WO2022258066A1 - 己酸羟孕酮在增强肿瘤治疗效果中的应用 - Google Patents

己酸羟孕酮在增强肿瘤治疗效果中的应用 Download PDF

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WO2022258066A1
WO2022258066A1 PCT/CN2022/098284 CN2022098284W WO2022258066A1 WO 2022258066 A1 WO2022258066 A1 WO 2022258066A1 CN 2022098284 W CN2022098284 W CN 2022098284W WO 2022258066 A1 WO2022258066 A1 WO 2022258066A1
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hydroxyprogesterone caproate
tumor
medicament
application according
antibody
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French (fr)
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杜涛
胡涛
杜新
张玉倩
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深圳埃格林医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • the present application belongs to the field of tumor treatment. Specifically, the present application provides a method for inhibiting tumors using hydroxyprogesterone caproate, and receptor tyrosine kinase inhibitors and/or anti-PD-1/PD-L1 antibodies.
  • tumor immunotherapy mainly achieves the purpose of destroying cancer cells and inhibiting tumor growth by activating the body's own immune system.
  • clinical immunotherapy methods for tumors are also flourishing, such as non-specific immune stimulants, adoptive immune cell therapy, anti-tumor monoclonal antibodies, and tumor-specific vaccines.
  • Immunotherapy plays an increasingly important role in modern tumor treatment due to its high specificity and less harmfulness to the body. Among them, immune checkpoint inhibitors have the most extensive and sufficient clinical research.
  • Immune checkpoints are related molecules that regulate the strength of the immune response through ligand/receptor interactions in the tumor immune signaling pathway, maintain autoimmune tolerance and participate in tumor immune escape.
  • Immune checkpoint inhibitors are monoclonal antibody drugs developed against corresponding immune checkpoints, which can kill tumor cells by activating tumor-specific T cells and rebuilding the immune system.
  • CTLA-4 cytotoxic T lymphocyte-associated antigen 4
  • PD-1 programmed cell death receptor 1
  • PD-L1 programmed death receptor-ligand 1
  • LAG-3 lymphocyte activation gene 3
  • TIM-3 T cell immunoglobulin mucin molecule 3
  • TAGIT T cell immunoglobulin and ITIM domain protein
  • VISTA T cell activation V region Immunoglobulin inhibitors
  • the anti-CTLA-4 antibody ipilimumab was approved for the treatment of melanoma in 2011;
  • the anti-PD-1 antibodies pembrolizumab and nivolumab were both approved for melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma in 2014
  • the anti-PD-L1 antibody atezolizumab was approved in 2016 for the treatment of bladder cancer and non-small cell carcinoma.
  • there are still monoclonal antibodies against the above immune checkpoints that have been approved for marketing or are in the clinical stage of cancer treatment research.
  • tumor cells will also evade the recognition and monitoring of the body's immune system by changing their surface antigens and adjusting the tumor microenvironment, thereby reducing the effect of immunotherapy.
  • anti-PD-1 antibodies only have a clinical response rate of about 20%, and immune escape has therefore become one of the challenges to be faced in clinical tumor immunotherapy.
  • tumor cell-related factors including abnormal expression of tumor cell surface antigens, abnormal expression of tumor surface receptors such as Fas, and secretion of immunosuppressive factors such as transforming growth factor ( TGF- ⁇ ) and interleukin 10 (IL-10), etc.
  • immunosuppressive factors such as transforming growth factor ( TGF- ⁇ ) and interleukin 10 (IL-10), etc.
  • Immune cell-related factors including immunosuppressive effect of regulatory T cells, natural killer (NK) cell phenotype transformation, tumor-associated macrophage transformation and dendritic 3) Factors related to immunosuppression in the tumor microenvironment, such as vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • Combination therapy including the combination of different immune checkpoint inhibitors, the combination of chemotherapy and immunotherapy, etc., will undoubtedly show a better effect in the clinical treatment of tumors for the problems of immune escape and immune tolerance of tumor cells. potential and efficacy.
  • the combination therapy of anti-PD-1 antibody nivolumab and anti-CTLA-4 antibody ipilimumab is effective in the treatment of melanoma, advanced renal cell carcinoma, colorectal cancer, breast cancer, non-small cell lung cancer and esophageal cancer. the therapeutic effect.
  • the US FDA also approved the combination therapy of nivolumab and ipilimumab for the first-line treatment of tumors expressing PD-L1 ( ⁇ 1%) and without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene mutations patients with non-small cell lung cancer.
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • the present application provides a method for inhibiting a tumor in a subject, characterized in that hydroxyprogesterone caproate, and a receptor tyrosine kinase inhibitor and/or anti-PD-1/PD are administered to the subject -L1 antibody.
  • the present application provides the application of hydroxyprogesterone caproate, and receptor tyrosine kinase inhibitor and/or anti-PD-1/PD-L1 antibody in the preparation of drugs for treating tumors.
  • the present application provides a drug for treating tumors, which is characterized in that it comprises hydroxyprogesterone caproate, and a receptor tyrosine kinase inhibitor and/or an anti-PD-1/PD-L1 antibody.
  • the tumor is endometrial cancer, intestinal tumor, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, urothelial carcinoma, biliary tract cancer, colorectal cancer cancer, gastric cancer, glioblastoma, ovarian cancer, pancreatic cancer, or triple-negative breast cancer.
  • the intestinal tumor is a colon tumor, preferably a tumor formed by CT26 tumor cells.
  • the dosage of hydroxyprogesterone caproate is 1-100mg/kg, preferably 5-80mg/kg, more preferably 10-70mg/kg, more preferably 20-60mg/kg, further preferably 20-40mg/kg, most preferably 20mg/kg.
  • the administration frequency of hydroxyprogesterone caproate is 2 times a day to 1 time every 5 days, preferably 1 time a day to 1 time every 3 days, most preferably once every 2 days.
  • the dose of the receptor tyrosine kinase inhibitor is 1-20 mg/kg, preferably 5-15 mg/kg, most preferably 10 mg/kg.
  • the administration frequency of the receptor tyrosine kinase inhibitor is 2 times a day to 1 time every 2 days, preferably 1 time a day.
  • the dose of anti-PD-1/PD-L1 antibody is 0.1-10 mg/kg, preferably 0.5-5 mg/kg, more preferably 1-3 mg/kg, most preferably 2 mg/kg.
  • the frequency of anti-PD-1/PD-L1 antibody administration is 2 times a day to 1 time every 6 days, preferably 1 time a day to 1 time every 5 days, most preferably once every 3 days.
  • the receptor tyrosine kinase inhibitors are Avapritinib, Capmatinib, Pemigatinib, Ripretinib, Serpatinib (Selpercatinib), Selumetinib, Tucatinib, Entrectinib, Erdafitinib, Fedratinib, Pexidatinib ( Pexidartinib), Upadacitinib, Zanubrutinib, Baricitinib, Binimetinib, Dacomitinib, Fostamatinib, Gilteritinib, Larotrectinib, Lorlatinib, Acalabrutinib, Brigatinib, Midostaurin, Laratinib Neratinib, Alectinib, Cobimetinib, Lenvatinib, Osimertinib, Ceritinib, Nintedanib (Nintedanib), Afatin
  • the anti-PD-1/PD-L1 antibody is 10F.9G2, RMP1-14, RMP1-1, Pembrolizumab, Nivolumab, Cemiplimab , Atezolizumab, Avelumab, Durvalumab, Camrelizumab, Tislelizumab, Terry Toripalimab, Sintilimab, Dostarlimab, and/or Retifanlimab.
  • hydroxyprogesterone caproate, receptor tyrosine kinase inhibitor and anti-PD-1/PD-L1 antibody are oral preparations or injections respectively; hydroxyprogesterone caproate, receptor tyrosine kinase inhibitor and anti-PD-L1
  • the specific dosage forms of PD-1/PD-L1 antibodies can be the same or different.
  • the content ratio of hydroxyprogesterone caproate, receptor tyrosine kinase inhibitor and anti-PD-1/PD-L1 antibody in the drug is 1-100:2-20:0.1-10, preferably 20- 60:5-15:0.5-5, most preferably 20:10:2.
  • the present application provides the use of hydroxyprogesterone caproate in enhancing the effect of receptor tyrosine kinase inhibitors and/or anti-PD-1/PD-L1 antibodies.
  • the present application provides the application of hydroxyprogesterone caproate in the preparation of drugs for enhancing the effect of receptor tyrosine kinase inhibitors and/or anti-PD-1/PD-L1 antibodies.
  • the effect includes inhibiting tumor growth.
  • the effect includes improving the regulation of tumor immunosuppressive microenvironment.
  • the effect includes enhancing the infiltration effect on CD8+ T cells.
  • said effects include improved regulation of tumor angiogenesis.
  • the tumor is endometrial cancer or intestinal tumor.
  • the intestinal tumor is a colon tumor, preferably a tumor formed by CT26 tumor cells.
  • the dosage of hydroxyprogesterone caproate is 1-100mg/kg, preferably 5-80mg/kg, more preferably 10-70mg/kg, more preferably 20-60mg/kg, further preferably 20-40mg/kg, most preferably 20mg/kg.
  • the administration frequency of hydroxyprogesterone caproate is 2 times a day to 1 time every 5 days, preferably 1 time a day to 1 time every 3 days, most preferably once every 2 days.
  • the receptor tyrosine kinase inhibitors are Avapritinib, Capmatinib, Pemigatinib, Ripretinib, Serpatinib (Selpercatinib), Selumetinib, Tucatinib, Entrectinib, Erdafitinib, Fedratinib, Pexidatinib ( Pexidartinib), Upadacitinib, Zanubrutinib, Baricitinib, Binimetinib, Dacomitinib, Fostamatinib, Gilteritinib, Larotrectinib, Lorlatinib, Acalabrutinib, Brigatinib, Midostaurin, Laratinib Neratinib, Alectinib, Cobimetinib, Lenvatinib, Osimertinib, Ceritinib, Nintedanib (Nintedanib), Afatin
  • the anti-PD-1/PD-L1 antibodies are 10F.9G2, RMP1-14, Pembrolizumab, Nivolumab, Cemiplimab, Atezol Atezolizumab, Avelumab, Durvalumab, Camrelizumab, Tislelizumab, Toripalizumab (Toripalimab), Sintilimab, Dostarlimab, and/or Retifanlimab.
  • hydroxyprogesterone caproate is an oral preparation or an injection.
  • the methods of the present application may be used for therapeutic or non-therapeutic use in vivo or in vitro.
  • the tumors in this application are not limited to the types listed in the application documents, and those skilled in the art of other tumors can expand the application based on relevant research.
  • the colon cancer model formed by CT26 tumor cells or other tumor cell lines is used to verify the effect of the drug, which does not mean that the tumors within the scope of protection of this application are limited to these cell lines or their corresponding cancer types.
  • the drug of the present application can be used alone or in further combination with other anti-tumor drugs or therapies, including but not limited to radiotherapy, chemotherapy drugs, targeted drugs, traditional Chinese medicine or Chinese patent medicines, and anti-tumor drugs. Functional health care products.
  • hydroxyprogesterone caproate is also called 17- ⁇ hydroxyprogesterone caproate, 17-HPC, 17-hydroxyprogesterone caproate, 17-hydroxyprogesterone caproate, and the CAS number is 630-56-8.
  • receptor tyrosine kinase inhibitors in this application include but are not limited to those listed in the documents of this application, and various existing commercially available and under development receptor tyrosine kinase inhibitors can be used in this application.
  • Lenvatinib in this application is also known as lenvatinib, lenvatinib, E7080 (study code).
  • Anti-PD-1/PD-L1 antibodies may be represented by their Chinese or English antibody names and drug names, and these representations have equivalent effects.
  • the anti-PD-1/PD-L1 antibodies in this application include but are not limited to the species listed in the application documents, and various existing anti-PD-1/PD-L1 antibodies on the market and under development can be used in this application Application.
  • the medicine described in this application is not limited to the pharmaceutical composition of a single dosage form. According to the different properties of the medicine and application requirements, the medicine described in this application can be a combination of several dosage forms, such as oral receptor tyrosine kinase inhibitors , a combination of hydroxyprogesterone caproate injection and anti-PD-1/PD-L1 antibody injection.
  • the available dosage forms of this application include but are not limited to injections such as injections, powder injections, etc., oral preparations such as tablets, capsules, oral liquids, etc., throat or nasal sprays, external preparations such as ointments, sprays, patches, etc.; Injectables and oral formulations are preferred.
  • the amount of the active ingredient contained in these dosage forms can be selected according to the condition of the subject (such as body weight, age, condition) and the dosage range recorded in the application; preferably, the active ingredient contained in the unit medicament is a single required dosage or its equivalent.
  • Figure 1 shows the changes in the tumor volume of combined drugs.
  • Figure 2 is the tumor weight at the end of the combined drug experiment.
  • Figure 3 shows that in the mouse CT26 colon cancer model, compared with the combination group of lenvatinib and anti-PD-1 antibody, hydroxyprogesterone caproate combined with lenvatinib and anti-PD-1 antibody significantly improved Increase the infiltration effect of CD4+ T cells in tumor tissue.
  • Figure 4 shows that in the mouse CT26 colon cancer model, hydroxyprogesterone caproate combined with lenvatinib and anti-PD-1 antibody significantly improved compared with the combination of lenvatinib and anti-PD-1 antibody. Increase the infiltration effect of CD8+ T cells in tumor tissue.
  • Figure 5 shows that in the mouse CT26 colon cancer model, hydroxyprogesterone caproate combined with lenvatinib and anti-PD-1 antibody significantly improved compared with the combination of lenvatinib and anti-PD-1 antibody. Increase the infiltration effect of natural killer cells in tumor tissue.
  • Figure 6 shows that in the mouse CT26 colon cancer model, hydroxyprogesterone caproate combined with lenvatinib and anti-PD-1 antibody significantly increased compared with the combination of lenvatinib and anti-PD-1 antibody The levels of TNF- ⁇ , IL-2 and IFN- ⁇ in tumor tissue.
  • Fig. 7 is the tumor growth curve of each administration group in the BALB/c mouse kidney cancer cell Renca tumor model.
  • Embodiment 1 model and administration
  • Lenvatinib was administered orally, once a day, at a dose of 10 mg/kg; hydroxyprogesterone caproate was administered by intraperitoneal injection (abbreviated as i.p. in the following table), once every two days; anti-PD- 1 Antibody (RMP1-14) was diluted in PBS, once every three days, with a dose of 200 ⁇ g/mouse.
  • hydroxyprogesterone caproate was administered by intraperitoneal injection (abbreviated as i.p. in the following table), once every two days
  • anti-PD- 1 Antibody (RMP1-14) was diluted in PBS, once every three days, with a dose of 200 ⁇ g/mouse.
  • Embodiment 2 combination drug effect
  • mice During the experiment, the general condition and nervous system of the mice were observed and recorded.
  • Body Weight and Food Intake Body weight and food intake were measured twice weekly.
  • Cytokines (IL-2, IL-4, IL-8, TGF- ⁇ , IFN- ⁇ ) in plasma samples were detected according to relevant standard operating procedures and kit guidance methods. Among them, the cytokine IFN- ⁇ in the quick-frozen tumor samples was detected using the Mouse IFN- ⁇ Immunoassay Quantikine ELISA Kit from R&D System. Cytokines IL-2 and TNF- ⁇ in tumor lysates were quantified using the Proinflammatory Panel 1 (mouse) Kit from Meso Scale Diagnostics.
  • Immunohistochemical (IHC) analysis was performed using an anti-KI67 antibody, a proliferation marker for the determination of tumor cell growth fraction.
  • CD4+ T cells were assessed by immunohistochemical (IHC) analysis using an anti-CD4 antibody, and natural killer cells were assessed by immunohistochemical (IHC) analysis using an anti-CD335 antibody.
  • Tumor microvessel density was measured by CD31 staining.
  • the change of the tumor volume of the combination drug is shown in Figure 1, and the tumor weight at the end of the combined drug experiment is shown in Figure 2.
  • the tumor inhibition rate is shown in Table 1.
  • Combined administration with hydroxyprogesterone caproate can further improve the regulation of lenvatinib and anti-PD-1 antibody on the immunosuppressive microenvironment of CT26 tumor in BALB/c mice.
  • Figure 3 The infiltration effects of CD4+T cells, CD8+T cells and natural killer cells in tumor tissues are shown in Figure 3, Figure 4, and Figure 5, respectively.
  • Figures 3 to 5 show that in the CT26 colon cancer model in mice, hydroxyprogesterone caproate combined with lenvatinib and anti-PD-1 antibody The combined administration can significantly increase the infiltration effect of immune cells including CD4+T cells, CD8+T cells and natural killer cells in tumor tissues.
  • the three-drug combination can also significantly increase the levels of cytokines with tumor-suppressing effects in tumor tissue, including TNF- ⁇ , IL-2, and IFN- ⁇ , as shown in FIG. 6 .
  • Combined administration with hydroxyprogesterone caproate can further improve the regulatory effect of lenvatinib and anti-PD-1 antibody on angiogenesis in CT26 tumors of BALB/c mice.
  • Humanized PD-1 mice were used, female, 6-8 weeks old, weighing about 20 grams.
  • MC38/hPD-L1 cells 5.0 ⁇ 10 6 ) dissolved in 100 ⁇ L PBS were injected subcutaneously into humanized PD-1 mice.
  • the tumor volume reached ⁇ 100mm 3
  • the experimental animals were randomly assigned to the control group and each drug administration group, and then the drug administration began.
  • Lenvatinib (Eisai, Japan) was administered orally, once a day, at a dose of 10 mg/kg; hydroxyprogesterone caproate was administered by intraperitoneal injection, once every two days; pembrolizumab was administered every three days Once, the dose was 200 ⁇ g/mouse.
  • the administration duration is about 20 days.
  • Tumor volume was measured twice a week. Tumor size was calculated as follows:
  • Tumor volume (mm 3 ) length ⁇ width 2 /2;
  • Hydroxyprogesterone caproate alone did not show good tumor suppressive effect in the MC38/hPD-L1 tumor model in humanized PD-1 mice.
  • combined administration with hydroxyprogesterone caproate could further enhance the antitumor effects of lenvatinib and pembrolizumab in humanized PD-1 mice in the MC38/hPD-L1 tumor model.
  • Lenvatinib (Eisai, Japan) was administered orally, once a day, at a dose of 10 mg/kg; hydroxyprogesterone caproate was administered by intraperitoneal injection, once every two days; 10F.9G2 was administered every three days , the dose is 200 ⁇ g/mouse.
  • the administration duration is about 20 days.
  • Tumor volume was measured twice a week. Tumor size was calculated as follows:
  • Tumor volume (mm 3 ) length ⁇ width 2 /2;
  • Hydroxyprogesterone caproate alone did not show a good tumor suppressive effect in the BALB/c mouse CT26 tumor model.
  • combined administration with hydroxyprogesterone caproate could further enhance the antitumor effect of lenvatinib and anti-PD-L1 antibody (10F.9G2) in BALB/c mouse CT26 tumor model.
  • Lenvatinib was administered orally, once a day, at a dose of 10mg/kg; different progestogens were administered by intraperitoneal injection, once every two days; anti-PD-1 antibody (RMP1-14) was administered through PBS Dilute, once every three days, the dose is 200 ⁇ g/mouse.
  • the administration duration is about 20 days.
  • Tumor volume was measured twice a week. Tumor size was calculated as follows:
  • Tumor volume (mm 3 ) length ⁇ width 2 /2.
  • hydroxyprogesterone caproate enhanced the anti-tumor effect of lenvatinib and anti-PD-1 antibody in BALB/c mouse CT26 tumor model most significantly.
  • Embodiment 6 Renca renal cell carcinoma model and administration
  • mice 6-8 weeks old, weighing about 20 grams, were used. Renca cells (3.0 ⁇ 10 6 ) dissolved in 100 ⁇ L PBS were injected subcutaneously into BALB/c mice. When the tumor volume reached about 70 mm 3 , the experimental animals were randomly assigned to the control group and each drug administration group for the experiment.
  • Lenvatinib is administered orally, once a day, at a dose of 7.5mg/kg; hydroxyprogesterone caproate is administered by intraperitoneal injection (abbreviated as i.p. in the following table), once every two days; anti-PD -1 antibody (BioXCell, Supplier: Yicon (Beijing) Medical Technology Inc.) was diluted in PBS, once every four days, with a dose of 100 ⁇ g/mouse.
  • mice During the experiment, the general condition and nervous system of the mice were observed and recorded.
  • Body Weight and Food Intake Body weight and food intake were measured twice weekly.
  • the change of tumor volume in each administration group is shown in FIG. 7 , and the tumor inhibition rate is shown in Table 2.
  • Hydroxyprogesterone caproate alone showed a certain tumor inhibitory effect in the BALB/c mouse Renca tumor model, and the tumor inhibition rate was higher than that of anti-PD-1 antibody alone.
  • Combined administration with hydroxyprogesterone caproate can further enhance the inhibitory effect of lenvatinib and anti-PD-1 antibody on Renca tumor growth in BALB/c mice.

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Abstract

己酸羟孕酮、酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体联合应用于肿瘤治疗的方法。本申请还提供了相应制药用途和药物产品。与己酸羟孕酮的共同给药可以进一步提高仑伐替尼和抗PD-1/PD-L1抗体对肿瘤的治疗效果。

Description

己酸羟孕酮在增强肿瘤治疗效果中的应用 技术领域
本申请属于肿瘤治疗领域，具体地，本申请提供了使用己酸羟孕酮、以及受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体抑制肿瘤的方法。
背景技术
与传统的肿瘤治疗手段如手术切除、化学疗法和放射疗法不同，肿瘤的免疫治疗主要是通过激活人体自身免疫系统来达到消灭癌症细胞和抑制肿瘤生长的目的。随着肿瘤免疫学相关研究的不断拓展和深入，临床上针对肿瘤的免疫治疗手段亦蓬勃发展，如非特异性免疫刺激剂，过继免疫细胞疗法，抗肿瘤单克隆抗体以及肿瘤特异性疫苗等。免疫治疗由于其特异性高，对机体伤害性较小等特点在现代肿瘤治疗中发挥愈加重要的作用，其中又以免疫检查点抑制剂的临床研究最为广泛和充分。免疫检查点是在肿瘤免疫信号通路中通过配体/受体相互作用调节免疫应答的强度，维持自身免疫耐受并参与肿瘤免疫逃逸的相关分子。免疫检查点抑制剂则是针对相应的免疫检查点开发的单抗类药物，通过活化肿瘤特异性T细胞以及重建免疫系统来实现对肿瘤细胞的杀伤作用。目前在肿瘤免疫治疗领域比较重要的免疫检查点有细胞毒性T淋巴细胞相关抗原4(CTLA-4)、程序性细胞死亡受体1(PD-1)、程序性死亡受体-配体1(PD-L1)、淋巴细胞激活基因3(LAG-3)、T细胞免疫球蛋白黏蛋白分子3(TIM-3)、T细胞免疫球蛋白和ITIM结构域蛋白(TIGIT)以及T细胞激活V区免疫球蛋白抑制剂(VISTA)等，尤其是针对CTLA-4、PD-1以及PD-L1的单克隆抗体已有部分产品获得美国FDA批准上市用于肿瘤的治疗。例如，抗CTLA-4抗体ipilimumab于2011年被批准用于黑色素瘤的治疗；抗PD-1抗体pembrolizumab和nivolumab均于2014年被批准用于黑色素瘤、非小细胞肺癌、头颈鳞状细胞癌等的治疗；抗PD-L1抗体atezolizumab则于2016年被批准用于膀胱癌和非小细胞癌的治疗。目前仍有针对以上免疫检查点的单克隆抗体被批准上市或者正处于临床阶段治疗肿瘤的研究。
值得注意的是，在机体免疫系统发挥免疫功能的同时，肿瘤细胞也会通过改变其表面抗原以及调整肿瘤微环境来逃避机体免疫系统的识别和监视，从而降低免疫治疗的效果。例如，有报道指出抗PD-1抗体只有20％左右的临床反应率，免疫逃逸因此成为临床肿瘤 免疫治疗所要面临的挑战之一。研究表明，肿瘤细胞发生免疫逃逸的机制主要有：1)肿瘤细胞相关因素，包括肿瘤细胞表面抗原表达异常、肿瘤表面受体如Fas等的表达异常、肿瘤细胞分泌免疫抑制因子如转化生长因子(TGF-β)和白介素10(IL-10)等；2)免疫细胞相关因素，包括调节性T细胞的免疫抑制作用、自然杀伤(NK)细胞表型转化、肿瘤相关巨噬细胞转化以及树突状细胞(DC)功能障碍等；3)肿瘤微环境中与免疫抑制相关因素，如血管内皮生长因子(VEGF)等。上述肿瘤细胞、免疫细胞以及肿瘤微环境的改变密切联系并相互作用，最终引起肿瘤细胞发生免疫逃逸并对免疫治疗产生耐受性，导致临床上肿瘤的免疫治疗效果不理想。
针对肿瘤细胞出现的免疫逃逸、免疫耐受等问题，联合疗法包括不同免疫检查点抑制剂的联合、化学疗法和免疫疗法的联合等，毫无疑问将在肿瘤的临床治疗中表现出更好的潜力和疗效。有临床数据表明，抗PD-1抗体nivolumab和抗CTLA-4抗体ipilimumab联合疗法在治疗黑色素瘤、晚期肾细胞癌、结直肠癌、乳腺癌、非小细胞肺癌以及食管癌等均表现出较优的治疗效果。2020年5月，美国FDA也批准了nivolumab和ipilimumab联合疗法用于一线治疗肿瘤表达PD-L1(≥1％)且无表皮生长因子受体(EGFR)或间变性淋巴瘤激酶(ALK)基因变异的非小细胞肺癌患者。鉴于联合疗法更好的治疗潜力，在本领域中存在对可以增强肿瘤免疫治疗效果的药物的极大需要。
发明内容
一方面，本申请提供了一种用于抑制对象中肿瘤的方法，其特征在于，向所属对象施用己酸羟孕酮、以及受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体。
另一方面，本申请提供了己酸羟孕酮、以及受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体在制备治疗肿瘤的药物中的应用。
另一方面，本申请提供了一种治疗肿瘤的药物，其特征在于，其包含己酸羟孕酮、以及受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体。
进一步地，所述肿瘤为子宫内膜癌、肠道肿瘤、肝细胞癌、黑色素瘤、非小细胞肺癌、肾细胞癌、头颈部鳞状细胞癌、尿路上皮癌、胆道癌、结直肠癌、胃癌、胶质母细胞瘤、卵巢癌、胰腺癌或三阴性乳腺癌。
进一步地，所述肠道肿瘤为结肠肿瘤，优选CT26肿瘤细胞形成的肿瘤。
进一步地，己酸羟孕酮的剂量为1-100mg/kg，优选5-80mg/kg，更优选10-70mg/kg， 再优选20-60mg/kg，进一步优选20-40mg/kg，最优选20mg/kg。
进一步地，己酸羟孕酮施用频率为每日2次至每5日1次，优选每日1次至每3日1次，最优选每2日一次。
进一步地，受体酪氨酸激酶抑制剂剂量为1-20mg/kg，优选5-15mg/kg，最优选10mg/kg。
进一步地，受体酪氨酸激酶抑制剂施用频率为每日2次至每2日1次，优选每日1次。
进一步地，抗PD-1/PD-L1抗体剂量为0.1-10mg/kg，优选0.5-5mg/kg，更优选1-3mg/kg，最优选2mg/kg。
进一步地，抗PD-1/PD-L1抗体施用频率为每日2次至每6日1次，优选每日1次至每5日1次，最优选每3日一次。
进一步地，受体酪氨酸激酶抑制剂为阿伐普利尼(Avapritinib)、卡马替尼(Capmatinib)、培米替尼(Pemigatinib)、瑞普替尼(Ripretinib)、塞尔帕替尼(Selpercatinib)、司美替尼(Selumetinib)、图卡替尼(Tucatinib)、恩曲替尼(Entrectinib)、厄达替尼(Erdafitinib)、菲卓替尼(Fedratinib)、培西达替尼(Pexidartinib)、乌帕替尼(Upadacitinib)、泽布替尼(Zanubrutinib)、巴瑞替尼(Baricitinib)、比美替尼(Binimetinib)、达可替尼(Dacomitinib)、福坦替尼(Fostamatinib)、吉列替尼(Gilteritinib)、拉罗替尼(Larotrectinib)、劳拉替尼(Lorlatinib)、阿卡替尼(Acalabrutinib)、布加替尼(Brigatinib)、米哚妥林(Midostaurin)、来那替尼(Neratinib)、阿来替尼(Alectinib)、考比替尼(Cobimetinib)、仑伐替尼(Lenvatinib)、奥希替尼(Osimertinib)、色瑞替尼(Ceritinib)、尼达尼布(Nintedanib)、阿法替尼(Afatinib)、依鲁替尼(Ibrutinib)、曲美替尼(Trametinib)、阿西替尼(Axitinib)、博苏替尼(Bosutinib)、卡博替尼(Cabozantinib)、普纳替尼(Ponatinib)、瑞戈菲尼(Regorafenib)、托法替尼(Tofacitinib)、克唑替尼(Crizotinib)、鲁索替尼(Ruxolitinib)、凡德他尼(Vandetanib)、培唑帕尼(Pazopanib)、拉帕替尼(Lapatinib)、尼洛替尼(Nilotinib)、达沙替尼(Dasatinib)、舒尼替尼(Sunitinib)、索拉非尼(Sorafenib)、厄洛替尼(Erlotinib)、吉非替尼(Gefitinib)、和/或伊马替尼(Imatinib)；优选为仑伐替尼。
进一步地，抗PD-1/PD-L1抗体为10F.9G2、RMP1-14、RMP1-1、派姆单抗(Pembrolizumab)、纳武单抗(Nivolumab)、西米普利单抗(Cemiplimab)、阿特珠单抗 (Atezolizumab)、阿维鲁单抗(Avelumab)、德瓦鲁单抗(Durvalumab)、卡瑞利珠单抗(Camrelizumab)、替雷利珠单抗(Tislelizumab)、特瑞普利单抗(Toripalimab)、信迪利单抗(Sintilimab)、多塔利单抗(Dostarlimab)和/或瑞弗利单抗(Retifanlimab)。
进一步地,己酸羟孕酮、受体酪氨酸激酶抑制剂以及抗PD-1/PD-L1抗体分别为口服制剂或者注射剂；己酸羟孕酮、受体酪氨酸激酶抑制剂以及抗PD-1/PD-L1抗体的具体剂型可以相同或不同。
进一步地，所述药物中己酸羟孕酮、受体酪氨酸激酶抑制剂以及抗PD-1/PD-L1抗体的含量比例为1-100:2-20:0.1-10，优选20-60:5-15:0.5-5，最优选20:10:2。
另一方面，本申请提供了己酸羟孕酮在增强受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体效果中的应用。
另一方面，本申请提供了己酸羟孕酮在制备增强受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体效果的药物中的应用。
进一步地，所述效果包括抑制肿瘤生长。
进一步地，所述效果包括改善肿瘤免疫抑制性微环境的调控。
进一步地，所述效果包括增强对CD8+T细胞的浸润效果。
进一步地，所述效果包括改善对肿瘤血管生成的调控。
进一步地，所述肿瘤为子宫内膜癌或肠道肿瘤。
进一步地，所述肠道肿瘤为结肠肿瘤，优选CT26肿瘤细胞形成的肿瘤。
进一步地，己酸羟孕酮的剂量为1-100mg/kg，优选5-80mg/kg，更优选10-70mg/kg，再优选20-60mg/kg，进一步优选20-40mg/kg，最优选20mg/kg。
进一步地，己酸羟孕酮施用频率为每日2次至每5日1次，优选每日1次至每3日1次，最优选每2日一次。
进一步地，受体酪氨酸激酶抑制剂为阿伐普利尼(Avapritinib)、卡马替尼(Capmatinib)、培米替尼(Pemigatinib)、瑞普替尼(Ripretinib)、塞尔帕替尼(Selpercatinib)、司美替尼(Selumetinib)、图卡替尼(Tucatinib)、恩曲替尼(Entrectinib)、厄达替尼(Erdafitinib)、菲卓替尼(Fedratinib)、培西达替尼(Pexidartinib)、乌帕替尼(Upadacitinib)、泽布替尼(Zanubrutinib)、巴瑞替尼(Baricitinib)、比美替尼(Binimetinib)、达可替尼(Dacomitinib)、福坦替尼(Fostamatinib)、吉列替尼(Gilteritinib)、拉罗替尼(Larotrectinib)、劳拉替尼(Lorlatinib)、阿卡替尼(Acalabrutinib)、布加替尼(Brigatinib)、米哚妥林 (Midostaurin)、来那替尼(Neratinib)、阿来替尼(Alectinib)、考比替尼(Cobimetinib)、仑伐替尼(Lenvatinib)、奥希替尼(Osimertinib)、色瑞替尼(Ceritinib)、尼达尼布(Nintedanib)、阿法替尼(Afatinib)、依鲁替尼(Ibrutinib)、曲美替尼(Trametinib)、阿西替尼(Axitinib)、博苏替尼(Bosutinib)、卡博替尼(Cabozantinib)、普纳替尼(Ponatinib)、瑞戈菲尼(Regorafenib)、托法替尼(Tofacitinib)、克唑替尼(Crizotinib)、鲁索替尼(Ruxolitinib)、凡德他尼(Vandetanib)、培唑帕尼(Pazopanib)、拉帕替尼(Lapatinib)、尼洛替尼(Nilotinib)、达沙替尼(Dasatinib)、舒尼替尼(Sunitinib)、索拉非尼(Sorafenib)、厄洛替尼(Erlotinib)、吉非替尼(Gefitinib)、和/或伊马替尼(Imatinib)；优选为仑伐替尼。
进一步地，抗PD-1/PD-L1抗体为10F.9G2、RMP1-14、派姆单抗(Pembrolizumab)、纳武单抗(Nivolumab)、西米普利单抗(Cemiplimab)、阿特珠单抗(Atezolizumab)、阿维鲁单抗(Avelumab)、德瓦鲁单抗(Durvalumab)、卡瑞利珠单抗(Camrelizumab)、替雷利珠单抗(Tislelizumab)、特瑞普利单抗(Toripalimab)、信迪利单抗(Sintilimab)、多塔利单抗(Dostarlimab)和/或瑞弗利单抗(Retifanlimab)。
进一步地,己酸羟孕酮为口服制剂或者注射剂。
本申请的方法可用于体内或体外的治疗或非治疗用途。
本申请中的肿瘤不局限于申请文件中所列种类，其他肿瘤本领域技术人员可以根据相关研究扩展应用。本申请中以CT26肿瘤细胞或其他肿瘤细胞株形成的结肠癌模型验证药物的效果，不代表本申请保护范围中的肿瘤局限于这些细胞株或者其对应的癌症种类。
本申请的药物可以单独使用或者与其他抗肿瘤药物或疗法进一步联合使用，所述其他抗肿瘤药物或疗法包括但不限于放疗方法、化疗药物、靶向药物、中药或中成药药物以及有抗肿瘤功能的保健品。
本申请中己酸羟孕酮也被称为17-α己酸羟孕酮、17-HPC、17-己酸羟孕酮、17-羟己孕酮，CAS编号为630-56-8。
本申请中的受体酪氨酸激酶抑制剂包括但不限于本申请文件中所列的种类，各种现有市售的和研制中的受体酪氨酸激酶抑制剂均可用于本申请。
本申请中的仑伐替尼也被称为乐伐替尼、lenvatinib、E7080(研究代号)。
抗PD-1/PD-L1抗体可能以其中文或英文的抗体名称、药物名称来表示，这些表示方式具备等同的效力。本申请中的抗PD-1/PD-L1抗体包括但不限于本申请文件中所列的种 类，各种现有市售的和研制中的抗PD-1/PD-L1抗体均可用于本申请。
本申请中所述的药物不局限于单一剂型的药物组合物，根据药物性质和应用需求的不同，本申请所述的药物可以是数种剂型的组合，如口服受体酪氨酸激酶抑制剂、己酸羟孕酮注射剂和抗PD-1/PD-L1抗体注射剂的组合。
本申请的可用剂型包括但不限于注射剂如注射液、粉针剂等，口服制剂如片剂、胶囊剂、口服液等，咽喉或鼻喷剂，外用制剂如软膏剂、喷剂、贴剂等；优选注射剂和口服制剂。这些剂型中所包含有效成分的量可以根据用药对象情况(如体重、年龄、病情)以及本申请中记载的剂量范围选定；优选地，单位药剂中包含的有效成分为单次所需用量或其等分量。
本领域技术人员可以根据药学领域一般知识为为本申请所涉及的药物选择适合的辅料，可用的辅料种类包括但不限于溶剂、助溶剂、稳定剂、分散剂、粘度调节剂、抗氧化剂、甜味剂、粘合剂、气体发生剂等。
附图说明
图1为联合用药肿瘤体积的变化。
图2为联合用药实验结束时肿瘤重量。
图3示出了小鼠CT26结肠癌模型中，与仑伐替尼和抗PD-1抗体联用组相比，己酸羟孕酮与仑伐替尼和抗PD-1抗体联合给药显著增加肿瘤组织中CD4+T细胞的浸润效果。
图4示出了小鼠CT26结肠癌模型中，与仑伐替尼和抗PD-1抗体联用组相比，己酸羟孕酮与仑伐替尼和抗PD-1抗体联合给药显著增加肿瘤组织中CD8+T细胞的浸润效果。
图5示出了小鼠CT26结肠癌模型中，与仑伐替尼和抗PD-1抗体联用组相比，己酸羟孕酮与仑伐替尼和抗PD-1抗体联合给药显著增加肿瘤组织中自然杀伤细胞的浸润效果。
图6示出了小鼠CT26结肠癌模型中，与仑伐替尼和抗PD-1抗体联用组相比，己酸羟孕酮与仑伐替尼和抗PD-1抗体联用显著增加肿瘤组织中TNF-α、IL-2和IFN-γ水平。
图7为BALB/c小鼠肾癌细胞Renca肿瘤模型中各给药组肿瘤生长曲线。
具体实施方式
实施例1模型和给药
BALB/c小鼠CT26肿瘤模型的建立：
采用BALB/c雌性小鼠，6-8周龄，体重约20克。溶于100μL PBS内的CT26细胞(5.0×10 6)通过皮下注射进入BALB/c小鼠。当肿瘤体积达到约100mm 3，实验动物随机分配到对照组和各给药组用于实验。
仑伐替尼通过口服的方法进行给药，每日一次，剂量为10mg/kg；己酸羟孕酮通过腹膜内注射给药(以下表格中简写为i.p.)，每两天一次；抗PD-1抗体(RMP1-14)经过PBS稀释，每三天一次，剂量为200μg/鼠。
实施例2联合用药效果
Figure PCTCN2022098284-appb-000001
药效评估
观察：在实验过程中，对小鼠一般情况和神经系统进行观察并记录。
体重和食物摄入：体重和食物摄入每周测定两次。
肿瘤体积：
肿瘤大小通过卡尺进行二维测量，每周两次。体积通过公式计算，并用mm 3表达。V＝(X 2Y)/2，此处X和Y分别为肿瘤的较短和较长的直径。
肿瘤生长抑制率(TGI，％)＝(对照组的肿瘤体积-给药组的肿瘤体积)/(对照组的肿瘤体积)*100％
细胞因子检测：
血浆样本中的细胞因子(IL-2,IL-4,IL-8,TGF-β,IFN-γ)根据相关的标准操做规程和试剂盒指导方法进行检测。其中，速冻肿瘤样本中的细胞因子IFN-γ使用来自R&D System的Mouse IFN-γImmunoassay Quantikine ELISA Kit试剂盒检测。肿瘤裂解样本中的细胞因子IL-2和TNF-α使用来自Meso Scale Diagnostics的Proinflammatory Panel 1(mouse)Kit试剂盒定量分析。
癌细胞活力和增殖的评估：
使用抗KI67抗体进行免疫组化(IHC)分析，此抗体为测定肿瘤细胞生长分数的增殖标志物。
CD8+T细胞浸润肿瘤位点的评估：使用抗CD8抗体进行免疫组化(IHC)分析。
CD4+T细胞的评估是使用抗CD4抗体进行免疫组化(IHC)分析，自然杀伤细胞的评估是使用抗CD335抗体进行免疫组化(IHC)分析。
通过CD31染色来进行肿瘤微血管密度的测定。
检测肿瘤组织内的IFN-γ信号通路。
结果显示
1.联合用药肿瘤体积的变化如图1所示，联合用药实验结束时肿瘤重量如图2所示。肿瘤抑制率如表1所示。
表1.肿瘤抑制率(相对于溶剂对照组)
Figure PCTCN2022098284-appb-000002
图1、图2以及表1的结果表明：单用己酸羟孕酮在BALB/c小鼠CT26肿瘤模型中并未表现出良好的肿瘤抑制效果，甚至表现出相反的效果，促进肿瘤生长，增加了肿瘤体积。而与己酸羟孕酮联合给药可以进一步提高仑伐替尼和抗PD-1抗体对BALB/c小鼠CT26肿瘤生长的抑制效果。
2.与己酸羟孕酮联合给药可以进一步改善仑伐替尼和抗PD-1抗体对BALB/c小鼠CT26肿瘤免疫抑制性微环境的调控。
肿瘤组织中CD4+T细胞、CD8+T细胞和自然杀伤细胞的浸润效果分别如图3、图4、图5所示。图3至图5显示，在小鼠的CT26结肠癌模型中，与仑伐替尼和抗PD-1抗体联用组相比，己酸羟孕酮与仑伐替尼和抗PD-1抗体联合给药可以显著增加肿瘤组织中免疫细胞包括CD4+T细胞，CD8+T细胞和自然杀伤细胞的浸润效果。
三药联用同时也可以显著增加肿瘤组织中具有抑制肿瘤作用的细胞因子包括TNF-α、IL-2、IFN-γ水平，如图6所示。
以上结果表明己酸羟孕酮与仑伐替尼和抗PD-1抗体联合给药对肿瘤免疫抑制性微环境起到调控作用。
3.与己酸羟孕酮联合给药可以进一步改善仑伐替尼和抗PD-1抗体对BALB/c小鼠CT26肿瘤中血管生成的调控作用。
实施例3己酸羟孕酮，仑伐替尼(Lenvatinib)和派姆单抗三药联用
目的
比较己酸羟孕酮、仑伐替尼(Lenvatinib)和派姆单抗(Pembrolizumab)三药联用与仑伐替尼和派姆单抗两药联用在人源化PD-1小鼠中MC38/hPD-L1肿瘤模型的抗肿瘤效果。
研究设计
1.人源化PD-1小鼠中MC38/hPD-L1肿瘤模型的建立
采用人源化PD-1小鼠，雌性，6-8周龄，体重约20克。溶于100μL PBS的MC38/hPD-L1细胞(5.0×10 6)通过皮下注射进入人源化PD-1小鼠。当肿瘤体积达到～100mm 3，实验动物随机分配到对照组和各给药组，随后开始给药。
仑伐替尼(Eisai,Japan)通过口服的方法进行给药，每日一次，剂量为10mg/kg；己酸羟孕酮通过腹腔注射给药，每两天一次；派姆单抗每三天一次，剂量为200μg/鼠。给药持续时间为20天左右。
2.给药组
Figure PCTCN2022098284-appb-000003
3.药效评估
1)在给药时，对小鼠的体重及基本身体情况进行评估；
2)肿瘤体积每周测定两次。肿瘤大小的计算方法如下：
肿瘤体积(mm 3)＝长度×宽度 2/2；
3)评估CD8+T细胞浸润肿瘤位点的效果；
4)通过CD31染色来进行肿瘤微血管密度的测定；
5)检测肿瘤组织内的IFN-γ信号。
结果表明：
单用己酸羟孕酮在人源化PD-1小鼠中MC38/hPD-L1肿瘤模型中并未表现出良好的肿瘤抑制效果。但是，与己酸羟孕酮的联合给药可以进一步提高仑伐替尼和派姆单抗在人源化PD-1小鼠中MC38/hPD-L1肿瘤模型的抗肿瘤效果。
实施例4己酸羟孕酮，仑伐替尼(Lenvatinib)和抗PD-L1抗体(10F.9G2)三药联用
目的
比较己酸羟孕酮，仑伐替尼(Lenvatinib)和抗PD-L1抗体(10F.9G2)三药联用与仑伐替尼和抗PD-L1抗体(10F.9G2)两药联用在BALB/c小鼠的CT26肿瘤模型的抗肿瘤效果。研究设计
1.BALB/c小鼠CT26肿瘤模型的建立
采用BALB/c雌性小鼠，6-8周龄，体重约20克。溶于100μL PBS内的CT26细胞(5.0×10 6)通过皮下注射进入BALB/c小鼠。当肿瘤体积达到～100mm 3，实验动物随机分配到对照组和给药组，随后开始给药。
仑伐替尼(Eisai,Japan)通过口服的方法进行给药，每日一次，剂量为10mg/kg；己酸羟孕酮通过腹腔注射给药，每两天一次；10F.9G2每三天一次，剂量为200μg/鼠。给药持续时间为20天左右。
2.给药组
Figure PCTCN2022098284-appb-000004
3.药效评估
1)在给药时，对小鼠的体重及基本身体情况进行评估；
2)肿瘤体积每周测定两次。肿瘤大小的计算方法如下：
肿瘤体积(mm 3)＝长度×宽度 2/2；
3)评估CD8+T细胞浸润肿瘤位点的效果；
4)通过CD31染色来进行肿瘤微血管密度的测定；
5)检测肿瘤组织内的IFN-γ信号。
结果表明：
单用己酸羟孕酮在BALB/c小鼠CT26肿瘤模型中并未表现出良好的肿瘤抑制效果。但是，与己酸羟孕酮的联合给药可以进一步提高仑伐替尼和抗PD-L1抗体(10F.9G2)在BALB/c小鼠CT26肿瘤模型的抗肿瘤效果。
实施例5不同孕激素与仑伐替尼和RMP1-14三药联用
目的
对比不同孕激素(己酸羟孕酮、醋酸甲羟孕酮、炔诺酮、黄体酮)，仑伐替尼(Lenvatinib)和抗PD-1抗体(RMP1-14)联合给药对BALB/c小鼠体内CT26肿瘤模型的治疗效果。实验设计：
1.BALB/c小鼠CT26肿瘤模型的建立
采用BALB/c雌性小鼠，6-8周龄，体重约20克。溶于100μL PBS内的CT26细胞(5.0×10 6)通过皮下注射进入BALB/c小鼠。当肿瘤体积达到～100mm 3，实验动物随机分配到对照组和给药组，随后开始给药。
仑伐替尼通过口服的方法进行给药，每日一次，剂量为10mg/kg；不同的孕激素均通过腹腔注射给药，每两天一次；抗PD-1抗体(RMP1-14)经过PBS稀释，每三天一次，剂量为200μg/鼠。给药持续时间为20天左右。
2.给药组
Figure PCTCN2022098284-appb-000005
Figure PCTCN2022098284-appb-000006
3.药效评估
1)在给药时，对小鼠的体重及基本身体情况进行评估；
2)肿瘤体积每周测定两次。肿瘤大小的计算方法如下：
肿瘤体积(mm 3)＝长度×宽度 2/2。
结果表明
与其他类型孕激素相比，己酸羟孕酮提高仑伐替尼和抗PD-1抗体在BALB/c小鼠CT26肿瘤模型的抗肿瘤效果最为显著。
实施例6 Renca肾细胞癌模型和给药
目的
比较己酸羟孕酮、仑伐替尼(Lenvatinib)和抗PD-1抗体三药联用与仑伐替尼和抗PD-1抗体两药联用在BALB/c小鼠肾癌细胞Renca肿瘤模型中的抗肿瘤效果。
研究设计
1.BALB/c小鼠中Renca肿瘤模型的建立
采用BALB/c雌性小鼠，6-8周龄，体重约20克。溶于100μL PBS内的Renca细胞(3.0×10 6)通过皮下注射进入BALB/c小鼠。当肿瘤体积达到约70mm 3，实验动物随机分配到对照组和各给药组用于实验。
仑伐替尼通过口服的方法进行给药，每日一次，剂量为7.5mg/kg；己酸羟孕酮通过腹膜内注射给药(以下表格中简写为i.p.)，每两天一次；抗PD-1抗体(BioXCell，Supplier:Yicon(Beijing)Medical Technology Inc.)经过PBS稀释，每四天一次，剂量为100μg/鼠。
2.联合用药效果
Figure PCTCN2022098284-appb-000007
Figure PCTCN2022098284-appb-000008
3.药效评估
观察：在实验过程中，对小鼠一般情况和神经系统进行观察并记录。
体重和食物摄入：体重和食物摄入每周测定两次。
肿瘤体积：
肿瘤大小通过卡尺进行二维测量，每周两次。体积通过公式计算，并用mm 3表达。V＝(X 2Y)/2，此处X和Y分别为肿瘤的较短和较长的直径。
肿瘤生长抑制率(TGI，％)＝(对照组的肿瘤体积-给药组的肿瘤体积)/(对照组的肿瘤体积)*100％
4.结果显示
各给药组肿瘤体积的变化如图7所示，肿瘤抑制率如表2所示。
表2.肿瘤抑制率(相对于溶剂对照组)
Figure PCTCN2022098284-appb-000009
图7以及表2的结果表明：
单用己酸羟孕酮在BALB/c小鼠Renca肿瘤模型中表现出一定的肿瘤抑制效果，肿瘤抑制率高于单用抗PD-1抗体。与己酸羟孕酮联合给药可以进一步提高仑伐替尼和抗PD-1抗体对BALB/c小鼠Renca肿瘤生长的抑制效果。

Claims (52)

  1. 一种用于抑制对象中肿瘤的方法，其特征在于，向所属对象施用己酸羟孕酮、以及受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体。
  2. 己酸羟孕酮、以及受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体在制备治疗肿瘤的药物中的应用。
  3. 一种治疗肿瘤的药物，其特征在于，其包含己酸羟孕酮、以及受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体。
  4. 根据权利要求1-3任一项所述的方法、药物或应用，其中所述肿瘤为肠道肿瘤、子宫内膜癌、肝细胞癌、黑色素瘤、非小细胞肺癌、肾细胞癌、头颈部鳞状细胞癌、尿路上皮癌、胆道癌、结直肠癌、胃癌、胶质母细胞瘤、卵巢癌、胰腺癌或三阴性乳腺癌。
  5. 根据权利要求4所述的方法、药物或应用，其中所述肠道肿瘤为结肠肿瘤，优选CT26肿瘤细胞形成的肿瘤。
  6. 根据权利要求1-5任一项所述的方法、药物或应用，其中己酸羟孕酮的剂量为1-100mg/kg。
  7. 根据权利要求6所述的方法、药物或应用，其中己酸羟孕酮的剂量为5-80mg/kg。
  8. 根据权利要求7所述的方法、药物或应用，其中己酸羟孕酮的剂量为10-70mg/kg。
  9. 根据权利要求8所述的方法、药物或应用，其中己酸羟孕酮的剂量为20-60mg/kg。
  10. 根据权利要求9所述的方法、药物或应用，其中己酸羟孕酮的剂量为20-40mg/kg。
  11. 根据权利要求10所述的方法、药物或应用，其中己酸羟孕酮的剂量为20mg/kg。
  12. 根据权利要求1-11任一项所述的方法、药物或应用，其中己酸羟孕酮施用频率为每日2次至每5日1次。
  13. 根据权利要求12所述的方法、药物或应用，其中己酸羟孕酮施用频率为每日1次至每3日1次。
  14. 根据权利要求13所述的方法、药物或应用，其中己酸羟孕酮施用频率为每2日一次。
  15. 根据权利要求1-14任一项所述的方法、药物或应用，其中受体酪氨酸激酶抑制剂剂量为1-20mg/kg。
  16. 根据权利要求15所述的方法、药物或应用，其中受体酪氨酸激酶抑制剂剂量为5-15mg/kg。
  17. 根据权利要求16所述的方法、药物或应用，其中受体酪氨酸激酶抑制剂剂量为10mg/kg。
  18. 根据权利要求1-17任一项所述的方法、药物或应用，其中受体酪氨酸激酶抑制剂施用频率为每日2次至每2日1次。
  19. 根据权利要求18所述的方法、药物或应用，其中受体酪氨酸激酶抑制剂施用频率为每日1次。
  20. 根据权利要求1-19任一项所述的方法、药物或应用，其中抗PD-1/PD-L1抗体剂量为0.1-10mg/kg。
  21. 根据权利要求20所述的方法、药物或应用，其中抗PD-1/PD-L1抗体剂量为0.5-5mg/kg。
  22. 根据权利要求21所述的方法、药物或应用，其中抗PD-1/PD-L1抗体剂量为1-3mg/kg。
  23. 根据权利要求22所述的方法、药物或应用，其中抗PD-1/PD-L1抗体剂量为2mg/kg。
  24. 根据权利要求1-23任一项所述的方法、药物或应用，其中抗PD-1/PD-L1抗体施用频率为每日2次至每6日1次。
  25. 根据权利要求24所述的方法、药物或应用，其中抗PD-1/PD-L1抗体施用频率为每日1次至每5日1次。
  26. 根据权利要求25所述的方法、药物或应用，其中抗PD-1/PD-L1抗体施用频率为每3日一次。
  27. 根据权利要求1-26任一项所述的方法、药物或应用，其中受体酪氨酸激酶抑制剂为阿伐普利尼(Avapritinib)、卡马替尼(Capmatinib)、培米替尼(Pemigatinib)、瑞普替尼(Ripretinib)、塞尔帕替尼(Selpercatinib)、司美替尼(Selumetinib)、图卡替尼(Tucatinib)、恩曲替尼(Entrectinib)、厄达替尼(Erdafitinib)、菲卓替尼(Fedratinib)、培西达替尼(Pexidartinib)、乌帕替尼(Upadacitinib)、泽布替尼(Zanubrutinib)、巴瑞替尼(Baricitinib)、比美替尼(Binimetinib)、达可替尼(Dacomitinib)、福坦替尼(Fostamatinib)、吉列替尼(Gilteritinib)、拉罗替尼(Larotrectinib)、劳拉替尼(Lorlatinib)、阿卡替尼(Acalabrutinib)、布加替尼(Brigatinib)、米哚妥林(Midostaurin)、来那替尼(Neratinib)、阿来替尼(Alectinib)、考比替尼(Cobimetinib)、仑伐替尼(Lenvatinib)、奥希替尼(Osimertinib)、色瑞替尼(Ceritinib)、尼达尼布(Nintedanib)、阿法替尼(Afatinib)、依鲁替尼(Ibrutinib)、曲美替尼(Trametinib)、阿西替尼(Axitinib)、博苏替尼(Bosutinib)、卡博替尼(Cabozantinib)、普纳替尼(Ponatinib)、瑞戈菲尼(Regorafenib)、托法替尼(Tofacitinib)、克唑替尼(Crizotinib)、鲁索替尼(Ruxolitinib)、凡德他尼(Vandetanib)、培唑帕尼(Pazopanib)、 拉帕替尼(Lapatinib)、尼洛替尼(Nilotinib)、达沙替尼(Dasatinib)、舒尼替尼(Sunitinib)、索拉非尼(Sorafenib)、厄洛替尼(Erlotinib)、吉非替尼(Gefitinib)、和/或伊马替尼(Imatinib)；优选为仑伐替尼。
  28. 根据权利要求1-27任一项所述的方法、药物或应用，其中抗PD-1抗体/PD-L1为派姆单抗、10F.9G2、RMP1-14、RMP1-1、纳武单抗、西米普利单抗、特瑞普利单抗，信迪力单抗、特瓦鲁单抗、阿特珠单抗、阿维鲁单抗、卡瑞利珠单抗、替雷利珠单抗、多塔利单抗和/或瑞弗利单抗。
  29. 根据权利要求1-28任一项所述的方法、药物或应用，其中己酸羟孕酮、受体酪氨酸激酶抑制剂以及抗PD-1/PD-L1抗体分别为口服制剂或者注射剂。
  30. 根据权利要求2-29任一项所述的药物或应用，其中药物中己酸羟孕酮、受体酪氨酸激酶抑制剂以及抗PD-1/PD-L1抗体的含量比例为1-100:2-20:0.1-10。
  31. 根据权利要求30所述的药物或应用，其中药物中己酸羟孕酮、受体酪氨酸激酶抑制剂以及抗PD-1/PD-L1抗体的含量比例为20-60:5-15:0.5-5。
  32. 根据权利要求31所述的药物或应用，其中药物中己酸羟孕酮、受体酪氨酸激酶抑制剂以及抗PD-1/PD-L1抗体的含量比例为20:10:2。
  33. 己酸羟孕酮在增强受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体效果中的应用。
  34. 己酸羟孕酮在制备增强受体酪氨酸激酶抑制剂和/或抗PD-1/PD-L1抗体效果的药物中的应用。
  35. 根据权利要求33或34的应用，其中所述效果包括抑制肿瘤生长。
  36. 根据权利要求33或34的应用，其中所述效果包括改善肿瘤免疫抑制性微环境的调控。
  37. 根据权利要求33或34的应用，其中所述效果包括增强对CD8+T细胞的浸润效果。
  38. 根据权利要求33或34的应用，其中所述效果包括改善对肿瘤血管生成的调控。
  39. 根据权利要求33-38任一项的应用，其中所述的肿瘤为子宫内膜癌或肠道肿瘤。
  40. 根据权利要求39所述的应用，其中所述肠道肿瘤为结肠肿瘤，优选CT26肿瘤细胞形成的肿瘤。
  41. 根据权利要求33-40任一项的应用，其中己酸羟孕酮的剂量为1-100mg/kg。
  42. 根据权利要求41所述的应用，其中己酸羟孕酮的剂量为5-80mg/kg。
  43. 根据权利要求42所述的应用，其中己酸羟孕酮的剂量为10-70mg/kg。
  44. 根据权利要求43所述的应用，其中己酸羟孕酮的剂量为20-60mg/kg。
  45. 根据权利要求44所述的应用，其中己酸羟孕酮的剂量为20-40mg/kg。
  46. 根据权利要求45所述的应用，其中己酸羟孕酮的剂量为20mg/kg。
  47. 根据权利要求33-46任一项的应用，其中己酸羟孕酮施用频率为每日2次至每5日1次。
  48. 根据权利要求47所述的应用，其中己酸羟孕酮施用频率为每日1次至每3日1次。
  49. 根据权利要求48所述的应用，其中己酸羟孕酮施用频率为每2日一次。
  50. 根据权利要求33-49任一项的应用，其中受体酪氨酸激酶抑制剂为阿伐普利尼(Avapritinib)、卡马替尼(Capmatinib)、培米替尼(Pemigatinib)、瑞普替尼(Ripretinib)、塞尔帕替尼(Selpercatinib)、司美替尼(Selumetinib)、图卡替尼(Tucatinib)、恩曲替尼(Entrectinib)、厄达替尼(Erdafitinib)、菲卓替尼(Fedratinib)、培西达替尼(Pexidartinib)、乌帕替尼(Upadacitinib)、泽布替尼(Zanubrutinib)、巴瑞替尼(Baricitinib)、比美替尼(Binimetinib)、达可替尼(Dacomitinib)、福坦替尼(Fostamatinib)、吉列替尼(Gilteritinib)、拉罗替尼(Larotrectinib)、劳拉替尼(Lorlatinib)、阿卡替尼(Acalabrutinib)、布加替尼(Brigatinib)、米哚妥林(Midostaurin)、来那替尼(Neratinib)、阿来替尼(Alectinib)、考比替尼(Cobimetinib)、仑伐替尼(Lenvatinib)、奥希替尼(Osimertinib)、色瑞替尼(Ceritinib)、尼达尼布(Nintedanib)、阿法替尼(Afatinib)、依鲁替尼(Ibrutinib)、曲美替尼(Trametinib)、阿西替尼(Axitinib)、博苏替尼(Bosutinib)、卡博替尼(Cabozantinib)、普纳替尼(Ponatinib)、瑞戈菲尼(Regorafenib)、托法替尼(Tofacitinib)、克唑替尼(Crizotinib)、鲁索替尼(Ruxolitinib)、凡德他尼(Vandetanib)、培唑帕尼(Pazopanib)、拉帕替尼(Lapatinib)、尼洛替尼(Nilotinib)、达沙替尼(Dasatinib)、舒尼替尼(Sunitinib)、索拉非尼(Sorafenib)、厄洛替尼(Erlotinib)、吉非替尼(Gefitinib)、和/或伊马替尼(Imatinib)；优选为仑伐替尼。
  51. 根据权利要求34-50任一项的应用，其中抗PD-1/PD-L1抗体为派姆单抗、10F.9G2、RMP1-14、RMP1-1、纳武单抗、西米普利单抗、特瑞普利单抗，信迪力单抗、特瓦鲁单抗、阿特珠单抗、阿维鲁单抗、卡瑞利珠单抗、替雷利珠单抗、多塔利单抗和/或瑞弗利单抗。
  52. 根据权利要求34-51任一项的应用，其中己酸羟孕酮为口服制剂或者注射剂。
PCT/CN2022/098284 2021-06-11 2022-06-11 己酸羟孕酮在增强肿瘤治疗效果中的应用 WO2022258066A1 (zh)

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