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WO2024240025A1 - 一种联合用药物组合物及其应用 - Google Patents

一种联合用药物组合物及其应用 Download PDF

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WO2024240025A1
WO2024240025A1 PCT/CN2024/093313 CN2024093313W WO2024240025A1 WO 2024240025 A1 WO2024240025 A1 WO 2024240025A1 CN 2024093313 W CN2024093313 W CN 2024093313W WO 2024240025 A1 WO2024240025 A1 WO 2024240025A1
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cancer
group
pharmaceutical composition
tumor
ibrutinib
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PCT/CN2024/093313
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English (en)
French (fr)
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葛宝铭
朱军
宋玉琴
夏远峰
黄婉怡
黄海清
李不鱼
邓觅
米岚
吴家金
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无锡瓴方生物医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to the field of medical technology, and in particular to a combined pharmaceutical composition and its application.
  • Lymphoma is a common malignant tumor in my country, with an annual incidence of about 75,400 people, an incidence rate of 4.75/100,000, a death rate of 40,500, and a mortality rate of 2.64/100,000. There are also significant differences between regions and between urban and rural areas. Lymphoma can be divided into Hodgkin's lymphoma and non-Hodgkin's lymphoma, which have complex pathological types, diverse treatment methods, and different prognoses. Therefore, multidisciplinary teams are generally required in the diagnosis and treatment process. Among non-Hodgkin's lymphomas, diffuse large B-cell lymphoma (DLBCL) accounts for about 30% to 40%. Its standard treatment is immunotherapy combined with chemotherapy (R-CHOP).
  • R-CHOP chemotherapy
  • CCR2 and CCR5 are G protein-coupled receptors that can recognize chemokines and have 73% sequence homology.
  • the main ligand of CCR2 is the chemokine CCL2, and it can also recognize CCL7, CCL8, CCL12 and CCL13;
  • CCR5 has a high affinity for multiple chemokines such as CCL3, CCL4, CCL5, CCL3L1, CCL8, CCL11, etc.
  • CCR2 is mainly expressed on monocytes, NK cells and T cells, and these cells can be recruited to the inflammatory site under inflammatory conditions. In most cases, the CCR2-CCL2 axis mainly plays a pro-inflammatory role, but CCR2 expressed on Treg cells plays an anti-inflammatory role.
  • CCR5 is more widely expressed, including T cells, macrophages, granulocytes, DCs, microglia and even epidermal cells.
  • CCR2 and CCR5 mediate the migration and infiltration of lymphocytes, monocytes, and macrophages, promoting the occurrence and development of the disease.
  • CCR2 is more relevant to the migration and infiltration of monocytes and macrophages
  • CCR5 has a greater effect on lymphocytes. Therefore, although CCR2 and CCR5 have similarities in function, their emphasis is not the same.
  • Bruton tyrosine kinase is a key kinase in the BCR signal transduction pathway.
  • BTK is expressed in myeloid cells such as B lymphocytes, basophils, and monocytes.
  • Ibrutinib has been approved by the FDA for seven indications, including small lymphocytic lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, macroglobulinemia, graft-versus-host disease, and marginal zone lymphoma, of which the first three have been approved in China;
  • the second-generation highly selective BTK inhibitor Zanubrutinib is a new anticancer drug independently developed in China, and has also been approved in adult mantle cell lymphoma, Waldenstrom's macroglobulinemia, relapsed/refractory marginal zone lymphoma, and chronic lymphocytic leukemia.
  • the purpose of this application is to provide a combined pharmaceutical composition and its application to solve the problems in the prior art.
  • the combination of CCR2/5 dual receptor antagonist and BTK inhibitor is used to treat B cell lymphoma, especially diffuse large B cell lymphoma. This study provides a new direction for exploring the combination of the two in the treatment of B cell lymphoma.
  • the first aspect of the present application provides the use of a CCR2/5 dual receptor antagonist in the preparation of a drug for treating or preventing B-cell lymphoma.
  • the CCR2/5 dual receptor antagonist is selected from a combination of one or more of LF0376, BMS-813160, and Cenicriviroc; preferably, the CCR2/5 dual receptor antagonist is selected from LF0376.
  • the second aspect of the present application provides a pharmaceutical composition comprising a CCR2/5 dual receptor antagonist and a Bruton's tyrosine kinase inhibitor.
  • the Bruton's tyrosine kinase inhibitor is selected from zanubrutinib, ibrutinib, spebrutinib, acalabrutinib, olmutinib, poseltinib, tirabrutinib, evobrutinib, fenebrutinib, vecabrutinib, ARQ-531, BMS-986195, BMS-986142, CGI-1746, GDC-0834, RN-486, JNJ-642646 81.
  • the Bruton's tyrosine kinase inhibitor is selected from zanubrutinib or ibrutinib.
  • the pharmaceutical composition comprises LF0376 and ibrutinib; preferably, the The weight ratio of LF0376 to ibrutinib is 0.5-10:1.
  • the pharmaceutical composition comprises LF0376 and zanubrutinib; preferably, the weight ratio of LF0376 to zanubrutinib is 0.8-40:1.
  • the third aspect of the present application provides the use of the pharmaceutical composition in the preparation of drugs for treating or preventing cancer.
  • the cancer is selected from one or more combinations of B-cell lymphoma, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosal cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, stomach cancer, testicular cancer and thyroid cancer.
  • the B cell lymphoma is diffuse large B cell lymphoma.
  • the fourth aspect of the present application provides a drug for treating cancer, comprising the CCR2/5 dual receptor antagonist in the aforementioned use, or the aforementioned pharmaceutical composition, and pharmaceutically acceptable excipients and/or carriers.
  • LF0376 and Zebutinib has a significant tumor inhibitory effect on B-cell lymphoma compared with single drug use.
  • FIG1 shows the experimental design diagram for the combination therapy of LF0376 and Zanubrutinib.
  • Figure 2 shows the tumor inhibition curve of the experiment of LF0376 (200 mg) combined with Zanubrutinib in Example 1. Each data point is represented by mean ⁇ sem.
  • Figure 3 shows the tumor weight after 27 days of treatment in the experiment of LF0376 (200 mg) combined with Zanubrutinib in Example 1. Each data point is represented by mean ⁇ sem.
  • Figure 4 shows the percentage (%) of body weight change compared to the baseline of mice during the treatment period of Example 1. Each data point is represented by mean ⁇ sem.
  • FIG5 shows the experimental design diagram of the combination therapy of LF0376 and ibrutinib.
  • Figure 6 shows the tumor inhibition curve of the experiment of LF0376 (100 mg) combined with Ibrutinib in Example 1. Each data point is represented by mean ⁇ sem.
  • Figure 7 shows the tumor weight after 27 days of treatment in the experiment of LF0376 (100 mg) combined with Ibrutinib in Example 1. Each data point is represented by mean ⁇ sem.
  • Figure 8 shows the percentage (%) of body weight change compared to the baseline of mice during the treatment period of Example 1. Each data point is represented by mean ⁇ sem.
  • FIG. 9 shows the tumor volume change curves of all experimental groups in Example 2.
  • FIG. 10 shows the tumor volume change curves of the Vehicle group, LF0376 monotherapy group, Ibrutinib monotherapy group and LF0376+Ibrutinib group in Example 2.
  • FIG. 11 shows the tumor volume change curves of the Vehicle group, LF0376 monotherapy group, Zanubrutinib monotherapy group and LF0376+Zanubrutinib group in Example 2.
  • FIG. 12 shows the tumor weight of each experimental group at the end of the experiment in Example 2 (day 28).
  • FIG13 shows the tumor weights of the Vehicle group, the LF0376 monotherapy group, the Ibrutinib monotherapy group, and the LF0376+Ibrutinib group at the end of the experiment in Example 2 (Day 28).
  • FIG. 14 shows the tumor weights of the Vehicle group, the LF0376 monotherapy group, the Zanubrutinib monotherapy group, and the LF0376+Zanubrutinib group at the end of the experiment in Example 2 (Day 28).
  • FIG. 15 shows the average RCBW (%) curve of tumor-bearing mice during the treatment with the test drug in Example 2.
  • FIG. 16 shows the average body weight change curve of tumor-bearing mice during the treatment with the test drug in Example 2.
  • Figure 17 shows the changes in tumor volume during treatment of each group of mice. Note: Data points represent the mean of tumor volume in each group, and error bars represent SEM.
  • FIG. 18 shows the changes in individual tumor volumes of mice in each group during treatment.
  • Figure 19 shows the tumor weight of each group of PG-D13 mice. Note: Data points represent the tumor weight of mice, the midline represents the mean of the tumor weight of each group, and the error bars represent SEM.
  • Figure 20 shows the average body weight of each group of mice during treatment. Note: Data points represent the mean of body weight of each group. Error bars represent SEM.
  • the present application provides the use of a CCR2/5 dual receptor antagonist in the preparation of a drug for treating or preventing B-cell lymphoma.
  • the CCR2/5 dual receptor antagonist is selected from a combination of one or more of LF0376, BMS-813160, and Cenicriviroc.
  • CCR2/5 is a cell surface chemokine receptor 2 and 5, a member of the G protein-coupled receptor superfamily, expressed on the surface of a variety of cells, and exerts biological effects by binding to its specific ligand.
  • the CCR2/5 dual receptor antagonist is selected from LF0376, also known as an azabenzo eight-membered ring compound, and other code names are WXFL40050414 or WXSH0376.
  • LF0376 is produced by Shanghai WuXi AppTec New Drug Development Co., Ltd.
  • the present application provides a pharmaceutical composition comprising a CCR2/5 dual receptor antagonist and a Bruton's tyrosine kinase inhibitor.
  • the composition of the pharmaceutical composition is a clinically acceptable dose, depending on the species, weight, age and type of tumor to be treated, the condition of the individual case or its severity.
  • a doctor, clinician or veterinarian who has the relevant field of treatment technology can easily determine the effective dose of the pharmaceutical composition required to prevent, treat or inhibit the development of a disorder or disease.
  • the Bruton's tyrosine kinase inhibitor is selected from zanubrutinib, ibrutinib, spebrutinib, acalabrutinib, olmutinib, poseltinib, tirabrutinib, evobrutinib, fenebrutinib, vecabrutinib, ARQ-531, BMS-986195, BMS-986142, CGI-1746, GDC-0834, RN-486, JNJ-6426468 1.
  • Bruton's tyrosine kinase inhibitor is an important signaling molecule in the B cell receptor pathway. It is expressed at various developmental stages of B lymphocytes, participates in regulating the proliferation, differentiation, and apoptosis of B cells, and plays an important role in the survival and spread of malignant B cells.
  • the Bruton's tyrosine kinase inhibitor is selected from Zanubrutinib or Ibrutinib.
  • Zanubrutinib is a multi-target kinase inhibitor and the first approved BTK small molecule inhibitor. It inhibits the activity of the BTK enzyme by forming a covalent bond with the cysteine in the BTK active site.
  • Ibrutinib belongs to the second generation of BTK inhibitors, which irreversibly inactivates the enzyme by covalently binding to tyrosine kinase.
  • Zanubrutinib is produced by MCE and the item number is Lot#79640.
  • Ibrutinib is produced by MCE The product number is Lot#114225.
  • the pharmaceutical composition is LF0376 and ibrutinib, and the weight ratio of the two is 0.5 to 10:1.
  • the weight ratio of LF0376 and ibrutinib can be, for example, 0.5 to 1:1, 1 to 2.5:1, 2.5 to 5:1, 5 to 8:1, or 8 to 10:1. More specifically, the weight ratio of LF0376 and ibrutinib can be 5:1.
  • the efficacy of LF0376 and ibrutinib has a synergistic effect in the treatment of B-cell lymphoma.
  • the pharmaceutical composition is LF0376 and zanubrutinib, and the weight ratio of the two is 0.8-40:1.
  • the weight ratio of LF0376 and zanubrutinib can be, for example, 0.8-1:1, 1-5:1, 5-10:1, 10-20:1, 20-30:1, 30-40:1, or 40-50:1. More specifically, the weight ratio of LF0376 and zanubrutinib can be 40:1.
  • the efficacy of LF0376 and zanubrutinib has a synergistic effect in the treatment of B-cell lymphoma.
  • the mode of administration is simultaneous or sequential administration.
  • the therapeutically effective dose of the pharmaceutical composition depends on the species, weight, age and tumor type treated, the condition of the individual case or its severity. Doctors, clinicians or veterinarians who master the treatment techniques in the relevant field can easily determine the use of the aforementioned pharmaceutical composition in the preparation of a drug for treating or preventing cancer by the active ingredients required for preventing, treating or inhibiting the development of disorders or diseases.
  • treatment used herein includes treatment that slows down, alleviates or relieves at least one symptom in the subject or achieves delayed disease development. For example, treatment can be to reduce one or more symptoms of the disease or completely eliminate the disease, such as cancer.
  • treatment also refers to blocking, delaying the occurrence of the disease (i.e., the stage before the clinical manifestation of the disease) and/or reducing the risk of disease development or deterioration.
  • prevention used herein includes preventing at least one symptom, which is related to or caused by the prevented state, disease or disorder.
  • the cancer is selected from one or more combinations of B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, slow cell lymphoma, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, urogenital tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosal cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, stomach cancer, testicular cancer and thyroid cancer.
  • the B cell lymphoma is diffuse large B cell lymphoma.
  • the present application provides a drug for treating cancer, including the CCR2/5 dual receptor antagonist in the aforementioned use, or the aforementioned pharmaceutical composition, and pharmaceutically acceptable excipients and/or carriers.
  • pharmaceutically acceptable refers to those compounds, therapeutic agents (such as antibodies), materials, compositions and/or dosage forms that are suitable for contact with warm-blooded animals such as mammals or human tissues within a reasonable judgment range without excessive toxicity, irritation, allergic reactions and other problems or complications, and have a reasonable benefit/benefit ratio.
  • carrier or “excipient” as used herein include any and all solvents, dispersion media, coating agents, Surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, adhesives, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc., and combinations thereof, and must have sufficiently high purity and very low toxicity to make them suitable for being given to patients to be treated.
  • the carrier can be inert or it can itself have a medicinal benefit.
  • Some carriers can be listed in more than one category, such as: vegetable oil can be used as a lubricant in some preparations and as a diluent in other preparations.
  • Exemplary pharmaceutical carriers include sugar, starch, cellulose, malt, gelatin, talcum and vegetable oil.
  • Optional activating agents can be included in the pharmaceutical composition, which does not substantially affect the activity of the compound of the present invention.
  • the drug solution was kept at 4°C during administration.
  • the drug solution was kept at 4°C during administration.
  • the drug solution was kept at 4°C during administration.
  • Example 1 In vivo efficacy evaluation of the test drug on PDX tumor transplantation model
  • the LF0376 200mg/kg group was prepared with 5% DMSO + 95% (10% HP- ⁇ -CD).
  • Zanubrutinib is prepared with 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% saline.
  • the specific preparation method is: 60mg Zanubrutinib is added to 6ml DMSO to prepare the mother solution, and then divided into 5ml EP tubes at 0.4ml per tube.
  • NOG mice 40 female NOG mice were inoculated with patient PDX in the axilla.
  • NOG mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. They were 6-7 weeks old at the time of tumor inoculation.
  • Feeding and management conditions The mice were raised according to SPF animal feeding conditions, and the cages, bedding, feed and drinking water were sterilized by high temperature and high pressure. The cages were placed in the IVC, with 3-5 animals per cage. The indoor temperature of the animal room was 21-25°C, and the relative humidity was 40%-70%.
  • PDX came from patients with diffuse large B-cell lymphoma and belonged to the non-germinal center (non-GCB) subtype. Immunohistochemical results of the PDX model: CD10-, MUM-1 (100%+), Bcl6 (80%+), CD20+, Bcl2+, CD3-, Ki67 (90%+).
  • mice On the 30th day after inoculation, mice were regrouped according to tumor volume, with 8 mice in each group, a total of 4 groups, a total of 32 mice, and the mean tumor volume of each group reached 133.47 ⁇ 1.75mm 3 , which was Di 0 day. The remaining mice were killed after the end of the experiment or when the tumor load reached 1500mm 3. Each group of mice was administered according to the dose set for each group. The tumor volume was measured every 3 days. Each group was given different doses and drugs, see Table 3 and Figure 1 for details.
  • the vehicle control group was given 5% DMSO + 95% (10% HP- ⁇ -CD).
  • the vehicle and LF0376 were administered starting at Di0 (Di: Days of injection), twice a day, with an interval of 8 hours.
  • Zanubrutinib was administered by gavage once a day.
  • the tumor volume was measured every 3 days.
  • the body weight of the animals was measured every 3 days.
  • PRISM software was used for statistical analysis, one-way ANOVA was used for data analysis, and Tukey’s method was used for inter-group comparison.
  • This phase is a study on the combination of LF0376 and Zebutinib, with a total of 27 days of medication.
  • the tumors were weighed 27 days after administration, and it was found that the tumor weight in the LF0376 combined with zanubrutinib group was significantly smaller than that in the control group and the two single-drug groups.
  • the weight of mice in the control group increased significantly during treatment, which is consistent with the natural law that the tumor grows larger and the mice become heavier.
  • the LF0376 monotherapy group, the zanubrutinib group, and the LF0376 combined with zanubrutinib group significantly reduced the tumor volume of mice compared with the control group, thereby reducing the weight of mice, and all did not exceed the range of mouse weight loss, indicating that both combined medication and monotherapy were well tolerated and safe in mice.
  • the LF0376 100mg/kg group was prepared with 5% DMSO + 95% (10% HP- ⁇ -CD).
  • Ibrutinib is prepared with 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% saline.
  • the specific preparation method is: 240mg Ibrutinib is added to 6ml DMSO to prepare the mother solution, and then divided into 5ml EP tubes at 0.4ml per tube.
  • NOG mice 40 female NOG mice were inoculated with patient PDX in the axilla.
  • NOG mice were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. They were 6-7 weeks old at the time of tumor inoculation.
  • Feeding and management conditions The mice were raised according to SPF animal feeding conditions, and the cages, bedding, feed and drinking water were sterilized by high temperature and high pressure. The cages were placed in the IVC, with 3-5 animals per cage. The indoor temperature of the animal room was 21-25°C, and the relative humidity was 40%-70%.
  • PDX came from patients with diffuse large B-cell lymphoma and belonged to the non-germinal center (non-GCB) subtype. Immunohistochemical results of the PDX model: CD10-, MUM-1 (100%+), Bcl6 (80%+), CD20+, Bcl2+, CD3-, Ki67 (90%+).
  • mice On the 24th day after inoculation, mice were regrouped according to tumor volume, with 8 mice in each group, for a total of 4 groups. The mean tumor volume of each group reached 108.72 ⁇ 0.33mm 3 , which was day 0. The remaining mice were killed after the end of the experiment or when the tumor burden reached 1500mm 3. Mice were administered according to the dose set for each group. Tumor volume was measured once every 3 days, and body weight was weighed. Different doses and drugs were given to each group, see Table 4 and Figure 5 for details.
  • the vehicle control group was given 5% DMSO + 95% (10% HP- ⁇ -CD).
  • the vehicle and LF0376 were administered starting at Di 0 (Di: Days ofinjection), twice a day, with an interval of 8 hours.
  • Ibrutinib was administered by gavage once a day.
  • This phase is a study on the combination of LF0376 and ibrutinib, with a total of 27 days of administration.
  • the tumors were weighed 27 days after administration, and it was found that the tumor weight in the LF0376 combined with ibrutinib group was significantly smaller than that in the control group and the two single-drug groups.
  • the weight of mice in the control group increased significantly during treatment, which is consistent with the natural law that the tumor grows larger and the mice become heavier.
  • the LF0376 monotherapy group, the ibrutinib group, and the LF0376 combined with ibrutinib group significantly reduced the tumor volume of mice compared with the control group, thereby reducing the weight of mice, and all did not exceed the range of mouse weight loss, indicating that both combined medication and monotherapy were well tolerated and safe in mice.
  • Example 2 In vivo efficacy evaluation of the test drug on the human DLBCL xenograft tumor model LD1-0026-361717
  • This example mainly tests the growth inhibitory effect or complete cure ability of the test drugs LF0376 alone, Ibrutinib alone, Zanubrutinib alone, and LF0376 combined with Ibrutinib or Zanubrutinib on the human DLBCL in vivo transplanted tumor model LD1-0026-361717.
  • LD1-0026-361717 human DLBCL tumor tissue passed to FP3+2 generation, was used for this efficacy experiment.
  • the tumor mass of the FP3+1 generation LD1-0026-361717 human DLBCL in vivo transplanted tumor was cut into tumor tissues of approximately 3 mm ⁇ 3 mm ⁇ 3 mm (approximately 45-60 mg) and inoculated subcutaneously into NU/NU mice. The mice after inoculation were observed and the growth of the tumor was monitored. When the average tumor volume of the tumor-bearing mice was 137.11 ⁇ 6.36 mm 3 on the 28th day of inoculation, the grouping and administration were performed, and the day of grouping and administration was defined as day 0. Specific grouping information and dosing regimen are detailed in Table 7.
  • Dosing volume adjust the dosing volume according to the weight of tumor-bearing mice (0.2mL/20g); PO: intragastric administration; QD: once a day; BID: twice a day, with an interval of about 8 hours.
  • Tumor volume was measured twice a week using a vernier caliper.
  • the relative tumor volume (RTV) is calculated according to the results of tumor measurement.
  • TGI (%) [1-(T i -T 0 )/(V i -V 0 )] ⁇ 100%
  • T i is the average tumor volume of the compound group after the start of administration
  • T 0 is the average tumor volume of the compound group at the first administration
  • V 0 is the average tumor volume of the Vehicle group at the first administration
  • Vi is the average tumor volume of the Vehicle group after the start of administration. If TGI (%) > 50%, it is considered that the compound exhibits a significant inhibitory effect on tumor growth.
  • mice The weight of mice was measured every day.
  • the average tumor volume of the Vehicle group was 1470.55 ⁇ 411.29 mm 3
  • the average tumor volumes of the LF0376 monotherapy group, the Ibrutinib monotherapy group, the Zanubrutinib monotherapy group, the LF0376+Ibrutinib group and the LF0376+Zanubrutinib group were 1219.51 ⁇ 254.70 mm 3 , 906.95 ⁇ 185.57 mm 3 , 972.72 ⁇ 342.44 mm 3 , 566.26 ⁇ 159.12 mm 3 and 752.64 ⁇ 212.66 mm 3 , respectively.
  • TGI (%) were 18.60%, 42.24%, 37.33%, 67.86% and 53.86% respectively; T/C (%) were 84.86%, 61.94%, 66.29%, 38.45% and 51.21% respectively;
  • LF0376+Ibrutinib group and LF0376+Zanubrutinib group showed significant inhibitory effect on tumor growth in human DLBCL PDX model LD1-0026-361717 compared with Vehicle group.
  • LF0376+Ibrutinib group and LF0376+Zanubrutinib group showed stronger inhibitory effect on tumor growth compared with LF0376 monotherapy group and Ibrutinib/Zanubrutinib monotherapy group, indicating that LF0376 can enhance the anti-tumor effect of Ibrutinib or Zanubrutinib.
  • Table 8 Summary of the anti-tumor efficacy evaluation of the tested drugs in the LD1-0026-361717 human DLBCL subcutaneous xenograft tumor model
  • the average tumor weights of the Vehicle group, LF0376 monotherapy group, Ibrutinib monotherapy group, Zanubrutinib monotherapy group, LF0376+Ibrutinib group and LF0376+Zanubrutinib group were 1.239 ⁇ 0.375 g, 1.024 ⁇ 0.218 g, 0.739 ⁇ 0.162 g, 0.785 ⁇ 0.297 g, 0.475 ⁇ 0.134 g and 0.596 ⁇ 0.184 g, respectively, and the tumor weight results were basically consistent with the tumor volume results.
  • the RCBW (%) of the Vehicle group, LF0376 monotherapy group, Ibrutinib monotherapy group, Zanubrutinib monotherapy group, LF0376+Ibrutinib group and LF0376+Zanubrutinib group were 11.91 ⁇ 2.20%, 12.00 ⁇ 1.28%, 5.48 ⁇ 1.16%, 9.32 ⁇ 1.80%, 4.82 ⁇ 1.64% and 5.33 ⁇ 1.33%, respectively.
  • LF0376 alone, Ibrutinib alone, and Zanubrutinib alone did not show significant anti-tumor effects in this model at the current dose level; LF0376 combined with Ibrutinib and LF0376 combined with Zanubrutinib showed significant anti-tumor effects in this model, indicating that LF0376 can significantly enhance the anti-tumor effects of Ibrutinib and Zanubrutinib.
  • no animals in each group showed significant weight loss, indicating that the test drug was safe.
  • the purpose of this example is to evaluate the efficacy and explore the mechanism of the test drug in the Balb/c mouse A20 tumor model (mouse B cell lymphoma).
  • the animals were isolated and adaptively raised before experimental treatment.
  • A20 cells were cultured and expanded in vitro, and cells in the logarithmic growth phase were collected and resuspended in PBS.
  • the concentration of the cell suspension was 5 ⁇ 10 6 /mL.
  • the cell suspension was injected subcutaneously into the right side of Balb/c mice using a 1 mL syringe. Each animal was injected with 100 ⁇ L of the cell suspension. The number of cells inoculated was 5 ⁇ 10 5 /mouse.
  • Drug administration was started according to the grouping scheme. Each group was administered by gavage. The administration volume of each group was 5 mL/kg. The administration frequency was once or twice a day. During the experiment, the animal body weight was weighed and the tumor volume was measured three times a week.
  • the experimental endpoint was PG-D13, all mice were euthanized, tumor tissues were removed, weighed and photographed. Based on the tumor volume and body weight measured at PG-D12, the tumor volume inhibition rate (TGI) and animal body weight change rate (BWC%) were calculated respectively.
  • TGI tumor volume inhibition rate
  • BWC% animal body weight change rate
  • mice The dosing regimen for mice is shown in Table 12:
  • G Group; p.o.: intragastric administration;
  • the day of grouping was defined as PG-D0, and drug administration began on PG-D0;
  • mice After the experiment, the mice will be processed according to customer needs.
  • mice When the mean tumor volume reached approximately 60.75 ⁇ 0.48 mm 3 , the mice were randomly divided into 6 groups of 6 mice each according to the tumor volume. Detailed information is shown in Table 13 below: The cages were clearly marked with cage cards, including the animal number, sex, strain, date of receipt, treatment, study number, and group number.
  • a represents the long diameter of the tumor
  • b represents the short diameter of the tumor.
  • TGI Tumor volume inhibition rate
  • TGI [1-(TV Dt treatment group-TV D0 treatment group)/(TV Dt control group-TV D0 control group)] ⁇ 100%
  • TV Dt experimental group tumor volume of the treatment group on day t after drug administration
  • TV Dt control group tumor volume of the control group on day t after drug administration
  • TV D0 control group the tumor volume of the control group at the time of group drug administration.
  • Weight change rate (BW Dt - BW D0 )/BW D0 ⁇ 100%
  • BW D0 animal body weight at the time of group dosing.
  • W C represents the tumor weight of the control group
  • WT represents the tumor weight of the treatment group
  • the average tumor volume of the control group was 687.68 ⁇ 46.59 mm 3
  • the average tumor volumes of the LF0376 monotherapy group, the Ibrutinib monotherapy group, the Zanubrutinib monotherapy group, the LF0376+Ibrutinib group, and the LF0376+Zanubrutinib group were 551.12 ⁇ 40.66 mm 3 , 640.57 ⁇ 48.47 mm 3 , 651.25 ⁇ 39.04 mm 3 , 497.63 ⁇ 57.96 mm 3 , and 454.45 ⁇ 46.55 mm 3 , respectively
  • the TGIs were 21.74%, 7.47%, 5.79%, 30.30%, and 37.12%, respectively.
  • the LF0376+Ibrutinib group and the LF0376+Zanubrutinib group showed significant tumor growth inhibition.
  • the LF0376+Ibrutinib group and the LF0376+Zanubrutinib group showed more significant tumor inhibition.
  • Table 14 Average tumor volume of mice in each group during treatment (mm 3 )
  • the average tumor weight of the control group was 1.8387 ⁇ 0.2200 g
  • the average tumor weights of the LF0376 monotherapy group, Ibrutinib monotherapy group, Zanubrutinib monotherapy group, LF0376+Ibrutinib group, and LF0376+Zanubrutinib group were 1.1853 ⁇ 0.1562 g, 1.5809 ⁇ 0.1216 g, 1.4855 ⁇ 0.1700 g, 1.3331 ⁇ 0.1810 g, and 1.0855 ⁇ 0.1081 g, respectively, and the IRs were 35.54%, 14.02%, 19.21%, 27.50%, and 40.96%, respectively.
  • the tumor weight results were basically consistent with the tumor volume results.
  • n/n means: actual number of samples/original number of samples.
  • mice As shown in Figure 20 and Table 17, the average body weights of PG-D12, Group 1, Group 2, Group 3, Group 4, Group 5 and Group 6 mice were 25.97 ⁇ 1.13g, 24.73 ⁇ 0.89g, 26.33 ⁇ 1.20g, 25.68 ⁇ 0.69g, 24.52 ⁇ 1.06g and 24.80 ⁇ 0.32g, respectively.
  • mice in Group 1, Group 2, Group 3, Group 4, Group 5 and Group 6 increased with PG-D12, and the weight change rates were 9.6 ⁇ 1.4%, 5.3 ⁇ 1.4%, 9.6 ⁇ 2.5%, 7.9 ⁇ 3.0%, 5.2 ⁇ 2.8% and 5.8 ⁇ 1.8%, respectively.
  • the weight change rates of mice in the experimental groups during the treatment period ranged from -10.8% to 21.6%. No mice were suspended from the drug due to significant weight loss or poor condition.
  • the body weight change rate was calculated based on the body weight on PG-D0. Data are expressed as Mean ⁇ SEM.
  • LF0376 alone had a certain anti-tumor effect on A20, and the combined anti-tumor effect of LF0376+Ibrutinib and LF0376+Zanubrutinib was more significant, indicating that LF0376 can significantly enhance the anti-tumor effect of Ibrutinib and Zanubrutinib.

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Abstract

一种联合用药物组合物及其应用，所述药物组合物包括CCR2/5双受体拮抗剂和布鲁顿酪氨酸激酶抑制剂。其中，LF0376与泽布替尼的联合用药、LF0376与伊布替尼的联合用药，比单一用药在B细胞淋巴瘤上具有明显的抑瘤效果。

Description

一种联合用药物组合物及其应用 技术领域
本申请涉及医药技术领域，特别涉及一种联合用药物组合物及其应用。
背景技术
淋巴瘤是我国常见的恶性肿瘤，每年发病人数约为7.54万，发病率为4.75/10万，死亡人数为4.05万，死亡率为2.64/10万，而且地域之间、城乡之间的差异明显。淋巴瘤可分为霍奇金淋巴瘤和非霍奇金淋巴瘤，病理类型复杂、治疗方法多样、预后转归迥异，因此在诊断和治疗过程中一般需要多学科团队参与。非霍奇金淋巴瘤中，弥漫性大B细胞淋巴瘤(DLBCL)约占30～40％，其标准治疗为免疫联合化疗方案(R-CHOP)，约50％-60％的患者可通过当前标准治疗治愈，但仍有40～50％的患者治疗后出现难治或复发(约15％～25％的患者是原发难治(治疗期间或治疗后进展)，约20％～30％的患者在完全缓解(CR)后复发，还有5％患者处于部分缓解(PR)。对于上述复发/难治的患者，造血干细胞移植和CART的首推的治疗方法，但因为移植条件和价格昂贵等原因，导致受众人群有限，而其余治疗方法则以化疗为主，存在疗效局限和毒副作用较大的问题。此外，年轻高危或中高危患者、MYC和BCL2同时重排的“双打击”、加上BCL6重排的“三打击”、MYC和BCL2均表达的“双表达”、非生发中心B细胞样亚型淋巴瘤等均提示预后不良，目前尚无有效的治疗措施，存在未满足的临床需求。
CCR2和CCR5均为G蛋白偶联受体，可识别趋化因子，具有73％的序列同源性。CCR2的主要配体是趋化因子CCL2，此外还可以识别CCL7、CCL8、CCL12和CCL13；CCR5与CCL3、CCL4、CCL5、CCL3L1、CCL8、CCL11等多个趋化因子具有较高亲和力。CCR2主要表达在单核细胞、NK细胞和T细胞上，在炎症条件下可以招募这些细胞到达炎症部位。多数情况下，CCR2-CCL2轴主要发挥促炎作用，但表达在Treg细胞上的CCR2发挥抑炎作用。CCR5的表达更为广泛，包括T细胞、巨噬细胞、粒细胞、DC、小胶质细胞甚至表皮细胞等。
在多种疾病过程中，例如病毒感染和肝纤维化等包含炎症反应的疾病中，CCR2和CCR5均介导了淋巴细胞、单核细胞、巨噬细胞的迁移和浸润，促进了疾病的发生发展。研究表明，CCR2对单核细胞、巨噬细胞的迁移、浸润更相关，CCR5对淋巴细胞的作用更大。因此，CCR2和CCR5在功能上，虽有相同点，但侧重并不相同。
目前还没有研究表明CCR2/5双受体拮抗剂与B细胞淋巴瘤之间的具体联系。
布鲁顿酪氨酸激酶(Bruton tyrosine kinase，BTK)是BCR信号转导通路中的一个关键的激酶。BTK在B淋巴细胞、嗜碱性粒细胞、单核细胞等髓系细胞中表达。基于第一代BTK抑制剂Ibrutinib(伊布替尼)在多个临床试验中疗效突出，已被FDA获批用于7个适应症，包括小淋巴细胞性林巴瘤、套细胞淋巴瘤、慢性淋巴细胞白血病、华氏巨球蛋白血症、巨球蛋白血症、移植物抗宿主病和边缘区淋巴瘤，其中前三者已在国内获批；二代高选择性BTK抑制剂Zanubrutinib(泽布替尼)为中国自主研发抗癌新药，也相继在成人套细胞淋巴瘤、华氏巨球蛋白血症、复发/难治性边缘区淋巴瘤和慢性淋巴细胞白血病(CLL)或小淋巴细胞淋巴瘤(SLL)中获批。虽然BTK抑制剂未在DLBCL中获批，但基于临床实践，其被CSCO指南推荐用于该适应症。
发明内容
鉴于以上所述现有技术的缺点，本申请的目的在于提供一种联合用药物组合物及其应用，用于解决现有技术中的问题。选用CCR2/5双受体拮抗剂和BTK抑制剂联合用药，在治疗B细胞淋巴瘤，特别是弥漫性大B细胞淋巴瘤上，本研究为探索二者联合用药在B细胞淋巴瘤的治疗中提供了新的方向。
为实现上述目的及其他相关目的，本申请第一方面提供CCR2/5双受体拮抗剂在制备治疗或预防B细胞淋巴瘤药物中的用途。
在本申请的任意实施方式中，所述CCR2/5双受体拮抗剂选自LF0376、BMS-813160、Cenicriviroc中的一种或多种的组合；优选地，所述CCR2/5双受体拮抗剂选自LF0376。
本申请第二方面提供一种药物组合物，包括CCR2/5双受体拮抗剂和布鲁顿酪氨酸激酶抑制剂。
在本申请的任意实施方式中，所述布鲁顿酪氨酸激酶抑制剂选自泽布替尼、伊布替尼、spebrutinib、acalabrutinib、olmutinib、poseltinib、tirabrutinib、evobrutinib、fenebrutinib、vecabrutinib、ARQ-531、BMS-986195、BMS-986142、CGI-1746、GDC-0834、RN-486、JNJ-64264681、DTRMWXHS-12、CT-1530、AC0058TA、ICP-022、WXFL10230486、SHR1459、PRN-1008、PRN-473、PRN-2246、LOU-064、LOXO-305、ABBV-105、PCI-45292、TAK-020、M-7583、BIIB-068、BMS-935177、CNX-774、TAS-5315、TGH-663、LFM-A13中的一种或多种的组合。
在本申请的任意实施方式中，所述布鲁顿酪氨酸激酶抑制剂选自泽布替尼或伊布替尼。
在本申请的任意实施方式中，所述药物组合物包括LF0376和伊布替尼；优选地，所述 LF0376和伊布替尼的重量比为0.5～10：1。
在本申请的任意实施方式中，所述药物组合物包括LF0376和泽布替尼；优选地，所述LF0376和泽布替尼的重量比为0.8～40：1。
本申请第三方面提供所述的药物组合物在制备治疗或预防癌症药物中的应用。
在本申请的任意实施方式中，所述癌症选自B细胞淋巴瘤、膀胱癌、血癌、骨癌、脑癌、乳腺癌、中枢神经系统癌症、宫颈癌、结肠癌、子宫内膜癌、食管癌、胆囊癌、胃肠道癌、外生殖器癌、泌尿生殖道癌、头癌、肾癌、喉癌、肝癌、肺癌、肌肉组织癌症、颈癌、口腔或鼻黏膜癌、卵巢癌、胰腺癌、前列腺癌、皮肤癌、脾癌、小肠癌、大肠癌、胃癌、睾丸癌和甲状腺癌中的一种或多种的组合。
在本申请的任意实施方式中，所述B细胞淋巴瘤为弥漫性大B细胞淋巴瘤。
本申请第四方面提供一种治疗癌症的药物，包括前述的用途中的CCR2/5双受体拮抗剂，或前述的药物组合物，以及药学上可接受的辅料和/或载体。
与现有技术相比，本申请的有益效果为：
1、本申请首次披露使用LF0376在B细胞淋巴瘤上具有明显的抑瘤效果。
2、LF0376与泽布替尼的联合用药，比单一用药在B细胞淋巴瘤上具有明显的抑瘤效果。
3、LF0376与伊布替尼的联合用药，比单一用药在B细胞淋巴瘤上具有明显的抑瘤效果。
附图说明
图1显示为LF0376与泽布替尼的联合用药的实验设计图。
图2显示为实施例1LF0376(200mg)联合Zanubrutinib实验的抑瘤曲线。每个数据点用mean±sem表示。
图3显示为实施例1LF0376(200mg)联合Zanubrutinib实验，经治疗27天后的瘤重。每个数据点用mean±sem表示。
图4显示为实施例1治疗期间小鼠较基线的体重变化百分比(％)。每个数据点用mean±sem表示。
图5显示为LF0376与伊布替尼的联合用药的实验设计图。
图6显示为实施例1LF0376(100mg)联合Ibrutinib实验的抑瘤曲线。每个数据点用mean±sem表示。
图7显示为实施例1LF0376(100mg)联合Ibrutinib实验，经治疗27天后的瘤重。每个数据点用mean±sem表示。
图8显示为实施例1治疗期间小鼠较基线的体重变化百分比(％)。每个数据点用mean±sem表示。
图9显示为实施例2全部实验组肿瘤体积变化曲线。
图10显示为实施例2Vehicle组、LF0376单药组、Ibrutinib单药组和LF0376+Ibrutinib组肿瘤体积变化曲线。
图11显示为实施例2Vehicle组、LF0376单药组、Zanubrutinib单药组和LF0376+Zanubrutinib组肿瘤体积变化曲线。
图12显示为实施例2实验结束时(第28天)各实验组瘤重。
图13显示为实施例2实验结束时(第28天)Vehicle组、LF0376单药组、Ibrutinib单药组和LF0376+Ibrutinib组瘤重。
图14显示为实施例2实验结束时(第28天)Vehicle组、LF0376单药组、Zanubrutinib单药组和LF0376+Zanubrutinib组瘤重。
图15显示为实施例2受试药物治疗过程中荷瘤鼠平均RCBW(％)曲线。
图16显示为实施例2受试药物治疗过程中荷瘤鼠平均体重变化曲线。
图17显示为各组小鼠接受治疗期间的肿瘤体积变化图。注：数据点代表每组肿瘤体积的Mean，误差线代表SEM。
图18显示为各组小鼠接受治疗期间的个体肿瘤体积变化图。
图19显示为PG-D13各组小鼠的肿瘤瘤重图。注：数据点代表小鼠肿瘤体重，中线代表每组肿瘤体重的Mean，误差线代表SEM。
图20显示为各组小鼠治疗期间的平均体重图。注：数据点代表每组体重的Mean。误差线代表SEM。
图21各组小鼠治疗期间较基线的体重变化。注：数据点代表每组体重变化率的Mean，误差线代表SEM。
具体实施方式
为了使本申请的发明目的、技术方案和有益效果更加清晰，下面结合实施例对本申请作进一步说明。应理解，下述实施例只用于解释本申请，并非用于限定申请的范围。下述实施例中所使用的试验方法如无特殊说明，均为常规方法，熟悉此技术的人士可由本说明所揭露的内容容易地了解本申请的其他优点及功效。
本申请的发明人经过大量探索研究，发现了一种联合用药物组合物及其应用，在此基础 上完成了本申请。
本申请一方面提供CCR2/5双受体拮抗剂在制备治疗或预防B细胞淋巴瘤药物中的用途。
本申请提供的药物组合物中，CCR2/5双受体拮抗剂选自LF0376、BMS-813160、Cenicriviroc中的一种或多种的组合。CCR2/5为细胞表面趋化因子受体2和5，属于G蛋白偶联受体超家族成员，在多种细胞表面表达，与其特异性配体结合而发挥生物学作用。优选地，CCR2/5双受体拮抗剂选自LF0376，又称氮杂苯并八元环化合物，其他代号名称为WXFL40050414或WXSH0376。在本申请的一优选实施例中，LF0376为上海药明康德新药开发有限公司受申请人委托生产，批号为ES16578-17-P1，分子量为739.98，纯度为97.28％，常温保存。本申请首次披露CCR2/5双受体拮抗剂(LF0376)与B细胞淋巴瘤的具体联系，使用LF0376在B细胞淋巴瘤上具有明显的抑瘤效果。
本申请另一方面提供一种药物组合物，包括CCR2/5双受体拮抗剂和布鲁顿酪氨酸激酶抑制剂。
在一些实施方式中，药物组合物的组分配比为临床上可接受的剂量，取决于对象的物种、体重、年龄和所治疗的肿瘤类型、个体病例的病情或者其严重度。掌握相关领域治疗技术的医生、临床医生或兽医能容易地确定预防、治疗或抑制紊乱或疾病发展所需的药物组合物的有效剂量。
本申请提供的药物组合物中，布鲁顿酪氨酸激酶抑制剂选自泽布替尼、伊布替尼、spebrutinib、acalabrutinib、olmutinib、poseltinib、tirabrutinib、evobrutinib、fenebrutinib、vecabrutinib、ARQ-531、BMS-986195、BMS-986142、CGI-1746、GDC-0834、RN-486、JNJ-64264681、DTRMWXHS-12、CT-1530、AC0058TA、ICP-022、WXFL10230486、SHR1459、PRN-1008、PRN-473、PRN-2246、LOU-064、LOXO-305、ABBV-105、PCI-45292、TAK-020、M-7583、BIIB-068、BMS-935177、CNX-774、TAS-5315、TGH-663、LFM-A13中的一种或多种的组合。布鲁顿酪氨酸激酶抑制剂(BTK)是B细胞受体通路重要信号分子，在B淋巴细胞的各个发育阶段表达，参与调控B细胞的增殖、分化与凋亡，在恶性B细胞的生存及扩散中起重要作用。
本申请提供的药物组合物中，布鲁顿酪氨酸激酶抑制剂选自泽布替尼(Zanubrutinib)或伊布替尼(Ibrutinib)。Zanubrutinib是一种多靶点的激酶抑制剂，是第一个被批准的BTK小分子抑制剂，通过与BTK活性位点中的半胱氨酸形成共价键，从而抑制BTK酶的活性。Ibrutinib属于第二代的BTK抑制剂，其通过与酪氨酸激酶共价结合，使酶不可逆失活。在本申请的一优选实施例中，Zanubrutinib为MCE生产，货号为Lot#79640。Ibrutinib为MCE生 产，货号为Lot#114225。
本申请提供的药物组合物中，药物组合物为LF0376和伊布替尼，二者的重量比为0.5～10：1。在本申请一具体实施方式中，LF0376和伊布替尼的重量比例如可以为0.5～1：1、1～2.5：1、2.5～5：1、5～8：1、或8～10：1等。更具体的，LF0376和伊布替尼的重量比可以为5：1。在一些实施方式中，LF0376和伊布替尼的药效在治疗B细胞淋巴瘤上具有协同效果。
本申请提供的药物组合物中，药物组合物为LF0376和泽布替尼，二者的重量比为0.8～40：1。在本申请一具体实施方式中，LF0376和泽布替尼的重量比例如可以为0.8～1：1、1～5：1、5～10：1、10～20：1、20～30：1、30～40：1、或40～50：1等。更具体的，LF0376和泽布替尼的重量比可以为40：1。在一些实施方式中，LF0376和泽布替尼的药效在治疗B细胞淋巴瘤上具有协同效果。
本申请提供的药物组合物中，用药方式为同时或依序给药。治疗有效剂量的药物组合物取决于对象的物种、体重、年龄和所治疗的肿瘤类型、个体病例的病情病症或者其严重度。掌握相关领域治疗技术的医生、临床医生或兽医能容易地确定预防、治疗或抑制紊乱或疾病发展所需的各活性成分有前述的药物组合物在制备治疗或预防癌症药物中的应用。本文所用的术语“治疗”包括减缓、减轻或缓解对象中至少一种症状或者实现疾病发展延迟的治疗。例如，治疗可以是减少一种或多种疾病症状或者完全消除疾病，如癌症。在本公开意义内，术语“治疗”也指阻滞、延迟疾病发生(即疾病临床表征前的阶段)和/或降低疾病发展或恶化的风险。本文所用的术语“预防”包括预防至少一种症状，该症状与所预防状态、疾病或紊乱相关或由其导致。
本申请提供的应用中，癌症选自B细胞淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤、慢细胞淋巴瘤、膀胱癌、血癌、骨癌、脑癌、乳腺癌、中枢神经系统癌症、宫颈癌、结肠癌、子宫内膜癌、食管癌、胆囊癌、胃肠道癌、外生殖器癌、泌尿生殖道癌、头癌、肾癌、喉癌、肝癌、肺癌、肌肉组织癌症、颈癌、口腔或鼻黏膜癌、卵巢癌、胰腺癌、前列腺癌、皮肤癌、脾癌、小肠癌、大肠癌、胃癌、睾丸癌和甲状腺癌中的一种或多种的组合。
本申请提供的应用中，B细胞淋巴瘤为弥漫性大B细胞淋巴瘤。
本申请另一方面提供一种治疗癌症的药物，包括前述的用途中的CCR2/5双受体拮抗剂，或前述的药物组合物，以及药学上可接受的辅料和/或载体。本文所用术语“药学上可接受”指在合理判断范围内，适于接触温血动物如哺乳动物或人组织的那些化合物、治疗剂(如抗体)、材料、组合物和/或剂型，而没有过度毒性、刺激、过敏反应和其它问题或并发症，并具有合理的效益/收益比。本文所用的术语“载体”或“辅料”包括任何及所有溶剂、分散介质、包衣剂、 表面活性剂、抗氧化剂、防腐剂(例如抗细菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料等，以及其组合，并且必须具有足够高的纯度和十分低的毒性以使它们适于被给予待治疗的患者。载体可以是惰性或其可以本身具有药用益处。一些载体可以列在多于一种的类别中，如：植物油可以在一些制剂中用作滑润剂并在其他制剂中用作稀释剂。示例性药用载体包括糖、淀粉、纤维素、麦芽、明胶、滑石和植物油。可选的活性剂可以包括在药物组合物中，其基本上不影响本发明的化合物的活性。
下面通过实施例对本申请予以进一步说明，但并不因此而限制本申请的范围。
下述实施例所用主要试剂信息见表1。
表1主要试剂列表
下述实施例所用主要仪器信息见表2。
表2仪器信息

下列实施例所用受试药物信息如下：
1、LF0376
提供方：无锡瓴方生物医药科技有限公司Lot:CR-C-210219013-FP22001
纯度：98.6％
性状等描述：粉末
分子量：盐：835.09；游离碱：738.38
校正因子：1.15
保存于：RT
给药过程中药物溶液保存于4℃
2、Ibrutinib
提供方：MCE
Lot:136640，HY-10997
纯度：99.46％
校正因子：NA
性状等描述：粉末
保存于：4℃
给药过程中药物溶液保存于4℃
3、Zanubrutinib
提供方：MCE
Lot:79640，HY-101474A
纯度：99.08％
校正因子：NA
性状等描述：粉末
保存于：4℃
给药过程中药物溶液保存于4℃
实施例1受试药物对PDX肿瘤移植模型的体内药效评价
一、LF0376联合泽布替尼(Zanubrutinib，ZAN)用药
1.1化合物配制
LF0376200mg/kg组用5％DMSO+95％(10％HP-β-CD)配制。具体配置方法为：称取210mg LF0376加入0.53ml DMSO，漩涡震荡得到澄清黄色溶液。再加入9.975ml(10％HP-B-CD)漩涡震荡得到均一混悬液，将混悬液调至pH＝3,得到澄清溶液。配制后分装至5ml EP管中，每管3.3mL，4℃保存。每三天配制一次。
Zanubrutinib用10％DMSO+40％PEG300+5％吐温80+45％生理盐水配置。具体配置方法为：60mg Zanubrutinib加入6ml DMSO配置母液，后按每管0.4ml分装至5ml EP管，使用时按顺序加上1.6ml PEG300，0.2ml吐温80，1.8ml生理盐水，4℃保存。每三天配置一次。
1.2 PDX肿瘤移植模型构建
40只雌性NOG小鼠腋下接种含有患者PDX。NOG小鼠购自北京维通利华实验动物技术有限公司。肿瘤接种时为6-7周龄。饲养管理条件：按SPF级动物饲养条件饲养，鼠笼、垫料、饲料及饮用水均经高温高压灭菌处理。鼠笼放置在IVC中，每笼(3～5)只动物。动物房室内温度21～25℃，相对湿度40％～70％。PDX来自弥漫大B细胞淋巴瘤患者，属于非生发中心(non-GCB)亚型。PDX模型的免疫组化结果：CD10-，MUM-1(100％+)，Bcl6(80％+)，CD20+，Bcl2+，CD3-，Ki67(90％+)。
接种后第30天，按肿瘤体积重新分组，每组8只，共4组，共32只，各组瘤体积均值达到133.47±1.75mm3，为Di 0天。剩余小鼠在实验结束或肿瘤负荷达到1500mm3后处死。各组小鼠按各组设定的剂量给药。3天测量一次肿瘤体积。每组给以不同剂量和药品，详见表3和图1。
表3实验给药剂量及分组
注：溶媒对照组给予5％DMSO+95％(10％HP-β-CD)。溶媒和LF0376在Di0(Di:Days ofinjection)开始给药，每天两次，给药时间间隔8小时。Zanubrutinib灌胃给药，每天一次。
1.3指标观测
1.3.1肿瘤体积
3天测量一次肿瘤体积。肿瘤体积(TV)的计算公式为：TV＝1/2×a×b2。其中，a、b分别表示肿瘤块的长径和短径。
1.3.2体重
3天测量一次测量动物体重。
1.4数据分析
所有数据均以平均值±sem的形式表示。
使用PRISM软件进行统计分析，采用one-way ANOVA进行数据分析，组间比较应用Tukey’s法进行分析。
1.5实验结果
本阶段为LF0376与泽布替尼的联合用药研究，共给药27天。
如图2，观察整体抑瘤曲线可知，LF0376单药组、泽布替尼组、LF0376联合泽布替尼组相较于对照组，均能抑制肿瘤生长，其中联合组的抑瘤作用最显著。
如图3，给药27天后取瘤称重，发现LF0376联合泽布替尼组瘤重明显小于对照组和2个单药组。
如图4，治疗期间对照组的小鼠体重明显上升，这与肿瘤变大、小鼠变重的自然规律是一致的。用药之后，LF0376单药组、泽布替尼组、LF0376联合泽布替尼组相对于对照组显著减缓小鼠肿瘤体积，从而减少小鼠体重，且均未超出小鼠减重范围值，说明联合用药和单药治疗都在小鼠中耐受良好，安全性良好。
二、LF0376联合伊布替尼(Ibrutinib，IBR)用药
2.1化合物配制
LF0376 100mg/kg组用5％DMSO+95％(10％HP-β-CD)配制。具体配置方法为：称取210mg LF0376加入1.05ml DMSO，漩涡震荡得到澄清黄色溶液。再加入19.95ml(10％HP-B-CD)漩涡震荡得到均一混悬液，将混悬液调至pH＝3,得到澄清溶液。配制后分装至5ml EP管中，每管3.3mL，4℃保存。每三天配制一次。
Ibrutinib用10％DMSO+40％PEG300+5％吐温80+45％生理盐水配置。具体配置方法为：240mg Ibrutinib加入6ml DMSO配置母液，后按每管0.4ml分装至5ml EP管，使用时按顺序 加上1.6ml PEG300，0.2ml吐温80，1.8ml生理盐水，4℃保存。每三天配置一次。
2.2 PDX肿瘤移植模型构建
40只雌性NOG小鼠腋下接种含有患者PDX。NOG小鼠购自北京维通利华实验动物技术有限公司。肿瘤接种时为6-7周龄。饲养管理条件：按SPF级动物饲养条件饲养，鼠笼、垫料、饲料及饮用水均经高温高压灭菌处理。鼠笼放置在IVC中，每笼(3～5)只动物。动物房室内温度21～25℃，相对湿度40％～70％。PDX来自弥漫大B细胞淋巴瘤患者，属于非生发中心(non-GCB)亚型。PDX模型的免疫组化结果：CD10-，MUM-1(100％+)，Bcl6(80％+)，CD20+，Bcl2+，CD3-，Ki67(90％+)。
接种后第24天，按肿瘤体积重新分组，每组8只，共4组。各组瘤体积均值达到108.72±0.33mm3，为第0天。剩余小鼠在实验结束或肿瘤负荷达到1500mm3后处死。小鼠按各组设定的剂量给药。3天测量一次测量肿瘤体积，称体重。每组给以不同剂量和药品，详见表4和图5。
表4实验给药剂量及分组
注：溶媒对照组给予5％DMSO+95％(10％HP-β-CD)。溶媒和LF0376在Di 0(Di:Days ofinjection)开始给药，每天两次，给药时间间隔8小时。Ibrutinib灌胃给药，每天一次。
2.3指标观测
同1.3。
2.4数据分析
同1.4。
2.5实验结果
本阶段为LF0376与伊布替尼的联合用药研究，共给药27天。
如图6，观察整体抑瘤曲线可知，LF0376单药组、伊布替尼组、LF0376联合伊布替尼组相较于对照组，均能抑制肿瘤生长，其中联合组抑瘤作用最显著。
如图7，给药27天后取瘤称重，发现LF0376联合伊布替尼组瘤重明显小于对照组和2个单药组。
如图8，治疗期间对照组的小鼠体重明显上升，这与肿瘤变大、小鼠变重的自然规律是一致的。用药之后，LF0376单药组、伊布替尼组、LF0376联合伊布替尼组相对于对照组显著减缓小鼠肿瘤体积，从而减少小鼠体重，且均未超出小鼠减重范围值，说明联合用药和单药治疗都在小鼠中耐受良好，安全性良好。
实施例2受试药物对人源DLBCL异种移植瘤模型LD1-0026-361717的体内药效评价
本实施例主要是检测受试药物LF0376单药、Ibrutinib单药、Zanubrutinib单药和LF0376联合Ibrutinib或Zanubrutinib对人源性DLBCL体内移植瘤模型LD1-0026-361717的生长抑制作用或完全治愈能力。
1、化合物配制
详见表5：
表5受试药物配制
2、体内移植瘤模型
LD1-0026-361717人源性DLBCL肿瘤组织，传至FP3+2代用于本次药效实验。
LD1-0026-361717PDX模型基本信息，详见表6。
表6模型基本信息
95只NU/NU小鼠，雌性，体重18～21g，购买于北京维通利华实验动物技术有限公司(SCXK(京)2021-0006)，合格证号：110011231108918138。实验动物使用许可证号：SYXK(陕)2023-008。饲养环境：SPF级。动物在开始实验前适应观察3天。
将FP3+1代的LD1-0026-361717人源性DLBCL体内移植瘤的瘤块切成大小约为3mm×3mm×3mm(约45～60mg)的肿瘤组织，并将其接种于NU/NU小鼠皮下。观察接种后小鼠并监测肿瘤的生长，在接种第28天荷瘤小鼠平均肿瘤体积为137.11±6.36mm3时进行分组给药，分组给药当天定义为第0天。具体分组信息和给药方案详见表7。
表7给药和治疗
注：给药体积：根据荷瘤鼠体重调整给药体积(0.2mL/20g)；PO：灌胃给药；QD：每天给药一次；BID：每天给药2次，间隔时间约8小时。
3、指标观测
3.1肿瘤体积
使用游标卡尺每周两次测量，肿瘤体积计算公式为V＝0.5a×b2，a、b分别代表肿瘤的长径和宽径。
3.2相对肿瘤增殖率T/C(％)
计算公式如下：T/C％＝TRTV/CRTV×100％(TRTV：治疗组RTV；CRTV：Vehicle组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝Vt/V0，其中V0是分组给药时(即d0)测量所得平均肿瘤体积，Vt为某一次测量时的平均肿瘤体积，TRTV与CRTV取同一天数据。
3.3肿瘤生长抑制率TGI(％)
TGI(％)＝[1-(Ti-T0)/(Vi-V0)]×100％，Ti为化合物组开始给药后的平均肿瘤体积，T0为化合物组首次给药时的平均肿瘤体积，V0为Vehicle组首次给药时的平均肿瘤体积，Vi为Vehicle组开始给药后的平均肿瘤体积。TGI(％)>50％则认为化合物表现出显著的抑制肿瘤生长的作用。
3.4体重
每天测量。同时计算给药后小鼠体重相对变化比率：RCBW(％)＝(BWi–BW0)/BW0×100，BWi为开始给药后的体重，BW0为首次给药时的体重。
4、数据分析
所有数据均采用Mean±SEM表示，SEM＝SD/SQRT(n)，n＝实验组动物数。
5、实验结果
如图9、图10、图11和表8所示，第28天，Vehicle组平均肿瘤体积为1470.55±411.29mm3，LF0376单药组、Ibrutinib单药组、Zanubrutinib单药组、LF0376+Ibrutinib组和LF0376+Zanubrutinib组的平均肿瘤体积分别为1219.51±254.70mm3、906.95±185.57mm3、972.72±342.44mm3、566.26±159.12mm3和752.64±212.66mm3；TGI(％)分别为18.60％、42.24％、37.33％、67.86％和53.86％；T/C(％)分别为84.86％、61.94％、66.29％、38.45％和51.21％；LF0376+Ibrutinib组和LF0376+Zanubrutinib组与Vehicle组相比，均在人源DLBCL PDX模型LD1-0026-361717上表现出显著的抑制肿瘤生长的作用。LF0376+Ibrutinib组和LF0376+Zanubrutinib组各自分别与LF0376单药组和Ibrutinib/Zanubrutinib单药组相比，均表现出更强的抑制肿瘤生长的作用，表明LF0376能够增强Ibrutinib或Zanubrutinib的抗肿瘤作用。
表8受试药物在LD1-0026-361717人源性DLBCL皮下异种移植瘤模型上的抗肿瘤药效评价总结
如图12、图13、图14和表8所示，第28天，Vehicle组、LF0376单药组、Ibrutinib单药组、Zanubrutinib单药组、LF0376+Ibrutinib组LF0376+Zanubrutinib组的平均肿瘤瘤重分别为1.239±0.375g、1.024±0.218g、0.739±0.162g、0.785±0.297g、0.475±0.134g和0.596±0.184g，肿瘤瘤重结果与肿瘤体积结果基本相符。
如图15、图16和表9所示，第28天，Vehicle组、LF0376单药组、Ibrutinib单药组、Zanubrutinib单药组、LF0376+Ibrutinib组和LF0376+Zanubrutinib组RCBW(％)分别为11.91±2.20％、12.00±1.28％、5.48±1.16％、9.32±1.80％、4.82±1.64％和5.33±1.33％。
表9受试药物作用于LD1-0026-361717人源性DLBCL皮下异种移植瘤模型上的动物RCBW(％)

6、实验结论
LF0376单药、Ibrutinib单药和Zanubrutinib单药在当前剂量水平未对此模型表现出显著的抗肿瘤作用；LF0376联合Ibrutinib和LF0376联合Zanubrutinib对此模型表现出显著的抗肿瘤作用，提示LF0376能够显著增强Ibrutinib和Zanubrutinib的抗肿瘤作用。受试药物治疗期间，各组动物均未出现体重明显下降，提示受试药物安全性良好。
实施例3受试药物在Balb/c小鼠A20肿瘤模型上的药效评价
本实施例的目的是对受试药物在Balb/c小鼠A20肿瘤模型(小鼠B细胞淋巴瘤)上的药效评价和机制探索。
1、化合物配制
详见表10
表10受试药物配制
注：*给药浓度以有效成分计。
2、动物模型
动物信息见表11：
表11实验动物信息表
实验处理前动物进行隔离与适应性饲养。
A20细胞体外培养扩增，收取对数生长期细胞重悬于PBS中，细胞悬液浓度5×106/mL。
用1mL注射器将细胞悬液注入Balb/c小鼠右侧皮下，每只动物注射100μL，接种细胞数：5×105/只。
待平均肿瘤体积为60.75±0.48mm3时，淘汰体积过大、过小或者肿瘤形状不规则的动物，采用随机区组法将动物分为6组，每组6只；分组当天定义为PG-D0。
按照分组方案开始给药，各组均采用灌胃给药，各组给药体积均为5mL/kg，给药频率为每天一次或每天两次。实验期间，每周称量动物体重和测量肿瘤体积三次。
实验终点为PG-D13，对所有小鼠进行安乐死，剥取肿瘤组织，称重并拍照。根据PG-D12测得的肿瘤体积及体重，分别计算肿瘤体积抑制率(TGI)和动物体重变化率(BWC％)。
小鼠给药方案如表12：
表12各组小鼠给药方案表
注：G:Group；p.o.:灌胃给药；
1.分组当天定义为PG-D0天，并于PG-D0开始给药；
2.给药体积：根据小鼠体重调整；
3.实验结束后根据客户需求处理小鼠。
动物分组与标识：
当平均肿瘤体积达到大约60.75±0.48mm3时，根据肿瘤体积，将小鼠随机分成6组，每组6只。详细信息如下表13所示：饲养笼用笼卡明确标记，包括动物编号、性别、品系、接收日期、处理、研究编号和组别编号。
表13实验动物分组信息表
3、指标观测
3.1肿瘤体积(Tumorvolume,TV)
TV＝1/2×a×b2
其中：a表示肿瘤长径；b表示肿瘤短径。
3.2肿瘤体积抑制率(TGI)
TGI＝[1-(TVDt治疗组-TVD0治疗组)/(TVDt对照组-TVD0对照组)]×100％
TVDt实验组：给药后第t天治疗组的肿瘤体积
TVD0实验组：分组给药时治疗组的肿瘤体积
TVDt对照组：给药后第t天对照组的肿瘤体积
TVD0对照组：分组给药时对照组的肿瘤体积。
3.3动物体重变化率(BWC％)
体重变化率＝(BWDt-BWD0)/BWD0×100％
BWDt：给药后t天动物体重
BWD0：分组给药时动物体重。
3.4瘤重抑制率(IR)
IR＝(WC-WT)/WC×100％
其中，WC表示对照组瘤重；WT表示治疗组瘤重。
4、数据分析
5.1小鼠肿瘤体积
如图17、图18、表14以及表15所示，PG-D12，对照组平均肿瘤体积为687.68±46.59mm3，LF0376单药组、Ibrutinib单药组、Zanubrutinib单药组、LF0376+Ibrutinib组和LF0376+Zanubrutinib组平均肿瘤体积分别为551.12±40.66mm3、640.57±48.47mm3、651.25±39.04mm3、497.63±57.96mm3和454.45±46.55mm3，TGI分别为21.74％、7.47％、5.79％、30.30％和37.12％。LF0376+Ibrutinib组和LF0376+Zanubrutinib组与对照组相比，均表现出显著的抑制肿瘤生长的作用。LF0376+Ibrutinib组和LF0376+Zanubrutinib组各自分别与LF0376单药组和Ibrutinib/Zanubrutinib单药组相比，均表现出更显著的肿瘤抑制作用。
表14各组小鼠接受治疗期间平均肿瘤体积(mm3)
注：数据用Mean±SEM表示。
表15 PG-D12各实验组小鼠的TGI(％)
5.2小鼠肿瘤瘤重
如图19以及表16所示，PG-D13，对照组平均肿瘤瘤重为1.8387±0.2200g，LF0376单药组、Ibrutinib单药组、Zanubrutinib单药组、LF0376+Ibrutinib组和LF0376+Zanubrutinib组平均肿瘤瘤重分别为1.1853±0.1562g、1.5809±0.1216g、1.4855±0.1700g、1.3331±0.1810g和1.0855±0.1081g，IR分别为35.54％、14.02％、19.21％、27.50％和40.96％。肿瘤瘤重结果与肿瘤体积结果基本相符。
表16 PG-D13各组小鼠的肿瘤平均瘤重(g)
注：n/n表示：实际样本个数/原有样本个数。
5.3小鼠体重
如图20和表17所示，PG-D12，Group 1、Group 2、Group 3、Group 4、Group 5和Group 6小鼠平均体重分别为25.97±1.13g、24.73±0.89g、26.33±1.20g、25.68±0.69g、24.52±1.06g和24.80±0.32g。
如图21和表18所示，PG-D12，Group 1、Group 2、Group 3、Group 4、Group 5和Group 6小鼠平均体重均增长，体重变化率分别为9.6±1.4％、5.3±1.4％、9.6±2.5％、7.9±3.0％、5.2±2.8％和5.8±1.8％。治疗期间实验组小鼠的体重变化率在-10.8％～21.6％之间。无小鼠因体重明显下降或状态不佳导致药物暂停。
表17各组小鼠治疗期间的平均体重(g)

注：数据用Mean±SEM表示。
表18各组小鼠治疗期间较基线的体重变化率(％)
注：根据PG-D0的体重计算体重变化率。数据用Mean±SEM表示。
6、实验结论
治疗期间受试药安全性良好。LF0376单药对A20具有一定抑瘤作用，LF0376+Ibrutinib和LF0376+Zanubrutinib两药联合抑瘤作用更显著，提示LF0376能够显著增强Ibrutinib和Zanubrutinib的抗肿瘤作用。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本申请。任何熟悉此技术的人士皆可在不违背本申请的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本申请的权利要求所涵盖。

Claims (10)

  1. CCR2/5双受体拮抗剂在制备治疗或预防B细胞淋巴瘤药物中的用途。
  2. 如权利要求1所述的用途，其特征在于，所述CCR2/5双受体拮抗剂选自LF0376、BMS-813160、Cenicriviroc中的一种或多种的组合；优选地，所述CCR2/5双受体拮抗剂选自LF0376。
  3. 一种药物组合物，其特征在于，包括如权利要求1～2任一项所述的用途中的CCR2/5双受体拮抗剂，和布鲁顿酪氨酸激酶抑制剂。
  4. 如权利要求3所述的药物组合物，其特征在于，所述布鲁顿酪氨酸激酶抑制剂选自泽布替尼、伊布替尼、spebrutinib、acalabrutinib、olmutinib、poseltinib、tirabrutinib、evobrutinib、fenebrutinib、vecabrutinib、ARQ-531、BMS-986195、BMS-986142、CGI-1746、GDC-0834、RN-486、JNJ-64264681、DTRMWXHS-12、CT-1530、AC0058TA、ICP-022、WXFL10230486、SHR1459、PRN-1008、PRN-473、PRN-2246、LOU-064、LOXO-305、ABBV-105、PCI-45292、TAK-020、M-7583、BIIB-068、BMS-935177、CNX-774、TAS-5315、TGH-663、LFM-A13中的一种或多种的组合。
  5. 根据权利要求4所述的药物组合物，其特征在于，所述布鲁顿酪氨酸激酶抑制剂选自泽布替尼或伊布替尼。
  6. 如权利要求5所述的药物组合物，其特征在于，所述药物组合物包括LF0376和伊布替尼；优选地，所述LF0376和伊布替尼的重量比为0.5～10：1。
  7. 如权利要求5所述的药物组合物，其特征在于，所述药物组合物包括LF0376和泽布替尼；优选地，所述LF0376和泽布替尼的重量比为0.8～40：1。
  8. 如权利要求3～7任一项所述的药物组合物在制备治疗或预防癌症药物中的应用，所述癌症选自B细胞淋巴瘤、套细胞淋巴瘤、滤泡性淋巴瘤、慢细胞淋巴瘤、膀胱癌、血癌、骨癌、脑癌、乳腺癌、中枢神经系统癌症、宫颈癌、结肠癌、子宫内膜癌、食管癌、胆囊癌、胃肠道癌、外生殖器癌、泌尿生殖道癌、头癌、肾癌、喉癌、肝癌、肺癌、肌肉组织癌症、颈癌、口腔或鼻黏膜癌、卵巢癌、胰腺癌、前列腺癌、皮肤癌、脾癌、小肠癌、大肠癌、胃癌、睾丸癌和甲状腺癌中的一种或多种的组合。
  9. 如权利要求8所述的应用，其特征在于，所述B细胞淋巴瘤为弥漫性大B细胞淋巴瘤。
  10. 一种治疗癌症的药物，包括如权利要求1～2任一项所述的用途中的CCR2/5双受体拮抗剂，或如权利要求3～7任一项所述的药物组合物，以及药学上可接受的辅料和/或载体。
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