WO2022228497A1 - 药物在治疗肿瘤疾病中的应用 - Google Patents

药物在治疗肿瘤疾病中的应用 Download PDF

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Publication number
WO2022228497A1
WO2022228497A1 PCT/CN2022/089737 CN2022089737W WO2022228497A1 WO 2022228497 A1 WO2022228497 A1 WO 2022228497A1 CN 2022089737 W CN2022089737 W CN 2022089737W WO 2022228497 A1 WO2022228497 A1 WO 2022228497A1
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Prior art keywords
cancer
tumor
conjugate
pancreatic
group
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PCT/CN2022/089737
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English (en)
French (fr)
Inventor
葛均友
欧阳学农
金小平
刁依娜
刘格莎
程烨哲
王晶翼
许莹
饶春
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to EP22794967.4A priority Critical patent/EP4331614A4/en
Priority to CA3217111A priority patent/CA3217111A1/en
Priority to BR112023022540A priority patent/BR112023022540A2/pt
Priority to AU2022263701A priority patent/AU2022263701B2/en
Priority to US18/557,900 priority patent/US20240238434A1/en
Priority to CN202280025989.4A priority patent/CN117157106A/zh
Priority to MX2023012797A priority patent/MX2023012797A/es
Priority to IL308098A priority patent/IL308098A/en
Application filed by Sichuan Kelun Biotech Biopharmaceutical Co Ltd filed Critical Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority to KR1020237040823A priority patent/KR20240004657A/ko
Priority to JP2023565918A priority patent/JP2024516217A/ja
Priority to CN202610018019.1A priority patent/CN121490094A/zh
Publication of WO2022228497A1 publication Critical patent/WO2022228497A1/zh
Priority to CONC2023/0014715A priority patent/CO2023014715A2/es
Anticipated expiration legal-status Critical
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
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    • 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
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    • 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
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    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • 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
    • A61K47/6859—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 liver or pancreas cancer cell
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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Definitions

  • the present application relates to the use of drugs in the treatment of diseases associated with abnormal cell activity, including but not limited to tumor diseases, especially unresectable locally advanced or metastatic solid tumors that are refractory to existing standard treatment, such as after first-line chemotherapy Drug therapy failure and/or recurrent tumor, radiotherapy failure and/or recurrence tumor, and/or targeted drug therapy failure and/or recurrence tumor.
  • tumor diseases especially unresectable locally advanced or metastatic solid tumors that are refractory to existing standard treatment, such as after first-line chemotherapy Drug therapy failure and/or recurrent tumor, radiotherapy failure and/or recurrence tumor, and/or targeted drug therapy failure and/or recurrence tumor.
  • Cancer is a major global public health burden. In the United States, cancer remains the second leading cause of death after cardiovascular disease; in China, cancer incidence is also on the rise. In 2019, the number of new cases of malignant tumors in China was about 4.400 million, and the number of deaths was about 2.624 million. The rising number of cancer cases and deaths will lead to the overall expansion of the oncology treatment market.
  • Chemotherapy is one of the main methods of cancer treatment, but traditional chemotherapeutic drugs do not have the specificity of tumor recognition and are prone to accidentally injure normal cells, causing serious adverse reactions in patients.
  • traditional chemotherapeutic drugs do not have the specificity of tumor recognition and are prone to accidentally injure normal cells, causing serious adverse reactions in patients.
  • In order to improve the survival of cancer patients there is an urgent need for innovations in treatments to match advances in detection and diagnosis. Despite significant progress in many indications, mortality rates for some of the most difficult-to-treat solid tumors have not improved significantly since the 1970s, and more effective treatments with fewer side effects are still needed.
  • Molecularly targeted drugs are an important direction of current drug design.
  • ADC drugs namely antibody-drug conjugates
  • Monoclonal antibody drugs have the advantages of strong targeting, high specificity and low incidence of serious adverse reactions, but their molecular weight is large and the effect of monotherapy is limited.
  • Antibody-drug conjugates are a class of drugs that couple monoclonal antibodies, etc., with different numbers of small-molecule cytotoxins (effector molecules) through chemical linkers. After the ADC molecule enters the body, it can bind to the antigen on the surface of the target cell through the guiding effect of the monoclonal antibody and enter the target cell. The ADC molecule entering the cell can release the effector molecule through chemical and/or enzymatic action to achieve the elimination of the target. purpose of cells.
  • ADC drugs combine the advantages of strong targeting of monoclonal antibodies and high activity of small molecule toxins, which can not only reduce the toxic and side effects of small molecule cytotoxins, but also improve drug efficacy.
  • the present invention provides the use of the bioactive conjugate represented by formula (I) in the preparation of a medicament for treating tumor diseases;
  • R 1 and R 2 are each independently hydrogen (eg, protium or deuterium), halogen, carboxylate, sulfonic acid, cyano, C1-6 alkyl, halogenated C1-6 alkyl, cyano substituted C 1-6 alkyl (for example -CH 2 CN), C 1-6 alkoxy, C 2-10 alkenyl or C 2-10 alkynyl;
  • Z 1 is an amino acid or a peptide consisting of 2 to 10 amino acids ;
  • x1 and x2 are each independently 0 , 1 , 2 , 3 , 4, 5, or 6;
  • L2 is Wherein, y 1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and the 1 position of L 2 is connected to L 1 , and the 2 position of L 2 is connected to L 3 ;
  • L 3 is a 5-12-membered heteroaromatic ring
  • L4 is wherein Z 2 is selected from C 1-6 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, and C 3-8 cycloalkylene; R 3 is selected from H and C 1-6 alkane group; Z 3 does not exist or is a C 1-6 alkylene group; or, R 3 and Z 3 together with the nitrogen atom to which it is attached form a 4-8 membered heterocyclic group; ⁇ is 0, 1, 2, 3, 4 , 5 or 6, and the 2 position of L 4 is connected to E, and the 1 position of L 4 is connected to L 3 ;
  • each R is independently hydrogen (eg, protium or deuterium), ⁇ is 0, 1, or 2, and E is attached to A at the 2 position (eg, attached to a sulfhydryl group on A), and at the 1 position of E to L 4 connected;
  • n 1 , m 2 , and m 3 are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • D is a biologically active molecular fragment
  • ⁇ refers to the number of ⁇ D-[L 1 -(L 2 ) m1 -(L 3 ) m2 -(L 4 ) m3 -E] ⁇ moieties connected to A through a thioether bond, which is selected from 1 to 10 an integer of ; preferably, ⁇ is selected from an integer between 3 and 8 (eg 3, 4, 5, 6, 7 or 8);
  • A is an anti-Trop-2 monoclonal antibody or an antigen-binding fragment thereof.
  • the tumor disease is an unresectable locally advanced or metastatic solid tumor that has failed standard therapy, or has no standard therapy regimen, or is currently not eligible for standard therapy.
  • the standard treatment refers to the standard treatment regimen recommended by the NCCN guidelines and CSCO guidelines for the diagnosis and treatment of the tumor disease.
  • the tumor disease is a tumor that has failed and/or relapsed after first-line chemotherapy.
  • the first-line chemotherapeutic drugs refer to the first-line chemotherapeutic drugs for the tumor disease recommended by NCCN guidelines and CSCO diagnosis and treatment guidelines.
  • the neoplastic disease is a radiotherapy failed and/or recurrent tumor.
  • the radiotherapy refers to the radiotherapy regimen recommended by NCCN guidelines and CSCO guidelines for diagnosis and treatment of the tumor disease.
  • the tumor disease is a failed and/or relapsed tumor treated with a targeted drug or immunotherapy.
  • the targeted drug or immunotherapy refers to the targeted drug or immunotherapy for the tumor disease recommended by NCCN guidelines and CSCO diagnosis and treatment guidelines.
  • the tumor disease includes, but is not limited to, breast cancer, gastric cancer, lung cancer, ovarian cancer, urothelial cancer, esophageal cancer, liver cancer, colorectal cancer, cervical cancer, endometrial cancer, pancreatic cancer, bladder cancer cancer, or brain tumor; preferably breast cancer (eg triple negative breast cancer or Her2 positive breast cancer), ovarian cancer (eg epithelial ovarian cancer), stomach cancer, lung cancer, pancreatic cancer, bladder cancer, or urothelial cancer; more preferably Preferably, the tumor disease is triple-negative breast cancer, Her2-positive breast cancer, ovarian cancer, gastric cancer, lung cancer or pancreatic cancer; further preferably, the tumor disease is triple-negative breast cancer, Her2-positive breast cancer, ovarian cancer or gastric cancer .
  • the neoplastic disease is breast cancer.
  • the breast cancer includes, but is not limited to, the following types: Luminal A, Luminal B, Her-2 positive, and triple negative.
  • the neoplastic disease is triple negative breast cancer.
  • the neoplastic disease is Her2-positive breast cancer.
  • the neoplastic disease is ovarian cancer.
  • the ovarian cancer includes, but is not limited to, the following types: platinum sensitive, platinum resistant.
  • the neoplastic disease is gastric cancer.
  • the gastric cancer includes, but is not limited to, the following types: adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, neuroendocrine tumor.
  • the neoplastic disease is pancreatic cancer.
  • the pancreatic cancer includes, but is not limited to, the following types: epithelial tumor, exocrine tumor, borderline tumor, ductal adenocarcinoma, endocrine tumor, mature teratoma, mesenchymal tumor, malignant lymphoma, secondary tumors.
  • the neoplastic disease is bladder cancer.
  • the bladder cancer includes, but is not limited to, the following types: urothelial (transitional cell) carcinoma, squamous cell carcinoma, and adenocarcinoma.
  • the neoplastic disease is urothelial carcinoma.
  • the urothelial carcinoma includes, but is not limited to, the following types: basal-like, lumen-like, and wild-type.
  • the neoplastic disease is lung cancer.
  • the lung cancer includes, but is not limited to, the following types: small cell lung cancer, non-small cell lung cancer.
  • the conjugate has the following structure:
  • L1 is selected from And the 1 position of L 1 is connected to D, and the 2 position of L 1 is connected to L 2 ;
  • L2 is Wherein, y 1 is 3, 4, 5, 6, 7, 8, 9 or 10; and the 1 position of L 2 is connected to L 1 , and the 2 position of L 2 is connected to L 3 ;
  • L 3 is selected from 5-6 membered heteroaromatic rings, such as pyrazole or triazole;
  • L4 is wherein Z 2 is selected from C 1-3 alkylene; R 3 is H; Z 3 is selected from C 1-3 alkylene ; is connected to L3 ;
  • each R is independently hydrogen (eg, protium or deuterium), ⁇ is 0, 1, or 2, and E is attached to A at the 2 position (eg, attached to a sulfhydryl group on A), and at the 1 position of E to L 4 connected;
  • n 1 , m 2 and m 3 are all 1;
  • the biologically active molecule is selected from Preferably, the biologically active molecule is linked to the 1 position of L 1 through its own hydroxyl group;
  • ⁇ is selected from an integer between 3 and 8 (eg 3, 4, 5, 6, 7 or 8);
  • A is Sacituzumab or an antigen-binding fragment thereof.
  • the conjugate has the following structure:
  • L1 is selected from And the 1 position of L 1 is connected to D, and the 2 position of L 1 is connected to L 2 ;
  • L2 is Wherein, y 1 is 3, 4, 5, 6, 7, 8, 9 or 10; and the 1 position of L 2 is connected to L 1 , and the 2 position of L 2 is connected to L 3 ;
  • L 3 is selected from 5-6 membered heteroaromatic rings, such as pyrazole or triazole;
  • L4 is wherein Z 2 is selected from C 1-3 alkylene; R 3 is H; Z 3 is selected from C 1-3 alkylene ; is connected to L3 ;
  • each R is independently hydrogen (eg, protium or deuterium), ⁇ is 0, 1, or 2, and E is attached to A at the 2 position (eg, attached to a sulfhydryl group on A), and at the 1 position of E to L 4 connected;
  • n 1 , m 2 and m 3 are all 1;
  • the biologically active molecule is selected from Preferably, the biologically active molecule is linked to the 1 position of L 1 through its own hydroxyl group;
  • ⁇ is selected from an integer between 3 and 8 (eg 3, 4, 5, 6, 7 or 8);
  • A is Sacituzumab or an antigen-binding fragment thereof.
  • D is selected from
  • the conjugate is the structural conjugate A represented by the following formula:
  • ⁇ is an integer from 1 to 10; preferably, ⁇ is selected from an integer between 5 and 8.
  • the conjugate has a DAR value of 1 to 12; preferably, 1 to 10; further preferably, a DAR value of 5 to 8; , 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the present invention provides a method of treating a neoplastic disease, the method comprising administering to an individual in need thereof a therapeutically effective amount of a bioactive conjugate of formula (I) as described above and/or comprising The steps of the pharmaceutical composition of the biologically active compound conjugate of formula (I).
  • the tumor disease is an unresectable locally advanced or metastatic solid tumor that has failed standard therapy, or has no standard therapy regimen, or is currently not eligible for standard therapy.
  • the standard treatment refers to the standard treatment regimen recommended by the NCCN guidelines and CSCO guidelines for the diagnosis and treatment of the tumor disease.
  • the tumor disease is a tumor that has failed and/or relapsed after first-line chemotherapy.
  • the first-line chemotherapeutic drug refers to the first-line chemotherapeutic drug for the tumor disease recommended by NCCN guidelines and CSCO diagnosis and treatment guidelines.
  • the neoplastic disease is a radiotherapy failed and/or recurrent tumor.
  • the radiotherapy refers to the radiotherapy regimen recommended by NCCN guidelines and CSCO guidelines for diagnosis and treatment of the tumor disease.
  • the tumor disease is a failed and/or relapsed tumor treated with a targeted drug or immunotherapy.
  • the targeted drug or immunotherapy refers to the targeted drug or immunotherapy for the tumor disease recommended by NCCN guidelines and CSCO diagnosis and treatment guidelines.
  • the tumor disease includes, but is not limited to, breast cancer, gastric cancer, lung cancer, ovarian cancer, urothelial cancer, esophageal cancer, liver cancer, colorectal cancer, cervical cancer, endometrial cancer, pancreatic cancer, bladder cancer cancer, or brain tumor; preferably breast cancer (eg triple negative breast cancer or Her2 positive breast cancer), ovarian cancer (eg epithelial ovarian cancer), stomach cancer, lung cancer, pancreatic cancer, bladder cancer, or urothelial cancer; more preferably Preferably, the tumor disease is triple-negative breast cancer, Her2-positive breast cancer, ovarian cancer, gastric cancer, lung cancer or pancreatic cancer; further preferably, the tumor disease is triple-negative breast cancer, Her2-positive breast cancer, ovarian cancer or gastric cancer .
  • the neoplastic disease is breast cancer.
  • the breast cancer includes, but is not limited to, the following types: Luminal A, Luminal B, Her-2 positive, and triple negative.
  • the neoplastic disease is triple negative breast cancer.
  • the neoplastic disease is Her2-positive breast cancer.
  • the neoplastic disease is ovarian cancer.
  • the ovarian cancer includes, but is not limited to, the following types: platinum sensitive, platinum resistant.
  • the neoplastic disease is gastric cancer.
  • the gastric cancer includes, but is not limited to, the following types: adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, neuroendocrine tumor.
  • the neoplastic disease is pancreatic cancer.
  • the pancreatic cancer includes, but is not limited to, the following types: epithelial tumor, exocrine tumor, borderline tumor, ductal adenocarcinoma, endocrine tumor, mature teratoma, mesenchymal tumor, malignant lymphoma, secondary tumors.
  • the neoplastic disease is bladder cancer.
  • the bladder cancer includes, but is not limited to, the following types: urothelial (transitional cell) carcinoma, squamous cell carcinoma, and adenocarcinoma.
  • the neoplastic disease is urothelial carcinoma.
  • the urothelial carcinoma includes, but is not limited to, the following types: basal-like, lumen-like, and wild-type.
  • the neoplastic disease is lung cancer.
  • the lung cancer includes, but is not limited to, the following types: small cell lung cancer, non-small cell lung cancer.
  • the pharmaceutical composition comprises the bioactive conjugate and a pharmaceutically acceptable carrier and/or excipient.
  • the bioactive conjugate or the pharmaceutical composition is administered every 7-35 days, preferably every 7-28 days, eg, every 7 days, 14 days, 21 days, 28 days , or once every 35 days.
  • the route of administration of the conjugate or pharmaceutical composition includes, but is not limited to, oral, transdermal, rectal, transmucosal, intramuscular, intramedullary, intravenous, or Intraperitoneal injection, preferably intravenous injection.
  • the biologically active conjugate is administered at a dose of 1 mg/kg to 30 mg/kg; preferably 1 mg/kg to 20 mg/kg; more preferably 2 mg/kg to 12 mg, based on the patient's body weight per administration /kg; more preferably 2 to 5 mg/kg, 4 to 7 mg/kg, 6 to 9 mg/kg, 8 to 11 mg/kg, 10 to 13 mg/kg, or 12 to 15 mg/kg; for example: 2 mg/kg, 2.5 mg/kg, 3mg/kg, 3.5mg/kg, 4mg/kg, 4.5mg/kg, 5mg/kg, 5.5mg/kg, 6mg/kg, 6.5mg/kg, 7mg/kg, 7.5mg/kg, 8mg /kg, 8.5mg/kg, 9mg/kg, 9.5mg/kg, 10mg/kg, 11mg/kg or 12mg/kg.
  • the dosing regimen of the biologically active conjugate is divided into one or more administration phases (eg, one phase, two phases, three phases, or four phases), with each phase of administration
  • administration phases eg, one phase, two phases, three phases, or four phases
  • the dosing cycle and the dose administered are each independently selected from the dosing cycles or doses described above.
  • the use or method of the invention results in tumor elimination or volume reduction.
  • the use or method of the invention results in a reduction in tumor volume of at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, or at least 40%.
  • the drug-antibody conjugation ratio refers to the average loading of the antibody in the conjugate to the small molecule toxin drug. While the ratio of small molecule toxin drug moiety to antibody moiety binding has an exact value for a particular conjugate molecule, it should be understood that when used to describe a sample containing many molecules, this value refers to the specific conjugate molecule.
  • the percentage calculated as the average, the average loading is referred to herein as the Average Coupling Ratio or "DAR".
  • NCCN guidelines refer to clinical practice guidelines for various malignant tumors issued by the National Comprehensive Cancer Network (National Comprehensive Cancer Network).
  • CSCO diagnosis and treatment guidelines refer to the clinical diagnosis and treatment guidelines for various malignant tumors issued by the Chinese Society of Clinical Oncology (CSCO).
  • Objective response rate refers to the proportion of patients whose tumors shrink to a certain extent and maintain for a certain period of time, including cases of CR and PR. Objective tumor response was assessed using response evaluation criteria in solid tumors version 1.1 (RECIST1.1 criteria). Subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) according to RECIST 1.1 criteria.
  • CR complete remission
  • PR partial remission
  • SD stable disease
  • PD progressive disease
  • PD Disease progression: At least a 20% relative increase in diameter and relative increase in diameter and relative increase of at least 20% (or baseline value if baseline measurement is the smallest), referenced to the minimum of the sum of all measured target lesion diameters throughout the study; otherwise , the absolute value of the sum of the diameters must increase by at least 5mm (the appearance of one or more new lesions is also regarded as disease progression).
  • Stable disease The degree of reduction of target lesions does not reach the PR level, and the degree of increase does not reach the level of PD. Between the two, the minimum sum of diameters can be used as a reference in the study.
  • Partial remission At least 30% reduction in sum of target lesions compared to baseline.
  • CR Complete remission
  • DLT Dose Limiting Toxicities
  • Adverse Event refers to any adverse medical event that occurs after a patient or clinical research subject receives a drug, but is not necessarily causally related to the treatment.
  • Treatment Emergent Adverse Event refers to any AE that occurs or worsens on or after the first dose.
  • Figure 1 shows the in vitro plasma stability of Conjugate A and the marketed drug Trodelvy TM .
  • Example 1 4-((S)-2-(4-aminobutyl)-35-(4-((6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-amido) Methyl)-1H-1,2,3-triazol-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonaoxa- 3,9-diazatripentadecanoylamino)benzyl((S)-4-ethyl-11-(2-(N-isopropylmethylsulfonamido)ethyl)-3,14 -Dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indeno[1,2-b]quinolin-4-yl) Carbonate
  • Step 1 Synthesis of 6-(2-(methylsulfonyl)pyrimidin-5-yl)-N-(prop-2-yn-1-yl)hex-5-ynamide
  • Prop-2-yn-1-amine (189 mg, 3.4 mmol) and compound 3-4 (800 mg, 2.83 mmol) were dissolved in dichloromethane (10 mL) at 25°C, and N,N-diisopropyl was added sequentially Ethylamine (738mg, 5.67mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.63g, 4.25mmol ), and the reaction was stirred for 2h.
  • Step 2 4-((S)-35-azido-2-(4-(((4-methoxyphenyl)benzyl)amino)butyl)-4,8-dioxo -6,12,15,18,21,24,27,30,33-Nonaoxa-3,9-diazatripentadecanoylamino)benzyl((S)-4-ethyl-11 -(2-(N-Isopropylmethanesulfonamido)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro-2H-pyrano[2,3-b] Synthesis of -1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbonate
  • T-030 250 mg, 0.49 mmol was dissolved in dichloromethane (10 mL), cooled to 0 °C, and 4-dimethylaminopyridine (478 mg, 3.91 mmol) in dichloromethane (3 mL) was added. ) solution, and then slowly dropwise added triphosgene (72 mg, 0.24 mmol) in dichloromethane (10 mL) solution, after the addition, the reaction was stirred at 0°C for 20 min, and the reaction solution was blown with nitrogen for 20 min.
  • Step 3 (S)-4-ethyl-11-(2-(N-isopropylmethanesulfonamido)ethyl)-3,14-dioxo-3,4,12,14-tetrahydro -1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl(4-((S)-2-(4-((((4 -Methoxyphenyl)diphenylmethyl)amino)butyl)-35-(4-((6-(2-(methylsulfonyl)pyrimidin-5-yl)hex-5-amido) Methyl)-1H-1,2,3-triazol-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonyloxy- Synthesis of 3,9-diazatripentacosamide)benzyl)carbonate
  • Step 4 4-((S)-2-(4-aminobutyl)-35-(4-((6-(2-(methylsulfonyl)pyrimidin-5-yl)hexyl-5-amido )methyl)-1H-1,2,3-triazol-1-yl)-4,8-dioxo-6,12,15,18,21,24,27,30,33-nonaoxa -3,9-Diazatripentadecanoylamino)benzyl((S)-4-ethyl-11-(2-(N-isopropylmethylsulfonamido)ethyl)-3, 14-Dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indeno[1,2-b]quinolin-4-yl ) Synthesis of Carbonate (Compound IM-1)
  • Sacituzumab antibody (anti-Trop-2, 33.5 mg/mL), dilute with 0.25 mL of a solution (pH 7.6) containing 20 mM PB, 150 mM NaCl and 20 mM sodium edetate, and then add 0.45 mL of 20 mM PB and 150 mM NaCl
  • the solution (pH 7.6) was mixed evenly, the pH was adjusted to 7.4 with 1M Na 2 HPO 4 solution, 10 mM TCEP (tris(2-carboxyethyl) phosphine) solution was added, and the solution was kept at room temperature for 30 min.
  • conjugate A 10 times the amount of IM-1 trifluoroacetate dissolved in dimethyl sulfoxide was added to the above solution system, mixed well, and allowed to stand at room temperature for 2 hours. After completion, 6.1 ⁇ l of 100 mM cysteine was added to terminate the reaction. Finally, the G-25 gel column was used to replace the buffer with a PBS buffer solution with pH 6.5 to obtain a product conjugated between IM-1 and Sacituzumab antibody, which was named as conjugate A.
  • the molecular weight of conjugate A was analyzed by LCMS method, and the measured molecular weight of light chain and heavy chain of conjugate A was correlated with the theoretical molecular weight of light chain and heavy chain conjugated with different numbers of toxins.
  • 1 to 10 toxins are conjugated to each antibody molecule (that is, ⁇ is 1 to 10), and then the average conjugation ratio (DAR) is calculated according to the percentage of conjugate molecules conjugated with different numbers of toxins to be about 6.9 .
  • Example 2 prepare in batches to obtain conjugate A samples with DAR values ranging from 6 to 8 (eg, 7.3 or 7.4), and conduct the following non-clinical and clinical studies.
  • Chemiluminescence cell viability detection method (ie CTG method) was used to detect the effect of conjugate A on the proliferation of BxPC-3 cells (pancreatic cancer cell line, source: ATCC, TROP2 positive cells).
  • BxPC-3 cells pancreatic cancer cell line, source: ATCC, TROP2 positive cells.
  • BxPC-3 cells in exponential growth phase were collected, the concentration of cell suspension was adjusted with medium and added to a 96-well cell culture plate, the final cell concentration was 2000 cells/well, at 37°C, 5% CO 2 Incubate overnight in an incubator.
  • Conjugate A final concentration of 0.152-1000nM was diluted to 10-fold concentration working solution in a 1:3-fold gradient, and 10 ⁇ l of the corresponding 10-fold concentration working solution was added to each well, and each drug concentration was 3 times. Multiple wells were added, and the cells were cultured in a 37°C, 5% CO2 incubator for 72 hours after dosing.
  • the cynomolgus monkeys were divided into 10 groups (half male and female)/group, and the conjugate A was administered intravenously at doses of 25 mg/kg, 50 mg/kg and 75 mg/kg, once every 2 weeks, for a total of After 4 administrations, the electrocardiogram and respiratory rate of lead II were detected by the large animal non-invasive physiological signal telemetry system, and the arterial blood pressure was measured by non-invasive sphygmomanometer to evaluate the effect of conjugate A on cardiovascular and respiratory function of cynomolgus monkeys.
  • the cynomolgus monkeys were divided into 4 groups according to different doses: control group, 25 mg/kg dose group, 50 mg/kg dose group and 75 mg/kg dose group, with 5 males and 5 males in each group.
  • cynomolgus monkeys were intravenously injected with Conjugate A once every 2 weeks for 4 consecutive times; the monkeys in each group were given the 0 to 1 minute after the end of the drug), 4h, 24h, 48h, 96h, 168h, within 1 hour before the second and third doses and immediately after the end of the dose (0 to 1 minute after the end of the dose), 336h after the last dose Blood samples were collected.
  • the monkeys in the 75mg/kg dose group collected blood samples at 4h, 24h, 48h, 96h, and 168h after the third administration to detect the toxicokinetic behavior of the conjugate and its released toxin molecules in vivo.
  • the following table records the peak plasma concentration (C max ) and exposure (AUC) of conjugate A and the toxin molecules released by conjugate A in male and female monkeys after administration in the above manner.
  • C max peak plasma concentration
  • AUC exposure
  • the results showed that the highest non-severely toxic dose (HNSTD) of conjugate A was 50 mg/kg, and the exposure of male and female monkey toxin molecules after the last administration of this dose were 3.85h* ⁇ g/mL and 5.86h* ⁇ g/mL, respectively.
  • HNSTD non-severely toxic dose
  • mL the exposures of conjugate A female and male monkeys were 45.8h*mg/mL and 64.2h*mg/mL, respectively.
  • conjugate A and Trodelvy TM were respectively prepared into working solutions of 3.4 mg/mL using normal saline, and the working solutions of conjugate A and Trodelvy TM were respectively added to human blank plasma to obtain a concentration of 0.05 mg/ml.
  • Human plasma samples incubate the plasma samples at 37°C, measure the release of toxin molecules at 1h, 3h, 24h, 48h, 72h and 144h, and compare the in vitro plasma stability of Conjugate A and the marketed drug Trodelvy TM difference. The results are shown in Figure 1.
  • Figure 1 of the description shows: with the increase of incubation time, the production of free toxins in human plasma increases. After 24 hours of incubation, the release percentages of conjugate A and marketed ADC drug Trodelvy TM toxin molecules in human plasma are 28.5% and 93.4%, respectively.
  • TEAEs Treatment Emergent Adverse Events
  • grade 3 TEAEs including oral mucositis, occurred in the 4 mg/kg dose group , anemia, etc.
  • TEAEs of grade 3 or above occurred in the 6 mg/kg dose group, including decreased neutrophil count, decreased white blood cell count, etc.
  • the above-mentioned TEAEs of grade 3 or above can be recovered after symptomatic treatment, and medication can be continued, indicating that the conjugate A has a good clinical safety profile.
  • TNBC Triple Negative Breast Cancer
  • the conjugate A was intravenously infused at a dose of 4 mg/kg based on the patient's body weight according to the above-mentioned dosing cycle. After 15 weeks, partial remission of the disease was observed, which has continued for 10 weeks, and is still benefiting. After multiple efficacy evaluations, the total volume of target lesions was reduced by 62.8%, and one of the target lesions disappeared. The patient had no serious adverse events.
  • the conjugate A was intravenously infused at a dose of 4 mg/kg based on the patient's body weight according to the above-mentioned dosing cycle.
  • the disease was stable after 7 weeks and lasted for 30.3 weeks. After multiple efficacy evaluations, the target The total volume of the lesions was reduced by 8.8%, and no serious adverse events occurred in the patients.
  • conjugate A showed good curative effect at least initially in unresectable metastatic TNBC, ovarian cancer, HER2-positive breast cancer, gastric cancer and pancreatic cancer that failed the standard treatment. , without inducing severe toxicity that might preclude clinical use.

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Abstract

本发明涉及药物在治疗肿瘤疾病中的应用。具体地，本发明提供式(I)所示生物活性物偶联物在治疗肿瘤疾病中的应用，所述肿瘤疾病特别优选依照现有标准治疗难治的不可手术切除的局部晚期或转移性实体瘤，包括但不限于乳腺癌、胃癌、肺癌、卵巢癌、尿路上皮癌、食管癌、肝癌、结直肠癌、宫颈癌、子宫内膜癌、胰腺癌、和脑肿瘤。

Description

药物在治疗肿瘤疾病中的应用
本申请是以CN申请号为202110482012.2，申请日为2021年4月30日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本申请涉及药物在治疗与细胞活动异常相关的疾病中的应用，包括但不限于肿瘤疾病，特别是依照现有标准治疗难治的不可手术切除的局部晚期或转移性实体瘤，例如经一线化疗药物治疗失败和/或复发肿瘤，经放疗失败和/或复发肿瘤，和/或经靶向药物治疗失败和/或复发肿瘤。
背景技术
癌症是全球公共卫生的一大负担。在美国，癌症仍然是仅次于心血管疾病的第二大死因；在中国，癌症发病人数也呈上升趋势。2019年，中国恶性肿瘤新发病人数约为440.0万人，死亡人数约为262.4万人。癌症发病人数及死亡人数的不断上升将导致肿瘤治疗市场总体规模扩大。
化疗是癌症治疗的主要手段之一，但传统的化疗药物不具备肿瘤识别特异性，易误伤正常细胞，引起患者的严重不良反应。为了提高癌症患者的生存率，目前迫切需要在治疗方法上进行创新，以配合检测和诊断的进步。尽管在许多适应症方面已取得了重大进展，但自20世纪70年代以来，一些最难治疗的实体瘤死亡率并没有显著改善，仍需要副作用更少、更有效的治疗。分子靶向药物是当前药物设计的重要方向。
单克隆抗体药物具有靶向性强、特异性高和严重不良反应发生率低等优点，但其分子量较大、单独治疗的效果有限。ADC药物(Antibody-drug conjugates)，即抗体偶联药物，是一类通过化学接头将单克隆抗体等与不同数目小分子细胞毒素(效应分子)偶联起来的药物。ADC分子进入体内后，可通过单克隆抗体的导向作用与靶细胞表面的抗原结合，进入靶细胞内，进入细胞内的ADC分子可通过化学和/或酶促作用释放出效应分子以达到消灭靶细胞的目的。ADC药物结合了单克隆抗体靶向性强和小分子毒素高活性等优点，既可降低小分子细胞毒素的毒副作用，又可提高药物疗效。
目前全球已有多款ADC药物上市，适应症种类覆盖了白血病、淋巴瘤、乳腺癌等。但部分ADC药物在药代动力学性质及安全性方面的表现仍存在一定问题，导致 患者使用后可能产生较严重的不良反应，对于一些转移、复发、和/或难治性的癌症的治疗有效率也仍需进一步提高。因此，仍需要开发出ADC药物治疗这些转移、复发、和/或难治性癌症的用途或治疗方法，使其有效性最大化并使毒性最小化，以便满足癌症患者的用药需求。
发明内容
本发明提供了式(I)所示生物活性物偶联物在制备治疗肿瘤疾病的药物中的用途；
{D-[L 1-(L 2) m1-(L 3) m2-(L 4) m3-E]} γ-A
式(I)
其中，
L 1为
Figure PCTCN2022089737-appb-000001
各R 1和R 2各自独立地为氢(例如氕或氘)、卤素、羧酸基、磺酸基、氰基、C 1-6烷基、卤代C 1-6烷基、氰基取代的C 1-6烷基(例如-CH 2CN)、C 1-6烷氧基、C 2-10烯基或C 2-10炔基；Z 1为氨基酸或2～10个氨基酸组成的肽；x 1和x 2各自独立地为0、1、2、3、4、5或6；并且L 1的1位置处与D相连、L 1的2位置处与L 2相连；
L 2为
Figure PCTCN2022089737-appb-000002
其中，y 1为0、1、2、3、4、5、6、7、8、9或10；并且L 2的1位置处与L 1相连、L 2的2位置处与L 3相连；
L 3为5～12元杂芳环；
L 4为
Figure PCTCN2022089737-appb-000003
其中Z 2选自C 1-6亚烷基、C 2-10亚烯基、C 2-10亚炔基、和C 3-8亚环烷基；R 3选自H和C 1-6烷基；Z 3不存在或者为C 1-6亚烷基；或者，R 3与Z 3连同其所连接的氮原子形成4～8元杂环基；α为0、1、2、3、4、5或6，并且L 4的2位置处与E相连、L 4的1位置处与L 3相连；
E为
Figure PCTCN2022089737-appb-000004
其中，各R 4独立地为氢(例如氕或氘)，β为0、1或2，并且E的2位置处与A相连(例如与A上的巯基相连)、E的1位置处与L 4相连；
m 1、m 2和m 3各自独立地为0、1、2、3、4、5、6、7、8、9或10；
D为生物活性分子片段；
γ指与A通过硫醚键连接的{D-[L 1-(L 2) m1-(L 3) m2-(L 4) m3-E]}部分的数量，其选自1～10之间的整数；优选地，γ选自3～8之间的整数(例如3、4、5、6、7或8)；
A为抗Trop-2的单克隆抗体或其抗原结合片段。
在部分实施方案中，所述肿瘤疾病是经标准治疗失败，或无标准治疗方案，或现阶段不适用标准治疗的不可手术切除的局部晚期或转移性实体瘤。在一些实施方案中，所述标准治疗是指NCCN指南和CSCO诊疗指南推荐的针对所述肿瘤疾病的标准治疗方案。
在部分实施方案中，所述肿瘤疾病为经一线化疗药物治疗失败和/或复发肿瘤。在一些实施方案中，所述一线化疗药物是指NCCN指南和CSCO诊疗指南推荐的针对所述肿瘤疾病的一线化疗药物。
在部分实施方案中，所述肿瘤疾病为经放疗失败和/或复发肿瘤。在一些实施方案中，所述放疗是指NCCN指南和CSCO诊疗指南推荐的针对所述肿瘤疾病的放疗方案。
在部分实施方案中，所述肿瘤疾病为经靶向药物或免疫疗法治疗失败和/或复发肿瘤。在一些实施方案中，所述靶向药物或免疫疗法是指NCCN指南和CSCO诊疗指南推荐的针对所述肿瘤疾病的靶向药物或免疫疗法。
在部分实施方案中，所述肿瘤疾病包括但不限于乳腺癌、胃癌、肺癌、卵巢癌、尿路上皮癌、食管癌、肝癌、结直肠癌、宫颈癌、子宫内膜癌、胰腺癌、膀胱癌、或脑肿瘤；优选为乳腺癌(例如三阴性乳腺癌或Her2阳性乳腺癌)、卵巢癌(例如卵巢上皮癌)、胃癌、肺癌、胰腺癌、膀胱癌、或尿路上皮癌；更优选地，所述肿瘤疾病为三阴性乳腺癌、Her2阳性乳腺癌、卵巢癌、胃癌、肺癌或胰腺癌；进一步优选地，所述肿瘤疾病为三阴性乳腺癌、Her2阳性乳腺癌、卵巢癌或胃癌。
在部分实施方案中，所述肿瘤疾病为乳腺癌。
在部分实施方案中，所述乳腺癌包括但不限于以下类型：Luminal A型、Luminal B型、Her-2阳性型和三阴性型。
在部分实施方案中，所述肿瘤疾病为三阴性乳腺癌。
在部分实施方案中，所述肿瘤疾病为Her2阳性乳腺癌。
在部分实施方案中，所述肿瘤疾病为卵巢癌。
在部分实施方案中，所述卵巢癌包括但不限于以下类型：铂敏感型、铂耐药型。
在部分实施方案中，所述肿瘤疾病为胃癌。
在部分实施方案中，所述胃癌包括但不限于以下类型：腺癌、腺鳞癌、鳞状细胞癌、未分化癌、神经内分泌肿瘤。
在部分实施方案中，所述肿瘤疾病为胰腺癌。
在部分实施方案中，所述胰腺癌包括但不限于以下类型：上皮性肿瘤、外分泌肿瘤、交界性肿瘤、导管腺癌、内分泌肿瘤、成熟性畸胎瘤、间叶性肿瘤、恶性淋巴瘤、继发性肿瘤。
在部分实施方案中，所述肿瘤疾病为膀胱癌。
在部分实施方案中，所述膀胱癌包括但不限于以下类型：尿路上皮(移行细胞)癌、鳞状细胞癌和腺癌。
在部分实施方案中，所述肿瘤疾病为尿路上皮癌。
在部分实施方案中，所述尿路上皮癌包括但不限于以下类型：基底样型、管腔样型和野生型。
在部分实施方案中，所述肿瘤疾病为肺癌。
在部分实施方案中，所述肺癌包括但不限于以下类型：小细胞肺癌、非小细胞肺癌。
在部分实施方案中，所述偶联物具有下述结构：
L 1选自
Figure PCTCN2022089737-appb-000005
Figure PCTCN2022089737-appb-000006
并且L 1的1位置处与D相连、L 1的2位置处与L 2相连；
L 2为
Figure PCTCN2022089737-appb-000007
其中，y 1为3、4、5、6、7、8、9或10；并且L 2的1位置处与L 1相连、L 2的2位置处与L 3相连；
L 3选自5～6元杂芳环，例如吡唑或三氮唑；
L 4为
Figure PCTCN2022089737-appb-000008
其中Z 2选自C 1-3亚烷基；R 3为H；Z 3选自C 1-3亚烷基；α为0，并且L 4的2位置处与E相连、L 4的1位置处与L 3相连；
E为
Figure PCTCN2022089737-appb-000009
其中，各R 4独立地为氢(例如氕或氘)，β为0、1或2，并且E的2位置处与A相连(例如与A上的巯基相连)、E的1位置处与L 4相连；
m 1、m 2和m 3均为1；
所述生物活性分子选自
Figure PCTCN2022089737-appb-000010
优选地，所述生物活性分子通过自身羟基与L 1的1位置处相连；
γ选自3～8之间的整数(例如3、4、5、6、7或8)；
A为Sacituzumab或其抗原结合片段。
在部分实施方案中，所述偶联物具有下述结构：
L 1选自
Figure PCTCN2022089737-appb-000011
Figure PCTCN2022089737-appb-000012
并且L 1的1位置处与D相连、L 1的2位置处与L 2相连；
L 2为
Figure PCTCN2022089737-appb-000013
其中，y 1为3、4、5、6、7、8、9或10；并且L 2的1位置处与L 1相连、L 2的2位置处与L 3相连；
L 3选自5～6元杂芳环，例如吡唑或三氮唑；
L 4为
Figure PCTCN2022089737-appb-000014
其中Z 2选自C 1-3亚烷基；R 3为H；Z 3选自C 1-3亚烷基；α为1，并且L 4的2位置处与E相连、L 4的1位置处与L 3相连；
E为
Figure PCTCN2022089737-appb-000015
其中，各R 4独立地为氢(例如氕或氘)，β为0、1或2，并且E的2位置处与A相连(例如与A上的巯基相连)、E的1位置处与L 4相连；
m 1、m 2和m 3均为1；
所述生物活性分子选自
Figure PCTCN2022089737-appb-000016
优选地，所述生物活性分子通过自身羟基与L 1的1位置处相连；
γ选自3～8之间的整数(例如3、4、5、6、7或8)；
A为Sacituzumab或其抗原结合片段。
在部分实施方案中，D选自
Figure PCTCN2022089737-appb-000017
在部分技术方案中，所述偶联物为下式所示结构偶联物A：
Figure PCTCN2022089737-appb-000018
其中，γ为1～10的整数；优选的，γ选自5～8之间的整数。
在部分实施方案中，所述偶联物的DAR值为1～12；优选为1～10；进一步优选DAR值为5～8；例如，DAR值为6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0。
在另一个方面，本发明提供了一种肿瘤疾病的治疗方法，所述方法包括给予有此需要的个体治疗有效量的如上文所述式(I)的生物活性物偶联物和/或包含所述式(I)生物活性物偶联物的药物组合物的步骤。
在部分实施方案中，所述肿瘤疾病是经标准治疗失败，或无标准治疗方案，或现阶段不适用标准治疗的不可手术切除的局部晚期或转移性实体瘤。在一些实施方案中，所述标准治疗是指NCCN指南和CSCO诊疗指南推荐的针对所述肿瘤疾病的标准治疗方案。
在部分实施方案中，所述肿瘤疾病为经一线化疗药物治疗失败和/或复发肿瘤。在一些实施方案中，所述一线化疗药物是指NCCN指南和CSCO诊疗指南推荐的针对 所述肿瘤疾病的一线化疗药物。
在部分实施方案中，所述肿瘤疾病为经放疗失败和/或复发肿瘤。在一些实施方案中，所述放疗是指NCCN指南和CSCO诊疗指南推荐的针对所述肿瘤疾病的放疗方案。
在部分实施方案中，所述肿瘤疾病为经靶向药物或免疫疗法治疗失败和/或复发肿瘤。在一些实施方案中，所述靶向药物或免疫疗法是指NCCN指南和CSCO诊疗指南推荐的针对所述肿瘤疾病的靶向药物或免疫疗法。
在部分实施方案中，所述肿瘤疾病包括但不限于乳腺癌、胃癌、肺癌、卵巢癌、尿路上皮癌、食管癌、肝癌、结直肠癌、宫颈癌、子宫内膜癌、胰腺癌、膀胱癌、或脑肿瘤；优选为乳腺癌(例如三阴性乳腺癌或Her2阳性乳腺癌)、卵巢癌(例如卵巢上皮癌)、胃癌、肺癌、胰腺癌、膀胱癌、或尿路上皮癌；更优选地，所述肿瘤疾病为三阴性乳腺癌、Her2阳性乳腺癌、卵巢癌、胃癌、肺癌或胰腺癌；进一步优选地，所述肿瘤疾病为三阴性乳腺癌、Her2阳性乳腺癌、卵巢癌或胃癌。
在部分实施方案中，所述肿瘤疾病为乳腺癌。
在部分实施方案中，所述乳腺癌包括但不限于以下类型：Luminal A型、Luminal B型、Her-2阳性型和三阴性型。
在部分实施方案中，所述肿瘤疾病为三阴性乳腺癌。
在部分实施方案中，所述肿瘤疾病为Her2阳性乳腺癌。
在部分实施方案中，所述肿瘤疾病为卵巢癌。
在部分实施方案中，所述卵巢癌包括但不限于以下类型：铂敏感型、铂耐药型。
在部分实施方案中，所述肿瘤疾病为胃癌。
在部分实施方案中，所述胃癌包括但不限于以下类型：腺癌、腺鳞癌、鳞状细胞癌、未分化癌、神经内分泌肿瘤。
在部分实施方案中，所述肿瘤疾病为胰腺癌。
在部分实施方案中，所述胰腺癌包括但不限于以下类型：上皮性肿瘤、外分泌肿瘤、交界性肿瘤、导管腺癌、内分泌肿瘤、成熟性畸胎瘤、间叶性肿瘤、恶性淋巴瘤、继发性肿瘤。
在部分实施方案中，所述肿瘤疾病为膀胱癌。
在部分实施方案中，所述膀胱癌包括但不限于以下类型：尿路上皮(移行细胞)癌、鳞状细胞癌和腺癌。
在部分实施方案中，所述肿瘤疾病为尿路上皮癌。
在部分实施方案中，所述尿路上皮癌包括但不限于以下类型：基底样型、管腔样型和野生型。
在部分实施方案中，所述肿瘤疾病为肺癌。
在部分实施方案中，所述肺癌包括但不限于以下类型：小细胞肺癌、非小细胞肺癌。在部分实施方案中，所述药物组合物包含所述生物活性物偶联物以及药学上可接受的载体和/或赋形剂。
在部分实施方案中，所述生物活性物偶联物或所述药物组合物每7～35天施用一次，优选每7～28天施用一次，例如每7天、14天、21天、28天、或35天给药1次。
在部分实施方案中，所述偶联物或药物组合物的施用途径包括但不限于口服、经皮注射、直肠给药、经黏膜给药、肌内注射、髓内注射、静脉内注射、或腹膜内注射，优选静脉内注射。
在部分实施方案中，所述生物活性物偶联物的每次给药剂量基于患者体重为1mg/kg至30mg/kg；优选为1mg/kg至20mg/kg；更优选为2mg/kg至12mg/kg；进一步优选为2～5mg/kg、4～7mg/kg、6～9mg/kg、8～11mg/kg、10～13mg/kg、或者12～15mg/kg；例如：2mg/kg,2.5mg/kg,3mg/kg,3.5mg/kg,4mg/kg,4.5mg/kg,5mg/kg,5.5mg/kg,6mg/kg,6.5mg/kg,7mg/kg,7.5mg/kg,8mg/kg,8.5mg/kg,9mg/kg,9.5mg/kg,10mg/kg,11mg/kg或12mg/kg。
在部分实施方案中，所述生物活性物偶联物的给药方案分为一或多个给药阶段(例如一个阶段、两个阶段、三个阶段或四个阶段)，每一阶段的给药周期及给药剂量各自独立地选自上文所述的给药周期或剂量。
在部分实施方案中，本发明的用途或方法引起肿瘤消除或体积减小。
在部分实施方案中，本发明的用途或方法引起肿瘤体积减小至少5％、至少10％、至少15％、至少20％、至少30％或至少40％。
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
药物抗体偶联比(DAR)是指偶联物中的抗体对小分子毒素药物的平均负载量。虽然对 于特定偶联物分子而言，小分子毒素药物部分与抗体部分结合的比率具有确切值，但是应理解当用来描述含有许多分子的样品时，该值是指根据不同特定偶联物分子所占百分比计算得到的平均值，该负载量平均值在本文中称为平均偶联比或“DAR”。
NCCN指南是指美国国立综合癌症网络(National Comprehensive Cancer Network)发布的针对各种恶性肿瘤的临床实践指南。
CSCO诊疗指南是指中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)发布的针对各种恶性肿瘤的临床诊疗指南。
客观缓解率(Objective response rate，ORR)指肿瘤缩小达到一定程度并且保持一定时间的病人的比例，包含了CR和PR的病例。采用肿瘤缓解评估标准1.1版(response evaluation criteria in solid tumours version 1.1，RECIST1.1标准)来评定肿瘤客观缓解。受试者在基线时必须伴有可测量的肿瘤病灶，疗效评定标准根据RECIST 1.1标准分为完全缓解(CR)、部分缓解(PR)、疾病稳定(SD)，疾病进展(PD)。
疾病进展(PD)：以整个研究过程中所有测量的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)；除此之外，必须满足直径和的绝对值增加至少5mm(出现一个或多个新病灶也视为疾病进展)。
疾病稳定(SD)：靶病灶减小的程度没达到PR，增加的程度也没达到PD水平，介于两者之间，研究时可以直径之和的最小值作为参考。
部分缓解(PR)：靶病灶之和相比基线至少减少30％。
完全缓解(CR)：所有靶病灶消失，全部病理淋巴结(包括靶结节和非靶结节)短直径必须减少至＜10mm。
剂量限制性毒性(Dose Limiting Toxicities，DLT)：成为限制继续增大药物剂量的主要原因的药物毒副作用。
不良事件(Adverse Event，AE)：指患者或临床研究受试者接受一种药物后出现的任何不良医学事件，但并不一定与治疗有因果关系。
治疗期间出现的不良事件(Treatment Emergent Adverse Event，TEAE)：指在首次给药时或之后发生的或恶化的任何AE。
附图说明
此处所说明的附图用来提供对本发明的进一步理解，构成本申请的一部分，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图 中：
图1显示了偶联物A与已上市药物Trodelvy TM的体外血浆稳定性情况。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。以下对至少一个示例性实施例的描述实际上仅仅是说明性的，绝不作为对本发明及其应用或使用的任何限制。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1.4-((S)-2-(4-氨基丁基)-35-(4-((6-(2-(甲基磺酰基)嘧啶-5-基)己-5-酰胺基)甲基)-1H-1,2,3-三唑-1-基)-4,8-二氧代-6,12,15,18,21,24,27,30,33-九氧杂-3,9-二氮杂三十五烷酰胺基)苄基((S)-4-乙基-11-(2-(N-异丙基甲基磺酰胺基)乙基)-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]中氮茚并[1,2-b]喹啉-4-基)碳酸酯
Figure PCTCN2022089737-appb-000019
步骤一：6-(2-(甲基磺酰基)嘧啶-5-基)-N-(丙-2-炔-1-基)己-5-炔酰胺的合成
25℃下将丙-2-炔-1-胺(189mg,3.4mmol)和化合物3-4(800mg,2.83mmol)溶于二氯甲烷(10mL)中，依次加入N,N-二异丙基乙胺(738mg,5.67mmol)，O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(1.63g,4.25mmol),搅拌反应2h。反应液减压浓缩，残余物经快速硅胶柱纯化(乙酸乙酯/石油醚＝3/1)得标题化合物，700mg。ESI-MS(m/z):306.1[M+H]+。
步骤二：4-((S)-35-叠氮基-2-(4-(((4-甲氧基苯基)二苯甲基)氨基)丁基)-4,8-二氧代-6,12,15,18,21,24,27,30,33-九氧杂-3,9-二氮杂三十五烷酰氨基)苄基((S)-4-乙基-11-(2-(N-异丙基甲磺酰胺基)乙基)-3,14-二氧代-3,4,12,14-四氢-2H-吡喃并[2,3-b]-1H-吡喃并[3',4'：6,7]吲嗪并[1,2-b]喹啉-4-基)碳酸酯的合成
25℃氮气保护下，将T-030(250mg,0.49mmol)溶于二氯甲烷(10mL)中，降温至0℃，加入4-二甲氨基吡啶(478mg,3.91mmol)的二氯甲烷(3mL)溶液，然后缓慢滴加三光气(72mg,0.24mmol)的二氯甲烷(10mL)溶液，加毕，0℃搅拌反应20min，反应液用氮气吹20min。加入(S)-2-(32-叠氮基-5-氧代-3,9,12,15,18,21,24,27,30-九氧杂-6-氮杂三联乙酰胺基)-N-(4-(羟甲基)苯基)-6(((4-甲氧基苯基)二苯甲基)氨基)乙酰胺(518mg,0.49mmol)的二氯甲烷(7mL)溶液，加毕，0℃搅拌反应1h。反应液减压浓缩，残余物经制备高效液相色谱纯化得标题化合物，500mg。ESI-MS(m/z):1597.5[M+H]+。
步骤三：(S)-4-乙基-11-(2-(N-异丙基甲磺酰胺基)乙基)-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]吲嗪并[1,2-b]喹啉-4-基(4-((S)-2-(4-(((4-甲氧基苯基)二苯基甲基)氨基)丁基)-35-(4-((6-(2-(甲基磺酰基)嘧啶-5-基)己-5-酰胺基)甲基)-1H-1,2,3-三唑-1-基)-4,8-二氧代-6,12,15,18,21,24,27,30,33-壬氧基-3,9-二氮杂三十五烷酰胺基)苄基)碳酸酯的合成
室温下，将化合物33-1(14mg，0.05mmol)溶于二甲基亚砜和水(2.0mL：0.5mL)中，加入溴化亚铜(11mg，0.08mmol)，搅拌反应1h。经制备高效液相色谱纯化，得标题化合物，30mg。ESI-MS(m/z):815.9[(M-273)/2+H]+。
步骤四：4-((S)-2-(4-氨基丁基)-35-(4-((6-(2-(甲基磺酰基)嘧啶-5-基)己-5-酰胺基)甲基)-1H-1,2,3-三唑-1-基)-4,8-二氧代-6,12,15,18,21,24,27,30,33-九氧杂-3,9-二氮杂三十五烷酰胺基)苄基((S)-4-乙基-11-(2-(N-异丙基甲基磺酰胺基)乙基)-3,14-二氧代-3,4,12,14-四氢-1H-吡喃并[3',4':6,7]中氮茚并[1,2-b]喹啉-4-基)碳酸酯(化合物IM-1)的合成
将化合物33-2(30mg，0.02mmol)溶于二氯甲烷(1.0mL)反应液中加入三氟乙酸(0.2mL)，室温反应30min。经制备高效液相色谱纯化(方法C)，得标题化合物的三氟乙酸盐， 20.0mg。其结构表征如下：
1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.10(s,2H),8.38(t,J＝5.56Hz,1H),8.32(d,J＝8.40Hz,1H),8.22–8.20(m,2H),8.09(t,J＝5.68Hz,1H),7.91–7.87(m,2H),7.82–7.78(m,1H)，7.69(brs,3H),7.61(d,J＝8.56Hz,2H),7.32(d,J＝8.56Hz,2H),7.06(s,1H),5.56(d,J＝16.96Hz,1H),5.51(d,J＝16.96Hz,1H),5.47(d,J＝19.28Hz,1H),5.42(d,J＝19.28Hz,1H),5.14(d,J＝12.20Hz,1H),5.07(d,J＝12.16Hz,1H),4.48(t,J＝5.24Hz,2H),4.46–4.43(m,1H),4.29(d,J＝5.60Hz,2H),4.08–3.95(m,5H),3.79(t,J＝5.28Hz,2H),3.51–3.43(m,32H),3.40(s,3H),3.39–3.35(m,2H),3.30–3.26(m,2H),3.00(s,3H),2.82–2.74(m,2H),2.56(t,J＝7.08Hz,2H),2.29(t,J＝7.36Hz,2H),2.23–2.13(m,2H),1.82(p,J＝7.24Hz,2H),1.78–1.63(m,2H),1.61–1.49(m,2H),1.42–1.27(m,2H),1.15(d,J＝6.80Hz,3H),1.13(d,J＝6.76Hz,3H),0.90(t,J＝7.32Hz,3H).ESI-MS(m/z):816.0[M/2 +H] +。[α] D 20为-19.55°(c＝1.000g/100mL,CH 3CN).
实施例2.偶联物A的制备
取0.3mLSacituzumab抗体(抗Trop-2，33.5mg/mL)，用0.25mL含有20mM PB、150mM NaCl和20mM依地酸钠的溶液(pH7.6)稀释，后加入0.45mL含有20mM PB和150mM NaCl的溶液(pH 7.6)混匀，以1M Na 2HPO 4溶液调pH至7.4，加入10mM TCEP(三(2-羧乙基)膦)溶液混匀，室温放置30min。向上述溶液体系加入10倍物质的量的溶解在二甲基亚砜中的IM-1三氟乙酸盐，混匀，室温静置2h，完毕后加入100mM半胱氨酸6.1μl终止反应。最后采用G-25凝胶柱将缓冲液置换为pH6.5的PBS缓冲溶液，得到IM-1与Sacituzumab抗体偶联的产物，命名为偶联物A。
Figure PCTCN2022089737-appb-000020
用LCMS方法对偶联物A进行分子量分析，将偶联物A轻链、重链的实测分子量与偶联不同个数毒素的轻链、重链的理论分子量进行关联，测定得到偶联物A中的每个抗体分子上偶联1～10个毒素(即γ为1～10)，进而根据偶联不同数量毒素的偶联物分子各自所 占百分比计算得到平均偶联比(DAR)约为6.9。
参照实施例2，分批次制备，得到DAR值范围在6～8的偶联物A样品(如7.3或7.4)，并进行以下非临床及临床研究。
实验例1.检测偶联物对胰腺癌细胞株的增殖抑制作用
用
Figure PCTCN2022089737-appb-000021
化学发光细胞活率检测方法(即CTG方法)检测偶联物A对BxPC-3细胞(胰腺癌细胞系，来源：ATCC，TROP2阳性细胞)增殖的影响。试验第1天，收集处于指数生长期的BxPC-3细胞，以培养基调整细胞悬液浓度并加入96-孔细胞培养板，最终细胞浓度为2000细胞/孔，于37℃、5％CO 2培养箱中培养过夜。试验第2天，偶联物A(终浓度为0.152～1000nM)以1:3倍梯度稀释至10倍浓度工作液，每孔分别加入10μl相应的10倍浓度工作液，每个药物浓度各3个复孔，加药后细胞置于37℃、5％CO 2孵箱中培养72小时。试验第5天，每孔加入50μl(1/2培养体积)预先融化并平衡到室温的CTG溶液，用微孔板震荡器混匀2分钟，于室温放置20分钟后用Envision 2104读板仪测定荧光信号值。
测试结果表明，偶联物A对TROP2阳性细胞BxPC-3增殖有显著抑制，其IC 50为14.3nM，最大抑制率为95.3％。由此说明，偶联物A能抑制TROP2阳性的胰腺癌细胞增殖，提示其具有治疗胰腺癌的作用。
实验例2.检测偶联物对心血管和呼吸功能的影响
将食蟹猴分为10只(雌雄各半)/组，将偶联物A分别以25mg/kg，50mg/kg，75mg/kg的剂量静脉注射给药，每2周给药1次，共给药4次，采用大动物无创生理信号遥测系统检测Ⅱ导联心电图和呼吸频率，无创血压计测量动脉血压，以评价偶联物A对食蟹猴心血管和呼吸功能的影响。
结果发现：在第1次给药前、给药后2～3小时、24～25小时、72～73小时、7天、以及末次给药后约2～3小时及恢复期结束前，偶联物A各给药组猴的Ⅱ导联心电图未见心律失常，心率、R-R间期、P波时间、P-R间期、QRS波时间、Q-T间期、校正Q-T间期等Ⅱ导联心电图指标及收缩压、舒张压、平均动脉压、呼吸频率未见明显异常。以上说明偶联物A对食蟹猴心血管和呼吸系统均无影响，具有良好的临床用药安全性前景。
实验例3.检测偶联物在动物体内的毒性代谢行为
将食蟹猴按照不同给药剂量分为4组：对照组、25mg/kg剂量组、50mg/kg剂量组和75 mg/kg剂量组，每组雌雄各5只。在25mg/kg、50mg/kg的剂量水平下，食蟹猴每2周1次、连续4次静脉注射偶联物A；各组猴于首、末次给药前及给药结束后即刻(给药结束0～1分钟)、4h、24h、48h、96h、168h，第2、3次给药前1小时内及给药结束后即刻(给药结束0～1分钟)，末次给药后336h采集血样。75mg/kg剂量组猴另于第3次给药后4h、24h、48h、96h、168h采集血样，以检测偶联物及其释放的毒素分子在其体内的毒代动力学行为。
下表记载了以上述方式给药后，偶联物A及偶联物A所释放的毒素分子在雄猴及雌猴体内的峰值血药浓度(C max)以及暴露量(AUC)。结果表明：偶联物A的最高无严重毒性剂量(HNSTD)为50mg/kg，该剂量末次给药后雌、雄猴毒素分子的暴露量分别为3.85h*μg/mL、5.86h*μg/mL，偶联物A雌、雄猴的暴露量分别为45.8h*mg/mL、64.2h*mg/mL。
Figure PCTCN2022089737-appb-000022
根据试验结果可以看出：各组动物于首次给药和末次给药后，ADC和毒素的暴露量或C max数据均较为接近，表明偶联物A连续静脉给药后无明显毒性蓄积，且在动物体内具有耐受性良好，临床用药安全性前景好。
实验例4.偶联物体外代谢稳定性
本实验首先将偶联物A和Trodelvy TM分别使用生理盐水配制成3.4mg/mL的工作液，将偶联物A和Trodelvy TM工作液分别加入人空白血浆中，获得浓度均为0.05mg/ml人血浆样品，将血浆样品在37℃条件下进行孵育，于1h、3h、24h、48h、72h和144h测定毒素 分子的释放情况，比较偶联物A与已上市药物Trodelvy TM的体外血浆稳定性差异。结果如附图1所示。
说明书附图1显示：随着孵育时间的增加，人血浆中游离毒素生成量增加，孵育24小时后，人血浆中偶联物A及上市ADC药物Trodelvy TM毒素分子释放百分比分别为28.5％和93.4％；孵育48小时后，人血浆中偶联物A及上市ADC药物Trodelvy TM毒素分子释放百分比分别为44.6％和109.1％；孵育72小时后，人血浆中偶联物A及上市ADC药物Trodelvy TM毒素分子释放百分比分别为53.7％和100.6％；孵育144小时后，人血浆中偶联物A及上市ADC药物Trodelvy TM释放毒素分子的百分比分别为65.3％和104.8％。
结果表明，偶联物A在人血浆中毒素分子释放速率明显低于Trodelvy TM，说明偶联物A在人血浆中较为稳定，毒素在血浆中释放量少，有效达到靶向肿瘤部位再释放毒素的目的，同时，与上市药物Trodelvy TM相比，偶联物A能够降低因毒素在血浆内过快过多释放而导致的严重不良反应风险。
试验例1.I期临床研究
一、试验方案
对患有经组织学确诊的上皮来源的恶性肿瘤患者利用偶联物A进行治疗。所有患者均属于经标准治疗失败，或无标准治疗方案，或现阶段不适用标准治疗的不可手术切除的局部晚期或转移性实体瘤。基于患者体重，研究设计了2、4、6、9和12mg/kg共5个剂量水平，每2周静脉注射给药一次，每28天为一个周期，每周期给药直到疾病进展或发生不可耐受的毒性反应。采用BLRM方法评估所有计划剂量组和一些中间剂量组的毒性。基于模型分析，由申办方和研究者共同决定剂量递增决策。
二、安全性结果
在治疗过程中，2mg/kg剂量组未出现3级以上的“治疗期间出现的不良事件(Treatment Emergent Adverse Events，以下称为TEAEs)”；4mg/kg剂量组出现3级TEAEs，包括口腔粘膜炎，贫血等；6mg/kg剂量组出现3级以上的TEAEs，包括中性粒细胞计数降低，白细胞数降低等；上述3级以上的TEAEs在对症治疗后可恢复，可持续用药，说明偶联物A具有良好的临床安全性。
三、有效性结果
对各个适应症的治疗结果如下：
1.三阴性乳腺癌(TNBC)
在所有的三阴性乳腺癌患者中，有部分患者疾病得到部分缓解。
对一名以往接受过阿霉素/环磷酰胺/紫杉醇新辅助化疗、左乳房切除术、左胸放疗后进展的患者，以基于患者体重4mg/kg的剂量，按照上述给药周期静脉输注偶联物A，18周后观察到疾病部分缓解，持续6周。在多次疗效评估中，靶病灶总体积缩小比例可达40％。患者未出现严重不良事件。
2.卵巢癌
在所有的卵巢癌患者中，有部分患者的疾病得到部分缓解。
对一名以往接受过子宫切除术、卵巢肿瘤切除术、卡铂/紫杉醇、鲁卡帕尼、卡铂/多西他赛/贝伐珠单抗多线治疗失败的卵巢癌患者，以基于患者体重4mg/kg的剂量、按照上述给药周期静脉输注偶联物A，21周后观察到疾病部分缓解，持续15周。经多次疗效评估，靶病灶总体积缩小比例可达64.8％，且其中1个靶病灶完全消失。患者未出现严重不良事件。
3.HER2阳性的乳腺癌
对一名以往接受过乳腺癌改良根治术、表柔比星/紫杉醇、HER2单克隆抗体/多西他赛、卡培他滨治疗无效的HER2阳性的乳腺癌患者以基于患者体重6mg/kg的剂量、按照上述给药周期静脉输注偶联物A，8周后观察到疾病得到部分缓解。经多次疗效评估，靶病灶总体积缩小比例可达49.6％。
4.胃癌
对一名以往接受过全胃切除、紫杉醇/替吉奥、安罗替尼/替吉奥、安罗替尼/卡培他滨、奥沙利铂/氟尿嘧啶、奥沙利铂/雷替曲塞治疗无效的胃癌患者以基于患者体重4mg/kg的剂量、按照上述给药周期静脉输注偶联物A，15周后观察到疾病得到部分缓解，已持续10周，目前仍在获益。经多次疗效评估，靶病灶总体积缩小比例可达62.8％，其中一个靶病灶消失。患者未出现严重的不良反应事件。
5.胰腺癌
对一名以往接受过胰腺癌远端切除术、放疗、吉西他滨/卡培他滨、吉西他滨/伊利替康/氟尿嘧啶、吉西他滨/白蛋白紫杉醇/奥沙利铂/氟尿嘧啶、纳武单抗/cabiralizumab多线治疗失败的胰腺癌患者，以基于患者体重4mg/kg的剂量、按照上述给药周期静脉输注偶联物A，7周后观察到疾病稳定，持续30.3周，经多次疗效评估，靶病灶总体积缩小比例可达8.8％，且患者未出现严重不良事件。
综上可见，I期临床试验显示，偶联物A至少在上述经标准治疗失败的不可手术切除的转移性TNBC、卵巢癌、HER2阳性的乳腺癌、胃癌和胰腺癌中初步显示较好的疗效， 而没有诱发可能妨碍临床使用的严重毒性。这些结果证明偶联物A用于治疗肿瘤疾病具有良好的安全性和有效性，且不同批次制备的DAR值范围在6～8的偶联物A(如DAR值为7.3或DAR值为7.4)具有基本一致的有效性及安全性表现。
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (11)

  1. 式(I)所示生物活性物偶联物在制备治疗肿瘤疾病的药物中的用途；
    {D-[L 1-(L 2) m1-(L 3) m2-(L 4) m3-E]} γ-A
    式(I)
    其中，
    L 1为
    Figure PCTCN2022089737-appb-100001
    其中，各R 1和R 2各自独立地为氢(例如氕或氘)、卤素、羧酸基、磺酸基、氰基、C 1-6烷基、卤代C 1-6烷基、氰基取代的C 1-6烷基(例如-CH 2CN)、C 1-6烷氧基、C 2-10烯基或C 2-10炔基；Z 1为氨基酸或2～10个氨基酸组成的肽；x 1和x 2各自独立地为0、1、2、3、4、5或6；并且L 1的1位置处与D相连、L 1的2位置处与L 2相连；
    L 2为
    Figure PCTCN2022089737-appb-100002
    其中，y 1为0、1、2、3、4、5、6、7、8、9或10；并且L 2的1位置处与L 1相连、L 2的2位置处与L 3相连；
    L 3选自5～12元杂芳环；
    L 4为
    Figure PCTCN2022089737-appb-100003
    其中Z 2选自C 1-6亚烷基、C 2-10亚烯基、C 2-10亚炔基、和C 3-8亚环烷基；R 3选自H和C 1-6烷基；Z 3不存在或者选自C 1-6亚烷基；或者，R 3与Z 3连同其所连接的氮原子形成4～8元杂环基；α为0、1、2、3、4、5或6，并且L 4的2位置处与E相连、L 4的1位置处与L 3相连；
    E为
    Figure PCTCN2022089737-appb-100004
    其中，各R 4独立地为氢(例如氕或氘)，β为0、1或2，并且E的2位置处与A相连(例如与A上的巯基相连)、E的1位置处与L 4相连；
    m 1、m 2和m 3各自独立地为0、1、2、3、4、5、6、7、8、9或10；
    D为生物活性分子片段；
    γ选自1～10之间的整数；优选地，γ选自3～8之间的整数(例如3、4、5、6、7或8)；
    A为抗Trop-2的单克隆抗体或其抗原结合片段。
  2. 根据权利要求1所述的用途，其中所述肿瘤疾病为经标准治疗失败，或无标准治疗方案，或现阶段不适用标准治疗的不可手术切除的局部晚期或转移性实体瘤。
  3. 根据权利要求1或2所述的用途，所述肿瘤疾病包括但不限于乳腺癌(例如Luminal A型、Luminal B型、Her-2阳性型和三阴性型乳腺癌)、胃癌、肺癌、卵巢癌、尿路上皮癌、食管癌、肝癌、结直肠癌、宫颈癌、子宫内膜癌、胰腺癌、膀胱癌、或脑肿瘤；优选为乳腺癌(例如三阴性乳腺癌或Her2阳性乳腺癌)、卵巢癌(例如卵巢上皮癌)、胃癌、肺癌、胰腺癌、膀胱癌、或尿路上皮癌；更优选地，所述肿瘤疾病为三阴性乳腺癌、Her2阳性乳腺癌、卵巢癌、胃癌、肺癌或胰腺癌；进一步优选地，所述肿瘤疾病为三阴性乳腺癌、Her2阳性乳腺癌、卵巢癌或胃癌；
    优选地，所述卵巢癌选自铂敏感型和铂耐药型卵巢癌；
    优选地，所述胃癌选自胃腺癌、胃腺鳞癌、胃鳞状细胞癌、胃未分化癌、胃神经内分泌肿瘤；
    优选地，所述胰腺癌选自胰腺上皮性肿瘤、胰腺外分泌肿瘤、胰腺交界性肿瘤、胰腺导管腺癌、胰腺内分泌肿瘤、胰腺成熟性畸胎瘤、胰腺间叶性肿瘤、胰腺恶性淋巴瘤、胰腺继发性肿瘤；
    优选地，所述膀胱癌选自尿路上皮(移行细胞)癌、膀胱鳞状细胞癌和膀胱腺癌；优选地，所述尿路上皮癌选自基底样型、管腔样型和野生型尿路上皮癌；
    优选地，所述肺癌选自小细胞肺癌和非小细胞肺癌。
  4. 根据权利要求1～3任一项所述的用途，所述偶联物具有下述结构：
    L 1选自
    Figure PCTCN2022089737-appb-100005
    Figure PCTCN2022089737-appb-100006
    并且L 1的1位置处与D相连、L 1的2位置处与L 2相连；
    L 2为
    Figure PCTCN2022089737-appb-100007
    其中，y 1为3、4、5、6、7、8、9或10；并且L 2的1位置处与L 1相连、L 2的2位置处与L 3相连；
    L 3选自5～6元杂芳环，例如吡唑或三氮唑；
    L 4为
    Figure PCTCN2022089737-appb-100008
    其中Z 2选自C 1-3亚烷基；R 3为H；Z 3选自C 1-3亚烷基；α为1，并且L 4的2位置处与E相连、L 4的1位置处与L 3相连；
    E为
    Figure PCTCN2022089737-appb-100009
    其中，各R 4独立地为氢(例如氕或氘)，β为0、1或2，并且E的2位置处与A相连(例如与A上的巯基相连)、E的1位置处与L 4相连；
    m 1、m 2和m 3均为1；
    所述生物活性分子选自
    Figure PCTCN2022089737-appb-100010
    优选地，所述生物活性分子通过自身羟基与L 1的1位置处相连；
    γ选自3～8之间的整数(例如3、4、5、6、7或8)；
    A为Sacituzumab或其抗原结合片段。
  5. 根据权利要求1～4任一项所述的用途，所述偶联物结构如下：
    Figure PCTCN2022089737-appb-100011
    其中，γ为1～10的整数；优选的，γ选自5～8之间的整数；
    优选地，所述偶联物的DAR值为1～12；更优选地，所述偶联物的DAR值为1～10；进一步优选地，DAR值为5～8；例如，DAR值为6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、或8.0。
  6. 一种肿瘤疾病的治疗方法，所述方法包括给予有此需要的个体治疗有效量的如权利要求1、4或5任意一项所述的生物活性物偶联物和/或包含权利要求1、4或5任意一项所述的生物活性物偶联物的药物组合物的步骤；所述肿瘤疾病选自如权利要求1～3任意一 项所述的肿瘤疾病。
  7. 根据权利要求6所述的方法，所述药物组合物包含所述生物活性物偶联物以及药学上可接受的载体和/或赋形剂。
  8. 根据权利要求6或7所述的方法，所述生物活性物偶联物或所述药物组合物每7～35天施用一次，优选每7～28天施用一次，例如每7天、14天、21天、28天、或35天给药1次。
  9. 根据权利要求6～8任意一项所述的方法，所述偶联物或药物组合物的施用途径包括但不限于口服、经皮注射、直肠给药、经黏膜给药、肌内注射、髓内注射、静脉内注射、腹膜内注射，优选静脉内注射。
  10. 根据权利要求6～9任意一项所述的方法，所述生物活性物偶联物的每次给药剂量基于患者体重为1mg/kg至30mg/kg；优选为1mg/kg至20mg/kg；更优选为2mg/kg至12mg/kg；进一步优选为2～5mg/kg、4～7mg/kg、6～9mg/kg、8～11mg/kg、10～13mg/kg、或者12～15mg/kg。
  11. 根据权利要求6～10任意一项所述的方法，其分为一个或多个给药阶段(例如一个、二个、三个或四个阶段)，每一阶段的给药周期如权利要求8所述，和/或每一阶段的给药剂量如权利要求10所述。
PCT/CN2022/089737 2021-04-30 2022-04-28 药物在治疗肿瘤疾病中的应用 Ceased WO2022228497A1 (zh)

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WO2024240084A1 (zh) * 2023-05-22 2024-11-28 四川科伦博泰生物医药股份有限公司 药物偶联物治疗肿瘤疾病的用途及方法
WO2025002263A1 (zh) * 2023-06-30 2025-01-02 默沙东有限责任公司 治疗组合及其用途和治疗方法
WO2025209442A1 (zh) * 2024-04-03 2025-10-09 四川科伦博泰生物医药股份有限公司 偶联物在治疗肿瘤疾病中的用途及方法
WO2025241959A1 (zh) * 2024-05-22 2025-11-27 四川科伦博泰生物医药股份有限公司 抗体药物偶联物在预防或治疗疾病中的应用

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WO2024175042A1 (zh) * 2023-02-24 2024-08-29 四川科伦博泰生物医药股份有限公司 药物偶联物治疗肿瘤疾病的用途及方法
WO2024240084A1 (zh) * 2023-05-22 2024-11-28 四川科伦博泰生物医药股份有限公司 药物偶联物治疗肿瘤疾病的用途及方法
WO2025002263A1 (zh) * 2023-06-30 2025-01-02 默沙东有限责任公司 治疗组合及其用途和治疗方法
WO2025209442A1 (zh) * 2024-04-03 2025-10-09 四川科伦博泰生物医药股份有限公司 偶联物在治疗肿瘤疾病中的用途及方法
WO2025241959A1 (zh) * 2024-05-22 2025-11-27 四川科伦博泰生物医药股份有限公司 抗体药物偶联物在预防或治疗疾病中的应用

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