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)
Chinese (zh)
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 MX2023012797A priority Critical patent/MX2023012797A/es
Priority to IL308098A priority patent/IL308098A/en
Priority to US18/557,900 priority patent/US20240238434A1/en
Priority to JP2023565918A priority patent/JP2024516217A/ja
Priority to KR1020237040823A priority patent/KR20240004657A/ko
Priority to CN202610018019.1A priority patent/CN121490094A/zh
Priority to EP22794967.4A priority patent/EP4331614A4/en
Priority to CA3217111A priority patent/CA3217111A1/en
Application filed by Sichuan Kelun Biotech Biopharmaceutical Co Ltd filed Critical Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority to AU2022263701A priority patent/AU2022263701B2/en
Priority to CN202280025989.4A priority patent/CN117157106A/zh
Priority to BR112023022540A priority patent/BR112023022540A2/pt
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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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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