》；或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1：抗HER2抗体-药物缀合物的制备
根据WO2021190581A中描述的生产方法，使用了Trastuzumab(抗HER2抗体)与依喜替康类似物制备如下结构所示的抗HER2抗体-药物偶合物，HIC方法计算平均值：n＝6.0，即ADC-32。
Figure PCTCN2022125321-appb-000009
以下为Trastuzumab的序列：
轻链
Figure PCTCN2022125321-appb-000010
重链
Figure PCTCN2022125321-appb-000011
Figure PCTCN2022125321-appb-000012
实施例2.在乳腺癌BC#197模型BALB/C nude小鼠体内药效学研究
1、实验材料
1)实验动物
BALB/C-nude小鼠，SPF,7-8周，雌性，购自北京维通利华动物技术有限公司，许可证号：SCXK(京)2016-0006。动物合格证编号：1100111911040944。小鼠实验室环境适应10天。
2)肿瘤
人HER2阳性乳腺癌PDX模型BC#197由精迪生物医药技术有限公司提供。所用肿瘤为该模型的第6代。
2)实验药物
TDM-1，由江苏恒瑞医药股份有限公司提供；ADC-32，批号P1919，由江苏恒瑞医药股份有限公司提供。
DS-8201，江苏恒瑞医药股份有限公司提供。
2、实验方法及步骤
1)药物配置
TDM-1储存于3-5℃，使用前用生理盐水配置成2mg/ml的均匀溶液。给药体积为5ml/kg。
DS8201储存于3-5℃，使用前用生理盐水配置成0.6mg/ml的均匀溶液。给药体积为5ml/kg。
ADC-32储存于3-5℃，使用前用生理盐水配置成0.6mg/ml的均匀溶液。给药体积为5ml/kg。
2)肿瘤移植
取若干600-800mm 3大小的BC#197肿瘤，除去坏死组织及结缔组织，将其切成大小为15-30mm 3的肿瘤组织块。接种于64只Balb/c-nude鼠右肋部皮下，移植36天后，选取32只肿瘤体积为141-267mm 3的小鼠，将动物进行随机分组，使各组肿瘤体积差异小于均值的5％，每组各8只，共4组。分组当天记为0天，按表1给药。每周测两次小鼠瘤体积和体重，并记录数据。
表1.药效实验给药和治疗
组别 药物 N 剂量 给药途径 给药日程
G1 Vehicle 8   i.p Once
G2 TDM-1 8 10mg/kg i.p Once
G3 ADC-32 8 3mg/kg i.p Once
G4 DS-8201 8 3mg/kg i.p Once
备注：i.p.腹腔注射；N动物只数；给药体积为10μL/g
3)数据统计
使用Excel统计软件记录数据：平均值以avg计算；SD值以STDEV计算；SEM值以STDEV/SQRT(每组动物数)计算；采用GraphPad Prism软件作图，采用Two-way ANOVA、One-way ANOVA、t-test对数据进行统计学分析。
肿瘤体积(V)计算公式为：V＝1/2×L 长×L 短 2
相对肿瘤增殖率T/C(％)＝(T-T 0)/(C-C 0)×100，其中T、C为实验结束时治疗组和对照组的肿瘤体积；T 0、C 0为实验开始时的肿瘤体积。
抑瘤率TGI(％)＝100-T/C(％)。
3、实验结果及结论：
不同组对BC#197肿瘤的生长抑制作用如表2和图1、图2所示。
表2
Figure PCTCN2022125321-appb-000013
注:a.平均值±SEM；
b.肿瘤生长抑制由T/C(T/C(％)＝(T 30-T 0)/(C 30-C 0)×100)和TGI(TGI(％)＝100-T/C(％))计算；
c.p值：第1组Vs第2组p value＝0.000131，第1组Vs第3组p value＝0.044271，第1组Vs第4组p value＝0.000268，第2组Vs第4组p value＝0.591768，第3组Vs第4组p value＝0.072657；
本实验结果表明TDM-1(10mg/kg)对于BC#197没有显著抑制肿瘤生长作用，表明该模型对TDM1耐药；而单次注射DS8201(3mg/kg)及ADC-32(3mg/kg)给药组对BC#197肿瘤生长均有明显抑制作用。所有小鼠在实验过程中对测试药物均有很好的耐受性。
实施例3.在乳腺癌JIMT1模型BALB/C nude小鼠体内药效学研究
1、实验材料
1)实验动物
BALB/C-nude小鼠，SPF，6-7周，雌性，购自上海市计划生育科学研究所 实验动物经营部。
2)肿瘤
人乳腺癌细胞JIMT-1由上海恒瑞提供。在Balb/c-nude小鼠皮下接种成瘤后，静脉注射10mg/kg DS8201、每2至3周给药一次，且肿瘤体积生长至2000-2500mm 3后进行转接至新一批小鼠。如此连续给药约6个月，传至第三批小鼠，待10mg/kg DS8201的抑瘤率<25％后，认为该肿瘤模型已对DS8201耐药。10mg/kg DS8201在耐药前(第一代)及耐药后(第三代)JIMT1模型中的药效见图3。
2)实验药物
ADC-32，由江苏恒瑞医药股份有限公司提供。
式(III)所示化合物二马来酸盐(吡咯替尼)，由江苏恒瑞医药股份有限公司提供。
2、实验方法及步骤
1)药物配置
ADC-32用PBS稀释成20mg/mL的母液，分装存放于-80℃冰箱，给药前用PBS稀释成0.3mg/mL溶液，给药剂量为3mg/kg，每三周一次，腹腔注射体积10mL/kg。
吡咯替尼用纯水配置成2.5mg/ml澄清溶液，给药剂量为25mg/kg,每天给药，口服灌胃体积10ml/kg。
Vehicle为PBS，每三周一次，腹腔注射体积10mL/kg。
2)肿瘤移植
将此前在Balb/c-nude小鼠中接种成瘤的JIMT1肿瘤组织按照约40mm3接种于122只Balb/c-nude鼠右肋部皮下，待肿瘤体积长至约120～170mm 3后去除体重过重或过轻、肿瘤过大或过小的小鼠，按肿瘤体积将肿瘤随机分为平均体积相近的4组，第一批每组3只，第二批每组4只，如表1所示。分组当天为day0开始给药。每周测两次小鼠瘤体积和体重，并记录数据。分组及给药情况见表3。
表3.药效实验给药和治疗
Figure PCTCN2022125321-appb-000014
备注：Q2W每周两次；QD每日一次；P.O.灌胃给药；N动物只数；给药体积为10μL/g
3)数据统计
使用Excel统计软件记录数据：平均值以avg计算；SD值以STDEV计算；SEM值以STDEV/SQRT(每组动物数)计算；采用GraphPad Prism软件作图，采用Two-way ANOVA、One-way ANOVA、t-test对数据进行统计学分析。
肿瘤体积(V)计算公式为：V＝1/2×L 长×L 短 2
相对肿瘤增殖率T/C(％)＝(T-T 0)/(C-C 0)×100，其中T、C为实验结束时治疗组和对照组的肿瘤体积；T 0、C 0为实验开始时的肿瘤体积。
抑瘤率TGI(％)＝100-T/C(％)。
3、实验结果及结论：
不同组对JIMT1肿瘤的生长抑制作用如表4和图4、图5所示。
表4
Figure PCTCN2022125321-appb-000015
注:a.平均值±SEM；
b.肿瘤生长抑制由T/C(T/C(％)＝(T 30-T 0)/(C 30-C 0)×100)和TGI(TGI(％)＝100-T/C(％))计算；
c.p值：第1组Vs第2组p value＝0.000131，第1组Vs第3组p value＝0.044271，第1组Vs第4组p value＝0.000268，第2组Vs第4组p value＝0.591768，第3组Vs第4组p value＝0.072657；
本实验中，ADC-32+吡咯替尼联用均显示出比两者单药更强的肿瘤抑制效果。给药过程中，与分组Day0时相比，Vehicle组小鼠体重没有明显变化，提示目前所使用的溶剂没有明显的毒性作用。ADC-32单药组、吡咯替尼单药组、联用组小鼠体重均没有明显变化，这表明两药在当前剂量下单用及联用没有明显的毒性作用(图5)。
实施例4.ADC-32联合吡咯替尼治疗HER2阳性不可切除或转移性乳腺癌的开放、多中心Ⅰb/Ⅱ期临床研究。
研究设计：
本研究是一项多中心、开放、剂量探索及疗效拓展的Ib/II期研究。第一阶段为剂量探索阶段，采用3+3方式爬坡；第二阶段为疗效拓展阶段，采用随机分组。
第一阶段(剂量探索阶段)
剂量探索阶段旨在评价ADC-32联合吡咯替尼的安全性、耐受性、药代动力学特征和免疫原性，并初步观察其抗肿瘤疗效。
ADC-32联合吡咯替尼：
ADC-32的给药剂量为2.0mg/kg、3.2mg/kg、4.8mg/kg，静脉滴注，每3周给药一次，每3周(21天)为一个周期；吡咯替尼的给药剂量为240mg、320mg、400mg，口服，每天1次，每3周为一个周期。
将采用3+3剂量探索方式进行耐受性观察，直至观察到3～6例受试者中有≥2例受试者发生剂量限制性毒性(DLT)。
第二阶段(疗效拓展阶段)
疗效拓展阶段旨在观察和评价ADC-32联合吡咯替尼的初步有效性、安全性、药代动力学特征和免疫原性。
ADC-32联合吡咯替尼完成第一阶段剂量探索后，选择2～3个剂量组进行疗效拓展。筛选合格的受试者随机分为ADC-32联合吡咯替尼(剂量组A)、ADC-32联合吡咯替尼(剂量组B)、ADC-32联合吡咯替尼(剂量组C)和ADC-32单药(4.8mg/kg)。
入组标准：
1.18岁至75岁(含两端值)的女性。
2.经组织学或细胞学证实的HER2阳性(IHC3+或ISH+)不可切除或转移性乳腺癌。
3.复发转移阶段既往治疗如下：
●第一阶段(剂量探索)：复发/转移阶段接受过曲妥珠单抗及至少1线化疗。
●第二阶段(疗效拓展)：复发/转移阶段未接受过系统性抗肿瘤治疗(可接受≤1线内分泌治疗)。

Claims (17)

  1. 抗HER2抗体药物偶联物和酪氨酸激酶抑制剂联合在制备治疗肿瘤的药物中的用途，所述抗体药物偶联物的结构如式(I)所示：
    Figure PCTCN2022125321-appb-100001
    其中：
    n为3至8，n是小数或整数；
    Pc为抗HER2抗体或其抗原结合片段。
  2. 根据权利要求1所述的用途，所述的抗HER2抗体或其抗原结合片段选自Trastuzumab、Pertuzumab，或其抗原结合片段；优选为Trastuzumab或其抗原结合片段。
  3. 根据权利要求2所述的用途，所述的抗体药物偶联物具有如下式所示的结构：
    Figure PCTCN2022125321-appb-100002
    其中，n为3至8，n是小数或整数。
  4. 根据权利要求1-3任一项所述的用途，其中所述酪氨酸激酶抑制剂选自奈拉替尼、拉帕替尼、阿法替尼、达可替尼、图卡替尼或式(III)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022125321-appb-100003
    优选式(III)所示化合物或其药学上可接受的盐，最优选式(III)所示化合物的二马来酸盐。
  5. 根据权利要求1-4任一项所述的用途，所述的抗体药物偶联物具有如下式所示的结构：
    Figure PCTCN2022125321-appb-100004
    其中，n为3至8，n是小数或整数；所述的酪氨酸激酶抑制剂为式(III)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022125321-appb-100005
  6. 根据权利要求1-5任一项所述的用途，所述的肿瘤选自乳腺癌、胃癌、食管胃交界腺癌或结直肠癌，优选乳腺癌。
  7. 根据权利要求6所述的用途，所述的乳腺癌为HER-2阳性的乳腺癌。
  8. 根据权利要求7所述的用途，所述的乳腺癌为晚期或者转移性HER-2阳性乳腺癌。
  9. 根据权利要求6所述的用途，所述的肿瘤为经抗HER-2的药物治疗后耐药的肿瘤，所述抗HER-2的药物选自曲妥珠单抗、帕妥珠单抗、Trastuzumab emtansine(TDM-1)、Trastuzumab Deruxtecan(DS-8201)、奈拉替尼、拉帕替尼、阿法替尼、达可替尼、图卡替尼、式(I)所示化合物或式(III)所示化合物或其药学上可接受的盐中的一种或多种。
  10. 根据权利要求1-9任一项所述的用途，所述抗HER2抗体药物偶联物的单次给药剂量为1.0mg/kg-10.0mg/kg，优选1.0mg/kg、2.0mg/kg、3.2mg/kg、4.8mg/kg、6.4mg/kg或8.0mg/kg，给药频次为每一周一次，每二周一次，每三周一次或每四周一次。
  11. 根据权利要求1-10任一项所述的用途，所述的酪氨酸激酶抑制剂的给药剂量为100-1000mg，优选160mg、240mg、320mg或400mg，给药频次为一日一次或一日二次。
  12. 一种用于治疗肿瘤的抗HER2抗体药物偶联物，所述抗HER2抗体药物偶联物与酪氨酸激酶抑制剂联合使用，所述抗体药物偶联物如式(I)所示，
    Figure PCTCN2022125321-appb-100006
    其中：
    n为3至8，n是小数或整数；
    Pc为抗HER2抗体或其抗原结合片段。
  13. 一种用于治疗肿瘤的酪氨酸激酶抑制，所述酪氨酸激酶抑制与抗HER2抗体药物偶联物联合使用，所述抗体药物偶联物如式(I)所示，
    Figure PCTCN2022125321-appb-100007
    其中：
    n为3至8，n是小数或整数；
    Pc为抗HER2抗体或其抗原结合片段。
  14. 抗HER2抗体药物偶联物用于制备治疗耐药或难治性的HER-2表达的肿瘤的药物中的用途，所述抗体药物偶联物如式(I)所示，
    Figure PCTCN2022125321-appb-100008
    其中：
    n为3至8，n是小数或整数；
    Pc为抗HER2抗体或其抗原结合片段，优选Trastuzumab、Pertuzumab或其抗原结合片段；最优选Trastuzumab或其抗原结合片段。
  15. 根据权利要14所述的用途，所述的肿瘤为乳腺癌、胃癌、食管胃交界腺癌或结直肠癌，优选乳腺癌。
  16. 根据权利要求14所述的用途，所述的耐药或难治性的HER-2表达的肿瘤为经过选自曲妥珠单抗、帕妥珠单抗、Trastuzumab emtansine(TDM-1)、Trastuzumab Deruxtecan(DS-8201)、奈拉替尼、拉帕替尼、阿法替尼、达可替尼、图卡替尼、式(I)所示化合物或式(II)所示化合物或其药学上可接受的盐的一种或多种治疗后耐药的肿瘤。
  17. 根据权利要求14所述的用途，所述的耐药或难治性的HER-2表达的肿瘤为经过Trastuzumab emtansine(TDM-1)治疗后耐药的乳腺癌。
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