WO2024051792A1 - Ast-3424联用治疗白血病及淋巴瘤 - Google Patents

Ast-3424联用治疗白血病及淋巴瘤 Download PDF

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WO2024051792A1
WO2024051792A1 PCT/CN2023/117606 CN2023117606W WO2024051792A1 WO 2024051792 A1 WO2024051792 A1 WO 2024051792A1 CN 2023117606 W CN2023117606 W CN 2023117606W WO 2024051792 A1 WO2024051792 A1 WO 2024051792A1
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leukemia
lymphoma
akr1c3
ast
daunorubicin
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PCT/CN2023/117606
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English (en)
French (fr)
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谢燕彬
郝静
齐天阳
孟繁英
段建新
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深圳艾欣达伟医药科技有限公司
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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
    • A61K31/04—Nitro compounds
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to a method for treating tumors, especially the treatment of leukemia and lymphoma using AST-3424 in combination with drugs, and belongs to the field of tumor treatment.
  • the DNA alkylating agent prodrug AST-3424 (WO2016145092, WO2017087428), which targets overexpression of aldehyde-keto reductase 1C3 (AKR1C3), has a CAS number of 2097713-69-2 and its structure is as follows:
  • AST-3424 (also known as OBI-3424, TH-3424) enters cancer cells and is activated by the AKR1C3 enzyme overexpressed by cancer cells to release the metabolite AST-2660 (also known as AST-2660).
  • AST-3424 itself is less toxic to cancer cells.
  • AKR1C3 enzyme the prodrug AST-3424 metabolizes AST-2660 under the action of AKR1C3 enzyme and NADPH.
  • the expression level is positively correlated with drug efficacy (Meng F, Li WF, Jung D, et al.
  • Anovel selective AKR1C3-activated prodrug AST-3424/OBI-3424 exhibits broad anti-tumor activity.
  • AST-3424 has excellent inhibitory effects on HCC cell lines HepG2 and PLC/PRF/5 with high AKR1C3 expression, and it can be used in combination with oxaliplatin (OXA) or 5-fluorouracil (5- Fu), the inhibitory effect is stronger and has a synergistic effect.
  • OXA oxaliplatin
  • 5-fluorouracil 5-fluorouracil
  • the West-bolt test showed that the mechanism may be related to the upregulation of P21 protein, but may not be related to the expression of ⁇ -catenin ( ⁇ -catenin);
  • AST-3424 monotherapy and combination treatment with OXA or 5-Fu can block cells in the S phase.
  • Detection of AST-3424 monotherapy and OXA by flow cytometry Or the induction of apoptosis after combined treatment with 5-Fu suggests that AST-3424 monotherapy and combined treatment with OXA or 5-Fu may induce apoptosis by upregulating Bax and Caspase3 proteins and downregulating PARP proteins;
  • Transwell cell migration and invasion assays showed that AST-3424 monotherapy and combined treatment with OXA or 5-Fu can inhibit the migration and invasion of tumor cells, and the mechanism may be related to the downregulation of MMP-9 protein;
  • AST-3424 is related to the expression of AKR1C3 enzyme. Only patients or animal models with high expression of AKR1C3 enzyme have better efficacy, and published drug combinations (abiraterone, Prednisolone, 5-fluorouracil, sunitinib, oxaliplatin) in vitro cell proliferation experiments and CDX animal models are also related to AKR1C3 enzyme expression. These studies have shown that AST-3424, whether as a single agent or in combination, requires patients to have a higher level of AKR1C3 enzyme expression (detected by kits, such as IHC/q-PCR methods).
  • the inventor found that the inhibitory effect of AST-3424 in combination with cytarabine or daunorubicin on the proliferation of leukemia and lymphoma cells in vitro has nothing to do with the expression level of AKR1C3 in the cell lines. All cell lines have good in vitro proliferation inhibitory effects.
  • the above-mentioned combination regimen is expected to be developed into a new treatment regimen for the treatment of leukemia and lymphoma, without the need to limit patients' AKR1C3 enzyme overexpression or high expression (which often corresponds to higher RNA quantification values) as revealed in previous research literature. , higher IHC H-score).
  • the new treatment plan has significantly lowered the medication threshold for patients who will benefit. If the test result is positive and the expression is positive, this combination regimen can be used, as long as the medical personnel determine that the use of this regimen for treatment will benefit or benefit the patient. possible.
  • Treatment method use drugs containing AST-3424, AST-3423 or AST-2870 and their salts, esters, solvates, isotopomers and drugs containing cytarabine or daunorubicin and their salts, esters, solvents Drug combinations of compounds and isotopes are used to treat patients with leukemia and lymphoma.
  • AST-3424, AST-3423 or AST-2870 and its salts, esters, solvates, isotopomers are 7 parallel options, namely AST-3424, AST-3423, AST-2870, AST- Salts of AST-3424, AST-3423 or AST-2870, esters of AST-3424, AST-3423 or AST-2870, solvates of AST-3424, AST-3423 or AST-2870, AST-3424, AST-3423 or Isotopomers of AST-2870.
  • “Cytarabine or daunorubicin and its salts, esters, solvates and isotopomers” are 6 parallel options, namely cytarabine, daunorubicin, cytarabine or daunorubicin. Salts of erythromycin, esters of cytarabine or daunorubicin, solvates of cytarabine or daunorubicin, isotopic isomers of cytarabine or daunorubicin.
  • AST-3424, AST-3423 or AST-2870 and their salts, esters, solvates and isotopomers which are used in the preparation and preparation of products containing daunorubicin or cytarabine and their salts, esters, Drugs used in combination with solvates and isotopic isomers to treat leukemia or lymphoma.
  • AST-3423 is the enantiomer of AST-3424
  • AST-3424 is the S configuration
  • AST-3423 is the R configuration
  • AST-2870 is the racemate
  • the three have similar AKR1C3 enzyme activation properties. They are all catalyzed by NADPH and AKR1C3 and release the cytotoxic substance AST-2660, which exerts medicinal effects.
  • the drugs described herein refer to drugs or preparations.
  • the prepared drugs contain active ingredients in a specific dosage range or their salts or solvates, and/or the prepared drugs are administered in a specific dosage form and a specific administration method.
  • the prepared medicines, medicines and preparations may also contain pharmaceutically acceptable auxiliary materials or excipients.
  • the medicine can be in any dosage form for clinical use, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated agents, granules, dry powders, oral solutions, small injection needles , freeze-dried powder for injection or large infusion.
  • pharmaceutically acceptable excipients or excipients in the drug may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, viscosifiers, etc. Mixtures, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents, and pigments, etc.
  • Monotherapy refers to the use of only one anticancer drug in a course of treatment.
  • Combination therapy refers to the simultaneous or sequential use of two or more anti-cancer drugs in one course of treatment.
  • combination therapy needs to explore different dosages and dosage weeks based on the characteristics of the disease and the type of combined drugs. In this period, only based on the above situation, the explored combination drug treatment plan can achieve better therapeutic effects than single drug treatment.
  • the salt may be a basic salt, including the compound formed with an inorganic base (such as an alkali metal hydroxide, an alkaline earth metal hydroxide, etc.) or an organic base (such as a monoethanolamine, diethanolamine, or triethanolamine, etc.) Salt.
  • the salt may be an acid salt, including the compound with an inorganic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid, etc.) or with an organic acid (such as methanesulfonic acid). , trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid, etc.). Similarly, it may also react with certain acids or alcohols to form esters, so the compounds may also be administered in the form of esters.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid, etc.
  • organic acid such as methanesulfonic acid
  • methanesulfonic acid
  • these compounds may also form solvates with certain solvents, which are hydrates or alcoholates, and therefore the compounds may also be administered in the form of solvates.
  • solvents which are hydrates or alcoholates
  • the compounds may also be administered in the form of solvates.
  • the selection and preparation of acceptable salts, esters, solvates, and the like of compounds is well known in the art.
  • isotopic variant refers to compounds containing unnatural proportions of isotopes at one or more of the atoms that make up such compounds.
  • “isotopic variants” of compounds contain unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1H ), deuterium ( 2H ), tritium ( 3H ), carbon -11( 11 C), Carbon-12( 12 C), Carbon-13( 13 C), Carbon-14( 14 C), Nitrogen-13( 13 N), Nitrogen-14( 14 N), Nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), Fluorine-18( 18 F), Phosphorus-31( 31 P), Phosphorus-32( 32 P), Phosphorus-33( 33 P), Sulfur-32( 32 S), Sulfur-33( 33 S) , Sulfur-34( 34 S), Sulfur-35( 35
  • “isotopic variants" of a compound are in a stable form, that is, non-radioactive.
  • “isotopic variants” of compounds contain unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1H ), deuterium ( 2H ), carbon-12 ( 12C ) , Carbon-13( 13 C), Nitrogen-14( 14 N), Nitrogen-15( 15 N), Oxygen-16( 16 O), Oxygen-17( 17 O), Oxygen-18( 18 O), Fluorine -17( 17 F), phosphorus-31( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-36( 36 S), chlorine-35 ( 35 Cl), chlorine-37 ( 37 Cl), bromine-79 ( 79 Br), bromine-81 ( 81 Br) and iodine-127 ( 127 I).
  • “isotopic variants” of a compound are in unstable forms, that is, radioactive.
  • “isotopic variants” of a compound contain unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( 11 C), carbon-14 ( 14 C), Nitrogen-13( 13 N), Oxygen-14( 14 O), Oxygen-15( 15 O), Fluorine-18( 18 F), Phosphorus-32( 32 P), Phosphorus-33( 33 P) , sulfur-35 ( 35 S), chlorine-36 ( 36 Cl), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-129 ( 129 I) and iodine-131 ( 131 I).
  • any hydrogen can be, for example, 2H or D, or any carbon can be, for example, 13C , or any nitrogen can be, for example, 15N , where feasible according to the judgment of one skilled in the art.
  • any oxygen can be 18 O.
  • "isotopic variants" of a compound contain unnatural proportions of deuterium (D).
  • Leukemia also known as blood cancer, is a malignant tumor of the hematopoietic system.
  • the cause of the disease is the abnormal working of the hematopoietic tissue in the bone marrow due to mutations in intracellular DNA.
  • leukemia There are many types of leukemia.
  • the types of leukemia are mainly distinguished by the type of abnormal blood cells in the blood. Academically, there are many classification methods.
  • the commonly used classification methods include the FAB classification and the new WHO classification promoted by the World Health Organization. Law. These classifications can provide guidance on patient prognosis and management. Clinically, it is generally divided into acute leukemia and chronic leukemia, including:
  • Acute lymphoblastic leukemia Acute Lymphoblastic Leukemia, referred to as ALL
  • ALL can be diagnosed and divided into different subtypes based on different differentiation antigens on the surface of leukemia cells using immunological techniques. It is generally divided into T and B cell lines, that is, acute T lymphocytes leukemia T-ALL and acute B lymphoblastic leukemia B-ALL);
  • Acute myeloid leukemia also known as acute myeloid leukemia, AML, is a blood cancer in which bone marrow white blood cells (not lymphoid white blood cells) proliferate abnormally;
  • Chronic lymphocytic leukemia Chronic Lymphocytic Leukemia, referred to as chronic lymphocytic leukemia (CLL)
  • CLL chronic lymphocytic leukemia
  • B-CLL chronic B lymphocytic leukemia
  • T-CLL chronic T lymphocytic leukemia
  • Chronic myeloid leukemia (commonly known as "chronic myeloid"), also known as chronic myeloid leukemia, Chronic myeloid l eukemia, referred to as CML;
  • Lymphoma a malignant tumor originating from lymph nodes or other lymphoid tissues, can be divided into two categories: Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL).
  • HD Hodgkin's disease
  • NHL non-Hodgkin's lymphoma
  • B-cell lymphoma and T-cell and NK-cell lymphoma are divided into two major categories: B-cell lymphoma and T-cell and NK-cell lymphoma.
  • B-cell lymphoma is further divided into two categories: precursor B-cell lymphoma and mature B-cell lymphoma.
  • Precursor B-cell lymphoma refers to precursor B-lymphoblastic lymphoma, while mature B-cell lymphoma is clinically more
  • the common ones are small cell lymphoma, plasma cell myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse B-cell lymphoma, Burkitt Lymphoma etc.
  • precursor T cell lymphoma and mature T cell lymphoma are also included.
  • Precursor T cell lymphoma mainly refers to precursor T lymphoblastic lymphoma and mature T cell lymphoma.
  • Common cell lymphomas include T-cell prolymphocytic leukemia, adult T-cell lymphoma, extranodal NK-T lymphoma, anaplastic large cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, etc.
  • the leukemia includes lymphocytic leukemia (including acute lymphoblastic leukemia and chronic lymphocytic leukemia), and the lymphoma includes lymphoblastic lymphoma.
  • the leukemia is acute lymphoblastic leukemia, preferably acute T lymphoblastic leukemia, and the lymphoma is T lymphoblastic lymphoma.
  • leukemia includes acute lymphoblastic leukemia, Acute lymphoblastic leukemia, acute lymphoblastic T-cell leukemia, T-ALL, T-cell leukemia, acute lymphoblastic leukemia; lymphoma includes T-lymphoblastic leukemia. , specifically T lymphoblastic lymphoma, T cell lymph oblastic lymphoma.
  • the dosage of daunorubicin and cytarabine in combined treatment is lower than the clinical dosage of their single drugs.
  • Daunorubicin is used clinically as its hydrochloride, daunorubicin hydrochloride.
  • the dosage form is sterile powder for injection. Before use, add physiological saline for injection and dissolve it for intravenous injection or infusion. It is mainly used clinically.
  • Acute myeloid leukemia whether daunorubicin is used alone or in combination with other anti-tumor drugs, daunorubicin is suitable for the treatment of all stages of the disease. Also used to treat promyelocytic leukemia;
  • Daunorubicin is used to treat this disease, and the remission rate is very high. However, due to its severe side effects and the availability of other effective treatments, daunorubicin is only suitable for those who have developed reactions to other drugs. drug-resistant cases;
  • daunorubicin has been observed to have a good effect on neuroblastoma and rhabdomyosarcoma.
  • Cytarabine clinically used is cytarabine for injection (using cytarabine or cytarabine hydrochloride), the dosage form is lyophilized powder, benzyl alcohol injection prepared by adding benzyl alcohol and water before use Liquid (generally sold together with freeze-dried powder) for intravenous injection or subcutaneous injection, mainly suitable for induction of remission and maintenance treatment of acute non-lymphocytic leukemia in adults and children. It also has a therapeutic effect on other types of leukemia, such as acute lymphoblastic leukemia and chronic myeloid leukemia (blast phase). It can be used alone or in combination with other anti-tumor drugs. The combination of drugs has better efficacy.
  • RNA test corresponding to AKR1C3 in the blood sample of the leukemia patient was positive, and the AKR1C3 protein test in the tumor tissue sample of the lymphoma patient was positive;
  • the leukemia patient was tested positive for RNA corresponding to AKR1C3, and the lymphoma patient was tested positive for AKR1C3 protein.
  • AST-3424 single-agent or combination treatment regimens are limited to animal models or patients with excessive or overexpression of AKR1C3, and this treatment regimen/pharmaceutical use involves AST-3424 and daunorubicin.
  • the combined use of AKR1C3 and cytarabine in the treatment of leukemia/lymphoma only requires a positive test for the corresponding AKR1C3 protein or RNA to be expressed. It still has significant efficacy in positive cases.
  • Overexpression that is, overexpression
  • AKR1C3 in different tumors (solid tumors or blood cancers), please refer to the literature Evans K, Duan J, Pritchard T, et al.
  • OBI-3424 a Novel AKR1C3-Activated Prodrug, Exhibits Potent Efficacy against Preclinical Models of T -ALL.Clin Cancer Res.2019;25(14):4493-4503.doi:10.1158/1078-0432.CCR-19-0551 (Disclosure of AKR1C3 expression in acute lymphoblastic leukemia) and Guise CP, Abbattista MR, Singleton RS, et al.
  • the bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3. Cancer Res. 2010;70(4):1573-1584.doi:10.1158/0008-5472.CAN-09 -3237 (discloses AKR1C3 expression in different solid tumors).
  • RNA corresponding to AKR1C3 in the blood sample of the leukemia patient was detected with a Log 2 FPKM quantitative value, which was greater than or equal to 0.71.
  • the AKR1C3 protein quantification of the tumor tissue sample of the lymphoma patient was detected by western blot (WB) method.
  • WB western blot
  • the ratio of the AKR1C3 protein band to the reference protein band in the protein band is greater than or equal to 0.84;
  • RNA corresponding to AKR1C3 was detected in the leukemia patient, and the Log 2 FPKM quantitative value was detected, and the value was greater than or equal to 0.71.
  • the AKR1C3 protein quantification in the lymphoma patient was detected in the protein band detected by western blot (WB) method.
  • WB western blot
  • the ratio of the AKR1C3 protein band to the reference protein band, the value is greater than or equal to 0.84,
  • This application also provides a pharmaceutical combination, which includes the following substances as active ingredients:
  • AST-3424 AST-3423 or AST-2870 and their salts, esters, solvates, isotopomers, and
  • the active ingredients are formulated together or separately for use in combination, simultaneously or separately.
  • the drug combination of the present application includes at least two active ingredients, such as AST-3424 and daunorubicin, AST-3424 and cytarabine.
  • active ingredients such as AST-3424 and daunorubicin, AST-3424 and cytarabine.
  • pharmaceutically available excipients may also be included.
  • the two active ingredients that characterize the pharmaceutical combinations described herein may be formulated together (single dosage unit) or separately (set).
  • Two active ingredients formulated together or separately can usually be administered at the same time; or in view of the nature of their respective preparations, administered separately at a certain time interval, the time interval is conducive to the optimization of the compatibility of the two active ingredients .
  • the drug combination can be a compound drug, which is an active ingredient that is the above-mentioned AST-3424, AST-3423, AST-2870 or its salt, ester, solvate, isotope isomer and another active ingredient It is a pharmaceutical composition composed of daunorubicin, cytarabine or their salts, esters, solvates and isotopic isomers. In this case, the above active ingredients are formulated together and used simultaneously.
  • the drug combination could also be a kit similar to Pfizer's COVID-19 drug Paxlovid, sold together or separately.
  • the above-mentioned active ingredients are formulated separately, but the two or more separately formulated drugs can be administered at the same time, or they can be administered separately at a certain time interval according to the properties of the respective preparations.
  • the prepared medicine when formulated separately, contains the active ingredients AST-3424, AST-3423, AST-2870 or their salts, esters, solvates, isotopic isomers and pharmaceutical
  • the other drug contains the active ingredients daunorubicin, cytarabine or their salts, esters, solvates, isotopic isomers and pharmaceutically available excipients.
  • the drug combination composed of the above two drugs can be administered at the same time, or can be administered separately at a certain time interval according to the properties of the respective preparations.
  • the combined dosage of daunorubicin and cytarabine is lower than the clinical dosage of their single drugs.
  • This application also provides a pharmaceutical preparation, which is prepared from the active ingredients of the above-mentioned pharmaceutical combination and pharmaceutically available excipients.
  • the dosage form of the above-mentioned pharmaceutical preparation is selected from granules, tablets, pills, capsules or injections.
  • This application also provides the use of the above-mentioned drug combination and/or the above-mentioned pharmaceutical preparation in the preparation of anti-tumor drugs.
  • the above-mentioned tumor is selected from leukemia and lymphoma.
  • the leukemia includes lymphocytic leukemia, and the lymphoma includes lymphoblastic lymphoma; preferably, the leukemia is acute lymphoblastic leukemia, more preferably, it is acute T lymphocytic leukemia, and the lymphoma is T lymphoblastic lymphoma. .
  • Figure 1 shows the proliferation inhibition curves of three drugs on five cell lines
  • Figure 2 shows the experimental results of the effects of AST-3424, daunorubicin, and cytarabine alone or in combination on SUP-T1 cell proliferation;
  • Figure 3 shows the experimental results of the effects of AST-3424, daunorubicin, and cytarabine alone or in combination on the proliferation of CCRF-CEM cells;
  • Figure 4 shows the experimental results of the effects of AST-3424, daunorubicin, and cytarabine alone or in combination on the proliferation of PF-382 cells;
  • Figure 5 shows the experimental results of the effects of AST-3424, daunorubicin, and cytarabine alone or in combination on the proliferation of Jurkat, CloneE6-1 cells;
  • Figure 6 shows the experimental results of the effects of AST-3424, daunorubicin, and cytarabine alone or in combination on the proliferation of MOLT-4 cells.
  • Ara-c represents cytarabine
  • Daunorubicin represents daunorubicin
  • the 4th, 5th, and 6th bar graphs from left to right represent the results of single-agent administration of 0.1 nM, 20 nM, and 80 nM daunorubicin, respectively.
  • the percentage of cell survival, and the numbers 7, 8, and 9 on the right correspond to the percentage of cell survival when 0.1 nM, 20 nM, and 80 nM daunorubicin are combined with 0.13 nM AST-3424 respectively.
  • the numbers 10 and 11 on the right , 12 corresponds to the cell survival percentage of 0.1nM, 20nM, and 80nM daunorubicin combined with 1nM AST-3424 respectively.
  • the remaining contents of Figures 2 to 6 are similar to this.
  • test concentration compound working solution (AST-3424)
  • Cell viability can be calculated using the following formula:
  • the processed data will be used for nonlinear regression analysis using GraphPad Prism 5 analysis software to obtain a dose-response curve, as shown in Figure 1, and calculate the half-kill concentration (IC 50 ) of the compound on cells, as shown in Table 1 below.
  • Cytarabine, daunorubicin and the compound AST-3424 all showed good inhibitory effects in five cell lines: CCRF-CEM, PF-382, Jurkat, Clone E6-1, SUP-T1, and MOLT-4. . And except for Jurkat and Clone E6-1 cells, among the other four cell lines, the in vitro cytotoxicity of AST-3424 was better than that of daunorubicin and cytarabine.
  • Figure 2-6 shows the effects of AST-3424, daunorubicin, and cytarabine alone and in combination on SUP-T1, CCRF-CEM, respectively. Effects on cell proliferation of five cell lines: PF-382, Jurkat, Clone E6-1, and MOLT-4.
  • nM means concentration is nmol/L, the same below) and 1nM have no effect on SUP-T1 cell proliferation;
  • MOLT-4 and MOLT-3 were derived from a 19-year-old male patient with relapse of acute lymphoblastic leukemia who had previously received multiple drug combination chemotherapy.
  • the MOLT-4 cell line is of T lymphocyte origin. There is a G ⁇ A mutation in codon 248 of the p53 gene. It does not express p53, immunoglobulin or Epstein-Barr virus; it can produce high levels of terminal deoxyribose transferase; Expression of CD1 (49%), CD2 (35%), CD3A (26%) B (33%) C (34%), CD4 (55%), CD5 (72%), CD6 (22%), CD7 (77 %).
  • the cells are human acute lymphoblastic leukemia cells, and the corresponding disease is human acute lymphoblastic leukemia, or T-ALL.
  • PF-382 human acute lymphoblastic T-cell leukemia cells
  • the corresponding disease is human acute lymphoblastic T-cell leukemia, namely T-ALL.
  • Jurkat, Clone E6-1 is a clone of the Jurkat-FHCRC cell line, a derivative of the Jurkat cell line. This cell line was established from the peripheral blood of a 14-year-old male patient with acute T-cell leukemia. The cells are human T lymphocytic leukemia cells, and the corresponding disease is T-ALL.
  • T lymphoblastic lymphoma human T lymphoblastic lymphoma cell, the corresponding disease is T lymphoblastic lymphoma, English is T-cell Lymphoblastic Lymphoma (TLBL)
  • CCRF-CEM human acute lymphoblastic leukemia T lymphocyte serum culture cells.
  • the cells were obtained from the peripheral blood leukemia jersey of a four-year-old white female acute lymphoblastic leukemia patient in November 1964.
  • the cells are human acute T lymphoblastic leukemia cells, and the corresponding disease is acute T lymphoblastic leukemia, or T-ALL.
  • AKR1C3 enzyme expression and RNA expression levels of the above five leukemia cells and lymphoma cells were tested using methods reported in the literature. The results are shown in Table 2 below.
  • AKR1C3 RNA expression was based on the literature (Meng, F., Li, W.F., Jung, D., Wang, C.C., Qi, T., Shia, C.S., Hsu, R.Y., Hsieh, Y.C., & Duan, J. (2021) .
  • a novel selective AKR1C3-activated prodrug AST-3424/OBI-3424 exhibits broad anti-tumor activity.
  • American journal of cancer research 11(7), 3645-3659.
  • using RNA-Seq to analyze AKR1C3 in cells RNA expression level (AKR1C3 RNA expression level), and use Log2 FPKM for quantification.
  • the data in the table is the numerical value for Log2 FPKM quantification.
  • the detection of AKR1C3 protein expression is the ratio of the AKR1C3 protein band and the reference protein band in the protein band detected by western blot (WB) method.
  • WB western blot
  • the protein bands of AKR1C3 and ⁇ -Tubulin were measured by gray value processing using Image J software, and then the ratio of AKR1C3/ ⁇ -Tubulin was calculated as the relative expression quantitative value of the protein, and compared between different cell lines. comparison between.
  • the superscript 1 indicates that the data are the experimental test results of AST-3424. Please refer to the section 1.1 Single Drug In Vitro Cell Proliferation Inhibition Experiment.
  • the superscript 2 indicates that the data is the previous experimental test results of AST-3424.
  • Daunorubicin and cytarabine are both drugs used in clinical practice to treat leukemia or other tumors. Through investigation, comparison and conversion results, as shown in Table 3 below, it was found that the dosage of the combination regimen is far less than that in clinical practice. Medication dosage.
  • AKR1C3 In specific cell lines, leukemia and lymphoma cell lines, when the cell lines were detected to have different expressions of AKR1C3: the quantitative values of AKR1C3 protein and RNA ranged from 0.84-6.08 and 0.71-5.96. Within such a large range of expression levels, The in vitro combined effect of AST-3424 and daunorubicin or cytarabine has nothing to do with the expression level of AKR1C3.
  • test concentrations of daunorubicin and cytarabine in the in vitro combination experiment were far lower than the clinical dosage.
  • the experiment reveals that new treatment options for leukemia/lymphoma patients do not necessarily require patients to have higher (overexpression, excess) AKR1C3 protein or RNA expression.
  • a positive AKR1C3 protein or RNA test result may benefit from using this treatment option.
  • beneficial That is to say, the new treatment plan has significantly lowered the medication threshold for patients who will benefit.
  • This combination regimen can be used if the test result is positive and expressive, as long as the dedicated medical personnel determine that the use of this regimen for treatment will benefit the patient. possible.

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Abstract

治疗方法，使用含有AST-3424、AST-3423或AST-2870及其盐、酯、溶剂合物、同位素异构体的药物与含有阿糖胞苷或柔红霉素及其盐、酯、溶剂合物、同位素异构体的药物联用治疗白血病、淋巴瘤患者。在柔红霉素或阿糖胞苷浓度远低于其临床用药剂量的情况下，不必限定患者具有较高(过表达、过量)的AKR1C3蛋白或RNA表达，AST-3424与阿糖胞苷或柔红霉素联用对于白血病、淋巴瘤细胞体外增殖抑制作用仍然效果显著，联用对AKR1C3蛋白或RNA表达高低不同的细胞系均具有较好的体外增殖抑制作用。为此，上述联用方案有望开发为治疗白血病、淋巴瘤的新的治疗方案，而不需要限制患者的AKR1C3酶表达水平。

Description

AST-3424联用治疗白血病及淋巴瘤 技术领域
本发明涉及肿瘤的治疗方法，特别是AST-3424与药物联用治疗白血病及淋巴瘤，属于肿瘤治疗领域。
背景技术
以过表达醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化剂前药AST-3424(WO2016145092，WO2017087428)，CAS号为2097713-69-2，其结构如下：
AST-3424(又名OBI-3424、TH-3424)进入癌细胞内被癌细胞过表达的AKR1C3酶活化而释放代谢产物AST-2660(又名AST-2660)。AST-3424本身对癌细胞毒性较小，在其动物模型、体外药理实验中，其药理效果均与AKR1C3酶表达相关：前药AST-3424在AKR1C3酶、NADPH作用下代谢出AST-2660,酶的表达量与药效正相关(Meng F,Li WF,Jung D,et al.Anovel selective AKR1C3-activated prodrug AST-3424/OBI-3424 exhibits broad anti-tumor activity.Am J Cancer Res.2021；11(7):3645-3659；Evans K,Duan J,Pritchard T,et al.OBI-3424,a Novel AKR1C3-Activated Prodrug,Exhibits Potent Efficacy against Preclinical Models of T-ALL.Clin Cancer Res.2019；25(14):4493-4503.doi:10.1158/1078-0432.CCR-19-0551；WangY,LiuY,Zhou C,et al.An AKR1C3-specific prodrug with potent anti-tumor activities against T-ALL.Leuk Lymphoma.2020；61(7):1660-1668.doi:10.1080/10428194.2020.1728746；He P,Wang C,WangY,et al.A Novel AKR1C3 Specific Prodrug TH3424 With Potent Antitumor Activity in Liver Cancer [retracted in:Clin Pharmacol Ther.2021 Jul；110(1):262].Clin Pharmacol Ther.2021，110(1):229-237.doi:10.1002/cpt.2171)。
在临床试验中(美国NCT03592264，去势前列腺癌和肝癌；美国NCT04315324，T-ALLT淋巴细胞急性白血病；中国CTR20191399，各种实体瘤；CTR20201915，T淋巴细胞急性白血病和B淋巴细胞急性白血病)均包含探索AKR1C3与AST-3424药物疗效的关系，进一步的，在公开的I期临床试验结果(Safety,pharmacokinetics,and clinical activity of OBI-3424,an AKR1C3-activated prodrug,in patients with advanced or metastatic solid tumors:A phase 1 dose-escalation study.J Clin Oncol 40,2022(suppl 16；abstr 3030)，DOI：10.1200/JCO.2022.40.16_suppl.3030)中显示IHC方法检测的AKR1C3表达分数(H-score)只有在高于一定的数值时，患者才有药效响应，并决定在后续的临床试验中将挑选H-score大于或等于135的患者入组。
在联用实验中也重复了类似的结论，即AST-3424与阿比特龙联用对于AKR1C3高表达的VCap细胞的CDX模型、与泼尼松龙联用对于AKR1C3高表达的VCap细胞的CDX模型、与5-氟尿嘧啶联用对于AKR1C3高表达的SNU-16细胞的CDX模型、与舒尼替尼联用对于AKR1C3高表达的A498细胞的CDX模型、与吉西他滨联用对于AKR1C3高表达的A498细胞的CDX模型均具有比单药优异的疗效(Meng F,Li WF,Jung D,et al.A novel selective AKR1C3-activated prodrug AST-3424/OBI-3424 exhibits broad anti-tumor activity.Am J Cancer Res.2021；11(7):3645-3659)。
特别的最新的研究发现，AST-3424对于AKR1C3高表达的HCC细胞系HepG2、PLC/PRF/5均具有优异的抑制作用，而且在联用奥沙利铂(OXA)或5-氟尿嘧啶(5-Fu)后抑制作用更强，具有协同作用，通过不同实验手段发现AST-3424单药与OXA或5-Fu联合疗法可通过抑制细胞增殖、诱导S期细胞停滞、促进细胞凋亡诱导、抑制细胞转移等方式，对肝癌细胞发挥体外抗肿瘤的协同作用：
通过West-bolt测试显示其机制可能与P21蛋白的上调有关，而可能与β-连环蛋白(β-catenin)表达无关；
使用流式细胞术检测不同阶段细胞的百分比表明AST-3424单药治疗和与OXA或5-Fu的联合治疗可以阻断S期的细胞，通过流式细胞术检测AST-3424单药治疗和OXA或5-Fu联合治疗后细胞凋亡的诱导表明AST-3424单药治疗和与OXA或5-Fu的联合治疗可能通过上调Bax和Caspase3蛋白以及下调PARP蛋白来诱导细胞凋亡；
进行Transwell细胞迁移和侵袭试验表明AST-3424单药治疗和OXA或5-Fu联合治疗可抑制肿瘤细胞的迁移和侵袭，其机制可能与MMP-9蛋白的下调有关；
通过研究AST-3424单药治疗和OXA或5-Fu联合治疗对TGF-β信号通路的影响，实验结果表明AST-3424单药治疗和OXA或5-Fu联合治疗可以通过抑制TGF-β信号通路来降低增殖效应，并且仅在AST-3424和OXA联合使用时抑制作用显著。
发明内容
已有的研究均表明AST-3424发挥药效的强弱均与AKR1C3酶表达相关，高表达AKR1C3酶的患者或者动物模型才具有较好药效，并且已发表的药物联用(阿比特龙、泼尼松龙、5-氟尿嘧啶、舒尼替尼、奥沙利铂)体外细胞增殖实验、CDX动物模型也与AKR1C3酶表达相关。这些研究均显示AST-3424无论单药或联用治疗均需要患者的AKR1C3酶表达达到较高程度(通过试剂盒检测，比如IHC/q-PCR方法)。
发明人在联用研究中发现，AST-3424与阿糖胞苷或柔红霉素联用对于白血病、淋巴瘤细胞体外增殖抑制作用与细胞系的AKR1C3表达水平无关，联用对表达高低不同的细胞系均具有较好的体外增殖抑制作用。为此，上述联用方案有望开发为治疗白血病、淋巴瘤的新的治疗方案，而不需要根据先前研究文献揭示的需要限制患者的AKR1C3酶过表达或高表达(常常对应较高的RNA定量值，较高的IHC的H-score打分)。
新的治疗方案则较大幅度的降低了获益患者的用药门槛，检测结果是阳性有表达即可以施用本联用方案，只要医学专用人员判定施用本方案进行治疗对患者有获益或获益可能。
治疗方法，使用含有AST-3424、AST-3423或AST-2870及其盐、酯、溶剂合物、同位素异构体的药物与含有阿糖胞苷或柔红霉素及其盐、酯、溶剂合物、同位素异构体的药物联用治疗白血病、淋巴瘤患者。“AST-3424、AST-3423或AST-2870及其盐、酯、溶剂合物、同位素异构体”是7个并列的选项，分别为AST-3424，AST-3423，AST-2870，AST-3424、AST-3423或AST-2870的盐，AST-3424、AST-3423或AST-2870的酯，AST-3424、AST-3423或AST-2870的溶剂合物，AST-3424、AST-3423或AST-2870的同位素异构体。“阿糖胞苷或柔红霉素及其盐、酯、溶剂合物、同位素异构体”是6个并列的选项，分别为阿糖胞苷，柔红霉素，阿糖胞苷或柔红霉素的盐，阿糖胞苷或柔红霉素的酯，阿糖胞苷或柔红霉素的溶剂合物，阿糖胞苷或柔红霉素的同位素异构体。
AST-3424、AST-3423或AST-2870及其盐、酯、溶剂合物、同位素异构体的制药用途，其用于制备与含有柔红霉素或阿糖胞苷及其盐、酯、溶剂合物、同位素异构体的药物联用治疗白血病或淋巴瘤的药物。
根据专利WO2016145092，WO2017087428公开的数据，AST-3423为AST-3424的对映异构体，AST-3424为S构型，AST-3423为R构型，而AST-2870(TH2870)是消旋体，三者具有类似的AKR1C3酶活化性质，均在NADPH与AKR1C3作用下被催化并释放出发挥药效的细胞毒物质AST-2660。
关于本文所述药物是指药品或制剂，所制得的药品包含特定剂量范围的有效成分或其盐、溶剂合物，和/或所制得的药物为特定剂型、特定给药方式施用。
所制得的药品、药物、制剂还可包含药学上可接受的辅料或赋形剂。所述药物可以为临床施用的任何剂型，例如片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。根据具体剂型和施用方式，所述药物中的药学上可接受的辅料或赋形剂可以包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂、和色素等。
单药，即单药治疗。联用，即联合用药治疗。单药治疗是指在一个疗程中仅使用一种抗癌药物。联合治疗是指在一个疗程中同时或先后使用两种或两种以上的抗癌药物。
一般而言，联合治疗需要根据病情特点、联用药物种类探索不同的给药剂量、给药周 期，只有根据上述情况，探索得到的联合用药治疗方案才可能取得较单一用药治疗好的治疗效果。
单药和联用治疗方案的药物给药剂量、给药周期、给药方案通过临床试验探索得到。
关于本文所述化合物，化学结构中含有机胺结构和P＝O双键结构，因此所述化合物还可能被以盐的形式进行给药，即本发明提供所示化合物的药学上可接受的盐，所述盐可以为碱式盐，包括所述化合物与无机碱(例如碱金属氢氧化物、碱土金属氢氧化物等)或与有机碱(例如单乙醇胺、二乙醇胺或三乙醇胺等)形成的盐。或者，所述盐可以为酸式盐，包括所述化合物与无机酸(例如盐酸、氢溴酸、氢碘酸、硝酸、高氯酸、硫酸或磷酸等)或与有机酸(例如甲磺酸、三氟甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、富马酸、草酸、马来酸、柠檬酸等)形成的盐。同理，其也有可能与某些酸或者醇发生反应而成为酯，因此所述化合物还可能被以酯的形式进行给药。由于各种原因，这些化合物也可能会与某些溶剂形成溶剂合物，所述溶剂合物为水合物或醇合物，因此所述化合物还可能被以溶剂合物的形式进行给药。选择和制备化合物的可接受的盐、酯和溶剂化物等是本领域公知技术。
术语“同位素变体”是指在组成此类化合物的原子中的一或多者处含有非天然比例的同位素的化合物。在某些实施例中，化合物的“同位素变体”含有非天然比例的一或多种同位素，包括(但不限于)氢(1H)、氘(2H)、氚(3H)、碳-11(11C)、碳-12(12C)、碳-13(13C)、碳-14(14C)、氮-13(13N)、氮-14(14N)、氮-15(15N)、氧-14(14O)、氧-15(15O)、氧-16(16O)、氧-17(17O)、氧-18(18O)、氟-17(17F)、氟-18(18F)、磷-31(31P)、磷-32(32P)、磷-33(33P)、硫-32(32S)、硫-33(33S)、硫-34(34S)、硫-35(35S)、硫-36(36S)、氯-35(35Cl)、氯-36(36Cl)、氯-37(37Cl)、溴-79(79Br)、溴-81(81Br)、碘-123(123I)、碘-125(125I)、碘-127(127I)、碘-129(129I)及碘-131(131I)。在某些实施例中，化合物的“同位素变体”呈稳定形式，亦即非放射性。在某些实施例中，化合物的“同位素变体”含有非天然比例的一或多种同位素，包括(但不限于)氢(1H)、氘(2H)、碳-12(12C)、碳-13(13C)、氮-14(14N)、氮-15(15N)、氧-16(16O)、氧-17(17O)、氧-18(18O)、氟-17(17F)、磷-31(31P)、硫-32(32S)、硫-33(33S)、硫-34(34S)、硫-36(36S)、氯-35(35Cl)、氯-37(37Cl)、溴-79(79Br)、溴-81(81Br)及碘-127(127I)。在某些实施例中，化合物的“同位素变体”呈不稳定形式，亦即放射性。在某些实施例中，化合物的“同位素变体”含有非天然比例的一或多种同位素，包括(但不限于)氚(3H)、碳-11(11C)、碳-14(14C)、氮-13(13N)、氧-14(14O)、氧-15(15O)、氟-18(18F)、磷-32(32P)、磷-33(33P)、硫-35(35S)、氯-36(36Cl)、碘-123(123I)、碘-125(125I)、碘-129(129I)及碘-131(131I)。应理解，在如本文提供的化合物中，在根据本领域技术人员的判断为可行时，任何氢可为例如2H即D，或任何碳可为例如13C，或任何氮可为例如15N，及任何氧可为18O。在某些实施例中，化合物的“同位素变体”含有非天然比例的氘(D)。
白血病，白血病(Leukemia)，亦称作血癌，是一种造血系统的恶性肿瘤。病源是由于细胞内脱氧核糖核酸的变异形成的骨髓中造血组织的不正常工作。白血病有多种类型，白血病的类型主要由血液内不正常的血细胞的类型来区分，学术上，有多种分类方法，常用的分类法有FAB分类法，以及由世界卫生组织推动新的WHO分类法。这些分类法可以提供病人预后以及处置的指导。临床上，一般分急性白血病和慢性白血病，包括：
急性淋巴细胞性白血病，Acute Lymphoblastic Leukemia，简称ALL，根据白血病细胞表面不同的分化抗原利用免疫学技术，可以诊断并分为不同的亚型，一般分为T、B细胞系，即急性T淋巴细胞性白血病T-ALL和急性B淋巴细胞性白血病B-ALL)；
急性骨髓性白血病，也称为急性髓细胞白血病，Acute myeloid leukemia，简称AML是一种骨髓性白细胞(而非淋巴性白细胞)异常增殖的血癌；
慢性淋巴细胞性白血病，Chronic Lymphocytic Leukemia，简称慢淋(CLL)，主要包括慢性B淋巴细胞性白血病(B-CLL)，慢性T淋巴细胞性白血病(T-CLL)也有但少见；
慢性骨髓细胞性白血病(俗称“慢粒”)，也称为慢性髓细胞白血病，Chronic myeloid l  eukemia，简称CML；
淋巴瘤，起源于淋巴结或其他淋巴组织的恶性肿瘤，可分为霍奇金病(简称HD)和非霍奇金淋巴瘤(简称NHL)两大类。非霍奇金淋巴瘤分成B细胞淋巴瘤和T细胞以及NK细胞淋巴瘤两个大类。
B细胞淋巴瘤又分成前体B细胞淋巴瘤和成熟B细胞淋巴瘤两大类，其中前体B细胞淋巴瘤指的是前体B淋巴母细胞淋巴瘤，而成熟B细胞淋巴瘤临床上比较常见的是小细胞淋巴瘤、浆细胞骨髓瘤、结外边缘区B细胞淋巴瘤、结型边缘区B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、弥漫性B细胞淋巴瘤、Burkitt淋巴瘤等。
在T细胞和NK细胞淋巴瘤的分类中，也包括前体T细胞淋巴瘤和成熟T细胞淋巴瘤，其中前体T细胞淋巴瘤，主要指的是前体T淋巴母细胞淋巴瘤，成熟T细胞淋巴瘤常见的有T细胞幼淋巴细胞性白血病、成人T细胞淋巴瘤、结外NK-T淋巴瘤、间变性大细胞淋巴瘤、周围T细胞淋巴瘤、间变性大细胞淋巴瘤等。
特别的，所述白血病包括淋巴细胞白血病(包括急性淋巴细胞性白血病和慢性淋巴细胞性白血病)，淋巴瘤包括淋巴母细胞淋巴瘤。
进一步的，所述白血病为急性淋巴细胞白血病，优选为急性T淋巴细胞白血病，淋巴瘤为T淋巴母细胞淋巴瘤。
特别的，白血病包括急性淋巴细胞性白血病Acute lymphoblastic leukemia、急性淋巴细胞T细胞白血病T-ALL、T淋巴细胞白血病T-cell leukemia、急性淋巴细胞白血病Acute lympho blastic leukemia；淋巴瘤包括T淋巴母细胞瘤，具体为T淋巴母细胞性淋巴瘤，T cell lymph oblastic lymphoma。
联用治疗中柔红霉素、阿糖胞苷给药剂量低于其单药临床用药剂量。
柔红霉素，临床使用的是其盐酸盐即盐酸柔红霉素，剂型为注射用无菌粉针，临用前加入注射用生理盐水溶解后供静脉注射或滴注，临床上主要用于治疗：
(1)急性粒细胞性白血病，无论是单一使用柔红霉素或者与其它抗肿瘤药物合用，柔红霉素均适用于治疗该病的各个分期。亦用于治疗早幼粒性白血病；
(2)急性淋巴细胞性白血病，用柔红霉素治疗该病，缓解率很高，但由于其副作用大及尚有其它有效治疗方法，故柔红霉素只适用于那些对其它药物已产生耐药的病例；
(3)其他肿瘤，已观察到柔红霉素对神经母细胞瘤及横纹肌肉瘤有良好的疗效。
阿糖胞苷，临床使用的是注射用阿糖胞苷(使用阿糖胞苷或阿糖胞苷盐酸盐)，剂型为冻干粉，临用前加入苯甲醇与水配制的苯甲醇注射液(一般与冻干粉一并售卖)后供静脉注射或皮下注射，主要适用于成人和儿童急性非淋巴细胞性白血病的诱导缓解和维持治疗。其对其它类型的白血病也有治疗作用，如：急性淋巴细胞性白血病、慢性髓细胞性白血病(急变期)。可单独或与其它抗肿瘤药联合应用，联合用药疗效更好。
所述白血病患者的血液样本的AKR1C3对应的RNA检测为阳性，所述淋巴瘤患者的肿瘤组织样本的AKR1C3蛋白检测为阳性；
或
所述白血病患者被检测为AKR1C3对应的RNA阳性，所述淋巴瘤患者被检测出AKR1C3蛋白阳性。
在先前的研究和实验论文中都表明AST-3424单药或联用治疗方案均限定动物模型或患者是AKR1C3过量或过表达，而本治疗方案/制药用途涉及的AST-3424与柔红霉素/阿糖胞苷联用治疗白血病/淋巴瘤却只需要对应的AKR1C3蛋白或RNA检测为阳性即有表达即可，在阳性情况下依然有显著的疗效。
过量，即过表达Overexpression，是指相对于正常细胞，癌细胞的表达水平比正常细胞高，此种情况即为过量或过表达；或者基于统计，人为设定阈值，过量或过表达即为超出这个阈值。 AKR1C3在不同肿瘤(实体瘤或血液癌)过量或过表达的情况参见文献Evans K,Duan J,Pritchard T,et al.OBI-3424,a Novel AKR1C3-Activated Prodrug,Exhibits Potent Efficacy against Preclinical Models of T-ALL.Clin Cancer Res.2019；25(14):4493-4503.doi:10.1158/1078-0432.CCR-19-0551(公开了急性淋巴细胞白血病的AKR1C3表达情况)和Guise CP,Abbattista MR,Singleton RS,et al.The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3.Cancer Res.2010；70(4):1573-1584.doi:10.1158/0008-5472.CAN-09-3237(公开了不同实体瘤的AKR1C3表达情况)。
在以往的AKR1C3酶活化的抗癌前药中，经常需要在用药前测试AKR1C3酶表达水平并明确治疗方案只对高表达或过量表达AKR1C3的患者有效，而本次提供的新的联用药物组合其药物效果与AKR1C3几乎没有相关性，患者只需要有AKR1C3表达，即检测结果为阳性即可能有效果。
进一步的，所述白血病患者的血液样本的AKR1C3对应的RNA检测Log2FPKM定量值，其值大于或等于0.71，所述淋巴瘤患者的肿瘤组织样本的AKR1C3蛋白定量是western blot(WB)法检测的蛋白条带中AKR1C3蛋白条带与参比蛋白条带的比值，其值大于或等于0.84；
或
所述白血病患者被检测为AKR1C3对应的RNA，检测Log2FPKM定量值，其值大于或等于0.71，所述淋巴瘤患者被检测出AKR1C3蛋白定量是western blot(WB)法检测的蛋白条带中AKR1C3蛋白条带与参比蛋白条带的比值，其值大于或等于0.84，
满足上述情况下，效果可能更好。
也就是说，本联用方案拓宽了AST-3424治疗患者的获益人群，先前技术文献(Evans K,Duan J,Pritchard T,et al.OBI-3424,a Novel AKR1C3-Activated Prodrug,Exhibits Potent Efficacy against Preclinical Models of T-ALL.Clin Cancer Res.2019；25(14):4493-4503.doi:10.1158/1078-0432.CCR-19-0551；Guise CP,Abbattista MR,Singleton RS,et al.The biore ductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3.Cancer Res.2010；70(4):1573-1584.doi:10.1158/0008-5472.CAN-09-3237；Safety,pharma cokinetics,and clinical activity of OBI-3424,an AKR1C3-activated prodrug,in patients with advanced or metastatic solid tumors:A phase 1 dose-escalation study.J Clin Oncol 40,2022(suppl 16；abstr 3030)，DOI：10.1200/JCO.2022.40.16_suppl.3030)揭示的AST-3424治疗白血病或实体瘤的获益人群严格限定为AKR1C3蛋白或RNA表达过量或过表达(常常对应较高的RNA定量值，较高的IHC的H-score打分)，而新的治疗方案则较大幅度的降低了获益患者的用药门槛。在对患者给予本联用治疗方案治疗白血病/淋巴瘤前，进行AKR1C3测定其结果并不需要是先前文献限定的过表达/过量，检测结果是阳性有表达即可以施用本联用方案，只要医学专用人员判定施用本方案进行治疗对患者有获益或获益可能。
本申请还提供一种药物联用物，其包括如下物质作为活性成分：
AST-3424、AST-3423或AST-2870及其盐、酯、溶剂合物、同位素异构体，以及
柔红霉素及其盐、酯、溶剂合物、同位素异构体，或
阿糖胞苷及其盐、酯、溶剂合物、同位素异构体；
将所述活性成分共同配制或分开配制，用于配伍使用、同时使用或分开使用。
本申请的药物联用物至少包括两种活性成分，如AST-3424和柔红霉素、AST-3424和阿糖胞苷。当然，还可以包括药学上可用的辅料。
通常，作为本申请所述的药物联用物特征的两种活性成分可将所述活性成分共同配制(单剂量单位)或分开配制(套装)。
共同配制或分开配制的两种活性成分通常可同时给药；或鉴于它们各自制剂的性质，相隔一定时间间隔分开给药，所述时间间隔有利于所述两种活性成分配伍作用的最佳化。
药物联用物可以是一种复方药物，其为一种活性成分为上述AST-3424、AST-3423、AST-2870或其盐、酯、溶剂合物、同位素异构体和另一种活性成分为柔红霉素、阿糖胞苷或其盐、酯、溶剂合物、同位素异构体组成的药物组合物。此种情况下，上述活性成分共同配制，同时使用。
药物联用物也可以是一种类似于辉瑞新冠药物Paxlovid的套装，用于同时售卖或分开售卖。此种情况下，上述活性成分分开配制，但分开配制成的两种或两种以上的药物既可同时给药，也可根据各自制剂的性质，相隔一定时间间隔分开给药。
作为本申请的一个具体实施方式，分开配制时，配制成的一种药物为含有活性成分AST-3424、AST-3423、AST-2870或其盐、酯、溶剂合物、同位素异构体以及药学上可用的辅料，另一种药物为含有活性成分柔红霉素、阿糖胞苷或其盐、酯、溶剂合物、同位素异构体以及药学上可用的辅料。上述两种药物组成的药物联用物，可以同时给药，也可根据各自制剂的性质，相隔一定时间间隔分开给药。
药物联用物中，柔红霉素、阿糖胞苷的联用剂量低于其单药临床用药剂量。
本申请还提供一种药物制剂，其由上述药物联用物的活性成分与药学上可用的辅料制备而成。
作为本申请的一个特定实施例，上述药物制剂的剂型选自颗粒剂、片剂、丸剂、胶囊剂或注射剂。
本申请还提供上述药物联用物和/或上述药物制剂在制备抗肿瘤药物中的用途。
作为本申请的一个特定实施例，上述肿瘤选自白血病、淋巴瘤。
作为一种优选，白血病包括淋巴细胞白血病，淋巴瘤包括淋巴母细胞淋巴瘤；优选的，所述白血病为急性淋巴细胞白血病，更优选为急性T淋巴细胞白血病，淋巴瘤为T淋巴母细胞淋巴瘤。
附图说明
图1为三种药物对5种细胞系细胞的增殖抑制曲线；
图2为AST-3424和柔红霉素、阿糖胞苷单药及联用药对SUP-T1细胞增殖的影响实验结果；
图3为AST-3424和柔红霉素、阿糖胞苷单药及联用药对CCRF-CEM细胞增殖的影响实验结果；
图4为AST-3424和柔红霉素、阿糖胞苷单药及联用药对PF-382细胞增殖的影响实验结果；
图5为AST-3424和柔红霉素、阿糖胞苷单药及联用药对Jurkat,CloneE6-1细胞增殖的影响实验结果；
图6为AST-3424和柔红霉素、阿糖胞苷单药及联用药对MOLT-4细胞增殖的影响实验结果。
图2中Ara-c表示阿糖胞苷，Daunorubicin表示柔红霉素，自左至右第4、5、6个柱状图分别表示0.1nM、20nM、80nM的柔红霉素单药给药的细胞成活百分比，而在其右边的7、8、9则对应表示0.1nM、20nM、80nM的柔红霉素分别与0.13nM的AST-3424联用的细胞成活百分比，在其右边的10、11、12则对应表示0.1nM、20nM、80nM的柔红霉素分别与1nM的AST-3424联用的细胞成活百分比，其余的图2至图6的内容与此类似。
实施例
一、体外细胞实验
1.1单药体外细胞增殖抑制实验
操作步骤
第一天将细胞接种在96孔细胞培养板中(180μL/孔)。
第二天，加入20μL 10倍测试浓度的化合物工作液(AST-3424)，轻轻震荡细胞板，将其放置在37℃培养箱中继续培养。
第三天，加入20μL 10倍测试浓度的化合物(阿糖胞苷和柔红霉素)溶液，轻轻震荡细胞板，将其放置在37℃培养箱中继续培养72小时。
孵育结束后按照CellTiter Glo试剂说明书要求在细胞版中加入配制好的试剂(50μL/孔)，充分混匀后室温避光孵育10分钟。
将细胞板放入读板仪进行分析，设定读取化学发光并记录数据。
数据处理
每孔中的读数需要被转换成细胞存活率。细胞存活率可以使用下列公式计算得出：
处理后的数据将用GraphPad Prism 5分析软件来做非线性回归分析，得到剂量效应曲线，如图1所示，并计算出化合物对细胞的半数杀伤浓度(IC50)，如下表1所示。
表1：不同药物对不同细胞系细胞的增殖抑制作用数据
阿糖胞苷，柔红霉素以及化合物AST-3424在CCRF-CEM，PF-382，Jurkat,Clone E6-1，SUP-T1，MOLT-4这五株细胞中都表现出了良好的抑制作用。并且除Jurkat,Clone E6-1细胞外，其余4株细胞中，AST-3424的体外细胞毒性均优于柔红霉素和阿糖胞苷。
1.2药物联用体外细胞增殖抑制实验
操作步骤
第一天将细胞接种在96孔细胞培养板中(180μL/孔)。
第二天，加入10μL 20倍测试浓度AST-3424溶液(两个浓度IC25或IC10的20倍浓度)轻轻震荡细胞板，将其放置在37℃培养箱中继续培养。
第三天，在联合用药的孔内分别加入10μL 20倍测试浓度化合物(阿糖胞苷或柔红霉素)(各三个浓度IC50、IC25和IC5的20倍浓度)，在单独用药的孔内加入10μL含2％DMSO的培养基，轻轻震荡细胞板，将其放置在37℃培养箱中继续培养72小时。
孵育结束后按照CellTiter Glo试剂说明书要求在细胞版中加入配制好的试剂(50μL/孔)，充分混匀后室温避光孵育10分钟。
将细胞板放入读板仪进行分析，设定读取化学发光并记录数据。
数据处理
每孔中的读数需要被转换成细胞存活率，根据1.1节中的公示进行计算。
将最终的不同实验条件下的存活率制作为柱状图，如图2-6分别展示了AST-3424和柔红霉素、阿糖胞苷单药及联用对SUP-T1，CCRF-CEM，PF-382，Jurkat,Clone E6-1，MOLT-4这5个细胞系细胞增殖的影响。
实验结论
分析图2，AST-3424与柔红霉素、阿糖胞苷单药及联用药对SUP-T1细胞增殖的影响可知：
1、单药AST-34240.13nM(nM表示浓度为nmol/L，下同)和1nM对SUP-T1细胞增殖无影响；
2、三个浓度柔红霉素分别与0.13nM或1nMAST-3424联用均导致细胞存活率降低，且呈现AST-3424剂量依赖性的降低；与两个浓度的AST-3424联用，80nM柔红霉素联用效果强于0.1nM和20nM柔红霉素联用效果；
3、三个浓度阿糖胞苷分别与0.13nM或1nMAST-3424联用均导致细胞存活率的降低。0.64nM和400nM阿糖胞苷分别与AST-3424联用呈现AST-3424剂量依赖性的降低。
分析图3，AST-3424与柔红霉素、阿糖胞苷单药及联用药对CCRF-CEM细胞增殖的影响可知：
1、单药0.1nM和1nMAST-3424对CCRF-CEM细胞增殖无影响；
2、相较单药32nM柔红霉素组，药物与0.1nM或1nMAST-3424的联用导致细胞存活率的降低，但无AST-3424的剂量依赖性；与两个浓度的AST-3424联用，32nM柔红霉素联用效果强于16nM柔红霉素；与0.03nM柔红霉素联用无效果；
3、相较80nM阿糖胞苷单药，药物分别和0.1nM或1nMAST-3424的联用均导致细胞存活率的降低，且呈现AST-3424剂量依赖性的降低；与两个浓度的AST-3424联用，80nM阿糖胞苷联用效果强于40nM阿糖胞苷，0.6nM阿糖胞苷联用无效果。
分析图4，AST-3424与柔红霉素、阿糖胞苷单药及联用药对PF-382细胞增殖的影响可知：
1、单药0.64和2.5nMAST-3424对PF-382细胞增殖无显著影响；
2、三个浓度柔红霉素分别与0.64nM或2.5nMAST-3424的联用均导致细胞存活率降低，且呈现AST-3424剂量依赖性的降低；
3、三个浓度阿糖胞苷分别与0.64nM或2.5nMAST-3424的联用均导致细胞存活率降低，且呈现AST-3424剂量依赖性的降低。
分析图5，AST-3424与柔红霉素、阿糖胞苷单药及联用药对Jurkat,CloneE6-1细胞增殖的影响可知：
1、单药AST-3424 0.64nM和16nM对Jurkat，CloneE6-1细胞增殖无显著影响；
2、三个浓度柔红霉素分别与0.64nM或16nMAST-3424联用均导致细胞存活率降低，且呈现AST-3424剂量依赖性的降低；
3、三个浓度阿糖胞苷分别与0.64nM或16nMAST-3424的联用均导致细胞存活率降低，且呈现AST-3424剂量依赖性的降低。
分析图6，AST-3424与柔红霉素、阿糖胞苷单药及联用药对MOLT-4细胞增殖的影响可知：
1、单药3.2nM和6.4nMAST-3424对MOLT-4细胞增殖无显著影响；
2、40nM柔红霉素对细胞的增殖影响非常显著，无法判断联合用药的细胞存活率的影响；
3、相较单药5nM和20nM柔红霉素组，两个浓度柔红霉素分别和3.2nM或6.4nM AST-3424的联用均导致细胞存活率降低，且呈现AST-3424剂量依赖性的降低；与两个浓度的AST-3424联用，20nM柔红霉素联用效果强于5nM柔红霉素；
4、三个浓度阿糖胞苷分别与3.2nM或6.4nMAST-3424的联用均导致细胞存活率降低，且呈现AST-3424剂量依赖性的降低。与两个浓度的AST-3424联用，80nM和120nM阿糖胞苷联用效果强于3.2nM阿糖胞苷。
二、细胞系和药物说明
2.1细胞系说明
1、MOLT-4与MOLT-3来源于一名19岁的男性急性淋巴细胞性白血病的复发患者，该患者前期接受过多种药物联合化疗。MOLT-4细胞系为T淋巴细胞起源，p53基因的第248位密码子有一个G→A突变，不表达p53，不表达免疫球蛋白或EB病毒；可产生高水平的末端脱氧核糖转移酶；表达CD1(49％),CD2(35％),CD3A(26％)B(33％)C(34％),CD4(55％),CD5(72％),CD6(22％),CD7(77％)。该细胞是人急性淋巴母细胞白血病细胞，对应疾病是人急性T淋巴母细胞白血病即T-ALL。
2、PF-382，人急性淋巴细胞T细胞白血病细胞，对应疾病是人急性淋巴细胞T细胞白血病，即T-ALL。
3、Jurkat,Clone E6-1是Jurkat-FHCRC细胞系的克隆，Jurkat细胞系的衍生物，该细胞系是从一名14岁男性急性T细胞白血病患者的外周血中建立的。该细胞是人T淋巴细胞白血病细胞，对应疾病是T-ALL。
4、SUP-T1，人T淋巴母细胞瘤细胞，对应疾病是T淋巴母细胞性淋巴瘤，英文为T-cell Lymphoblastic Lymphoma(TLBL)
5、CCRF-CEM，人急性淋巴细胞白血病T淋巴血清培养细胞，细胞是1964年11月从一位四岁白人女性急性淋巴细胞白血病患者的外周血白血球衣中得到。该细胞是人急性T淋巴细胞白血病细胞，对应疾病是急性T淋巴细胞白血病即T-ALL。
2.2细胞AKR1C3表达水平数据
使用文献报道的方法测试而来上述5种白血病细胞和淋巴瘤细胞的AKR1C3酶表达和RNA表达水平，结果如下表2所示。
表2：不同细胞系的AKR1C3蛋白和RNA表达数据
AKR1C3 RNA表达是根据文献(Meng,F.,Li,W.F.,Jung,D.,Wang,C.C.,Qi,T.,Shia,C.S.,Hsu,R.Y.,Hsieh,Y.C.,& Duan,J.(2021).A novel selective AKR1C3-activated prodrug AST-3424/OBI-3424 exhibits broad anti-tumor activity.American journal of cancer research,11(7),3645-3659.)的记载方法，使用RNA-Seq分析细胞中AKR1C3的RNA表达水平(AKR1C3 RNA expression level)，并使用Log2 FPKM进行定量，表格中的数据就是Log2 FPKM进行定量的数值。
AKR1C3蛋白表达量的检测是western blot(WB)法检测的蛋白条带中AKR1C3蛋白条带与参比蛋白条带的比值。本实施例中，是通过Image J软件对AKR1C3和α-Tubulin的蛋白条带进行灰度值处理测定，然后计算AKR1C3/α-Tubulin的比值作为蛋白的相对表达定量值，并在不同细胞系之间比较。
上标1表示数据为AST-3424的本次实验测试结果，参见1.1单药体外细胞增殖抑制实验部分。
上标2表示数据为AST-3424的以往实验测试结果。
2.3药物说明
柔红霉素、阿糖胞苷均是临床实际中用于治疗白血病或其他肿瘤的药物，通过调查比对并折算结果如下表3所示，发现联用方案的给药量是远远小于临床用药剂量的。
表3：柔红霉素与阿糖胞苷的临床用药数据
总结
柔红霉素和阿糖胞苷分别与不同浓度的AST-3424联用均导致实验使用的癌细胞存活率降低，且呈现AST-3424剂量依赖性的降低。
MOLT-4，PF-382和Jurkat Clone E6-1细胞中的联用效果优于SUP-T1和CCRF-CEM。
在特定的细胞系白血病、淋巴瘤细胞系中，当细胞系检测出具有不同的AKR1C3表达时：AKR1C3蛋白与RNA定量值范围为0.84-6.08，0.71-5.96，在如此大的表达水平范围内，AST-3424与柔红霉素或阿糖胞苷体外联用效果强弱与AKR1C3表达水平无关。
体外联用实验的柔红霉素和阿糖胞苷测试浓度远低于临床用药剂量。
总之，实验揭示了新的治疗方案治疗白血病/淋巴瘤患者不必限定患者具有较高(过表达、过量)的AKR1C3蛋白或RNA表达，AKR1C3蛋白或RNA检测结果阳性就有可能使用本治疗方案而获益。也就是新的治疗方案较大幅度的降低了获益患者的用药门槛，检测结果是阳性有表达即可以施用本联用方案，只要医学专用人员判定施用本方案进行治疗对患者有获益或获益可能。

Claims (17)

  1. 治疗方法，使用含有AST-3424、AST-3423或AST-2870及其盐、酯、溶剂合物、同位素异构体的药物与含有阿糖胞苷或柔红霉素及其盐、酯、溶剂合物、同位素异构体的药物联用治疗白血病、淋巴瘤患者。
  2. 根据权利要求1所述的治疗方法，所述白血病包括淋巴细胞白血病，淋巴瘤包括淋巴母细胞淋巴瘤；优选的，所述白血病为急性淋巴细胞白血病，更优选为急性T淋巴细胞白血病，淋巴瘤为T淋巴母细胞淋巴瘤。
  3. 根据权利要求1所述的治疗方法，联用治疗中，柔红霉素、阿糖胞苷给药剂量低于其单药临床用药剂量。
  4. 根据权利要求1所述的治疗方法，其特征在于：
    所述白血病患者的血液样本的AKR1C3对应的RNA检测为阳性，所述淋巴瘤患者的肿瘤组织样本的AKR1C3蛋白检测为阳性；
    或
    所述白血病患者被检测为AKR1C3对应的RNA阳性，所述淋巴瘤患者被检测出AKR1C3蛋白阳性。
  5. 根据权利要求4所述的治疗方法，其特征在于：
    所述白血病患者的血液样本的AKR1C3对应的RNA检测Log2FPKM定量值，其值大于或等于0.71，
    所述淋巴瘤患者的肿瘤组织样本的AKR1C3蛋白定量是western blot(WB)法检测的蛋白条带中AKR1C3蛋白条带与参比蛋白条带的比值，其值大于或等于0.84；
    或
    所述白血病患者被检测为AKR1C3对应的RNA，检测Log2FPKM定量值，其值大于或等于0.71，
    所述淋巴瘤患者被检测出AKR1C3蛋白定量是western blot(WB)法检测的蛋白条带中AKR1C3蛋白条带与参比蛋白条带的比值，其值大于或等于0.84。
  6. AST-3424、AST-3423或AST-2870及其盐、酯、溶剂合物、同位素异构体的制药用途，其用于制备与含有柔红霉素或阿糖胞苷及其盐、酯、溶剂合物、同位素异构体的药物联用治疗白血病或淋巴瘤的药物。
  7. 根据权利要求6所述的制药用途，所述白血病包括淋巴细胞白血病，淋巴瘤包括淋巴母细胞淋巴瘤；优选的，所述白血病为急性淋巴细胞白血病，更优选为急性T淋巴细胞白血病，淋巴瘤为T淋巴母细胞淋巴瘤。
  8. 根据权利要求6所述的制药用途，联用治疗中，柔红霉素、阿糖胞苷给药剂量低于其单药临床用药剂量。
  9. 根据权利要求6所述的制药用途，其特征在于：
    所述白血病患者的血液样本的AKR1C3对应的RNA检测为阳性，所述淋巴瘤患者的肿瘤组织样本的AKR1C3蛋白检测为阳性；
    或
    所述白血病患者被检测为AKR1C3对应的RNA阳性，所述淋巴瘤患者被检测出AKR1C3蛋白阳性。
  10. 根据权利要求9所述的制药用途，其特征在于：
    所述白血病患者的血液样本的AKR1C3对应的RNA检测Log2FPKM定量值，其值大于或等于0.71，
    所述淋巴瘤患者的肿瘤组织样本的AKR1C3蛋白定量是western blot(WB)法检测的蛋白条带中AKR1C3蛋白条带与参比蛋白条带的比值，其值大于或等于0.84；
    或
    所述白血病患者被检测为AKR1C3对应的RNA，检测Log2FPKM定量值，其值大于或等于0.71，
    所述淋巴瘤患者被检测出AKR1C3蛋白定量是western blot(WB)法检测的蛋白条带中AKR1C3蛋白条带与参比蛋白条带的比值，其值大于或等于0.84。
  11. 一种药物联用物，其特征在于，包括如下物质作为活性成分：
    AST-3424、AST-3423或AST-2870及其盐、酯、溶剂合物、同位素异构体，以及
    柔红霉素及其盐、酯、溶剂合物、同位素异构体，或
    阿糖胞苷及其盐、酯、溶剂合物、同位素异构体；
    其中，将所述活性成分共同配制或分开配制，用于配伍使用、同时使用或分开使用。
  12. 根据权利要求11所述的药物联用物，其特征在于，所述柔红霉素、阿糖胞苷的联用剂量低于其单药临床用药剂量。
  13. 一种药物制剂，其特征在于，其由权利要求11所述药物联用物的活性成分与药学上可用的辅料制备而成。
  14. 根据权利要求13所述的药物制剂，其特征在于，所述药物制剂的剂型选自颗粒剂、片剂、丸剂、胶囊剂或注射剂。
  15. 一种权利要求11所述的药物联用物和/或权利要求13所述的药物制剂在制备抗肿瘤药物中的用途。
  16. 根据权利要求15所述的用途，其中，所述肿瘤选自白血病、淋巴瘤。
  17. 根据权利要求16所述的用途，其中，所述白血病包括淋巴细胞白血病，淋巴瘤包括淋巴母细胞淋巴瘤；优选的，所述白血病为急性淋巴细胞白血病，更优选为急性T淋巴细胞白血病，淋巴瘤为T淋巴母细胞淋巴瘤。
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