WO2022111714A1 - 用于治疗pik3ca突变癌症的组合疗法 - Google Patents

用于治疗pik3ca突变癌症的组合疗法 Download PDF

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WO2022111714A1
WO2022111714A1 PCT/CN2021/134189 CN2021134189W WO2022111714A1 WO 2022111714 A1 WO2022111714 A1 WO 2022111714A1 CN 2021134189 W CN2021134189 W CN 2021134189W WO 2022111714 A1 WO2022111714 A1 WO 2022111714A1
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cancer
inhibitor
day
pge2
pharmaceutical composition
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PCT/CN2021/134189
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French (fr)
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何南海
陈鹏
俞智勇
路杨
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杭州阿诺生物医药科技有限公司
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Priority to EP21897214.9A priority Critical patent/EP4252774A1/en
Priority to JP2023532591A priority patent/JP2023551046A/ja
Priority to CN202180080182.6A priority patent/CN116635074A/zh
Priority to KR1020237021709A priority patent/KR20230113594A/ko
Publication of WO2022111714A1 publication Critical patent/WO2022111714A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • 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
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • 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

Definitions

  • the present invention relates to a combination therapy method and pharmaceutical composition and/or pharmaceutical combination comprising administering to a subject in need thereof a PI3K inhibitor, a prostaglandin receptor (PGE2) inhibitor and a PD-1 inhibitor.
  • a PI3K inhibitor a prostaglandin receptor (PGE2) inhibitor
  • PGE2 prostaglandin receptor
  • Immune checkpoint inhibitors using anti-CTLA4 antibodies and anti-PD(L)1 antibodies have revolutionized cancer immunotherapy. Since the first immune checkpoint inhibitor (ICI) was approved in 2001, this family of drugs has attracted widespread attention due to their durable clinical effects in complex cancers. However, a large number of cancer patients still do not respond to ICI therapy. The response rate of cancer patients treated with ICI so far is about 20%, so it is very necessary to find a more effective immunotherapy modality to further harness the immune system to treat cancer.
  • Dysregulation of the PI3K-AKT-mTOR signaling pathway has a high incidence in cancer patients. It mainly regulates key cellular processes such as cell growth, proliferation, and metabolism, and can promote cancer cell survival, expansion, and dissemination in cancer patients.
  • the PI3K isoform p110 ⁇ encoded by the PIK3CA gene is the second most mutated proto-oncogene in human cancers.
  • PI3K ⁇ In the PI3K family, PI3K ⁇ is also involved in tumorigenesis, but PI3K ⁇ plays a major role. In addition, the other two isoforms, PI3K ⁇ and PI3K ⁇ , play an important role in regulating the immune system. PI3K ⁇ can regulate and maintain the function of regulatory T cells (Treg), and PI3K ⁇ can not only recruit suppressive myeloid cells to the cancer microenvironment, but also enhance their ability to suppress the anti-cancer effect of T cells.
  • Treg regulatory T cells
  • the compound of formula I (AN2025) and its pharmaceutically acceptable salts are oral pan-type I PI3K inhibitors, which are currently in the phase III clinical research and development stage, and their indication is head and neck squamous cell carcinoma. It can not only inhibit wild-type PI3 ⁇ , but also inhibit mutant P13K ⁇ , including mutation sites (H1047R, E542K and E545K). At the same time, it also has inhibitory activity against other PI3K isoforms (PI3K ⁇ , PI3K ⁇ , PI3K ⁇ ).
  • AN2025 has been clinically demonstrated to be effective in the occurrence of breast cancer caused by PI3K/PIK3CA mutations, and the patients with the highest response rate have PIK3CA mutations (Campone M et al. Eur J Cancer. 2018;103:147-154) .
  • AN2025 also downregulates Tregs and suppressor myeloid cell function and their ability to enter the tumor microenvironment by inhibiting PI3K ⁇ and PI3K ⁇ (O'Donnell JS et al. Semin Cancer Biol. 2018;48:91-103.Borazanci et al. The Oncol. 2020).
  • the signaling pathway composed of prostaglandin E2 (PGE2) and its subtype 4 receptor (EP-4) can not only promote the occurrence of cancer, but also form a cancer microenvironment that promotes cancer development and immunosuppression.
  • PGE2/EP-4 signaling pathway can activate the cAMP-PKA signaling pathway, which can effectively inhibit the function of T cells.
  • the PGE2/EP-4 signaling pathway can also negatively regulate DC maturation, inducing the formation of various immunosuppressive cells including M2 macrophages and myeloid suppressor cells (MDSCs) ( S et al. Front Immunol. 2019; 10:475).
  • the compound of formula (II) (AN0025) and its pharmaceutically acceptable salts is a highly selective small molecule inhibitor against E-type prostaglandin receptor 4.
  • AN0025 can effectively reduce immunosuppressive cells in the tumor microenvironment by inhibiting the PGE2/EP-4 signaling pathway.
  • AN0025 has been used in multiple clinical strategies.
  • FIH first in human
  • AN0025 has shown a certain single-drug efficacy; and in the neoadjuvant treatment of colorectal cancer, AN0025 combined with radiotherapy and chemotherapy showed good results Strong clinical efficacy (Wyrwicz et.al, Poster#540, ESMO2019).
  • AN0025 and anti-PD-1 antibody have entered clinical stage 1b/2 in multiple solid tumors (NCT04432857).
  • Preclinical and early clinical data support AN0025 as an immunomodulatory agent against the immunosuppressed cancer microenvironment by modulating M2 macrophages, MDSCs and T cells.
  • PD-1 and PD-L1 signaling pathways play key roles in regulating T cell activation.
  • PD-L1 is mainly expressed in immune cells and most human cancer cells. In the tumor microenvironment, cancer PD-L1 interacts with PD-1 on T cells, ultimately inhibiting the cancer cell-killing activity of T cells. A large number of successful cases of anti-PD-(L)1 therapy make it the cornerstone of modern tumor immunotherapy.
  • AN2025 and AN0025 are able to systemically modulate the immunosuppressive tumor microenvironment, which is complementary to the mechanism by which anti-PD(L)1 therapy kills cancer.
  • Targeting the PIK3CA mutation by AN2025 adds an additional mechanism of action, allowing patients to benefit from the immunomodulatory activity of this triple combination.
  • This triple combination provides an ideal treatment option for most patients with advanced solid tumors, especially those with PIK3CA mutations.
  • the technical problem to be solved by the present invention is to solve the problem of low response rate of cancer patients treated with ICI in the prior art.
  • the purpose of the present invention is to provide a more effective immunotherapy method to further utilize the immune system to treat cancer.
  • the present invention provides a method for treating cancer in combination with a PI3K inhibitor, a prostaglandin receptor (PGE2) inhibitor and a PD-1 inhibitor, the anti-tumor activity of the method is significantly better than any two Two combinations.
  • the present invention provides the following technical solutions:
  • a method for treating tumor/cancer and/or generating a memory immune response against tumor/cancer in a subject in need thereof comprising administering to the subject an effective amount of a PI3K inhibitor, a prostaglandin receptor (PGE2) inhibitor, and The PD-1 inhibitor, wherein the PI3K inhibitor, the prostaglandin receptor (PGE2) inhibitor and the PD-1 inhibitor can be administered simultaneously, separately or sequentially as a single dosage form.
  • PGE2 prostaglandin receptor
  • the PI3K inhibitor is selected from the group consisting of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K ⁇ subtype inhibitors.
  • the PI3K inhibitor is selected from the group consisting of Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leliolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib , Bimiralisib, GDC-0084, ACP-319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003, or any combination thereof.
  • the PI3K inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • prostaglandin receptor (PGE2) inhibitor is selected from EP-1, EP-2, EP-3 and EP-4 inhibitors.
  • the EP-4 inhibitor is selected from compounds of formula (II) or pharmaceutically acceptable salts thereof.
  • the PD-1 inhibitor comprises PD-1/PD-L1 antibody therapy.
  • the PD-1 inhibitor is selected from: PD-1 antibody, PD-L1 antibody and PD-L2 antibody; preferably, wherein the PD-1 inhibitor is selected from Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, toripalizumab, sintilimab, tislelizumab, camrelizumab, or any combination thereof.
  • the dosage form of the oral route can be a tablet, capsule, powder, pill, granule, Suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates
  • the dosage form for the extragastrointestinal route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal A dosage form for transdermal, transmucosal administration.
  • the PI3K inhibitor is administered once or twice a day; or every 2, 3, 4, 5, 6, 7, 8, 9, 10 days or every 1, 2 or 3
  • the PI3K inhibitor is administered once a week; or the PI3K inhibitor is administered once a day for 5 consecutive days a week, followed by 2 days apart.
  • the PI3K inhibitor is administered in adults at a dose of about 20 mg/day to about 200 mg/day, about 30 mg/day to about 160 mg/day, about 60 mg/day to about 120 mg/day Dosage range administration.
  • PI3K inhibitor is administered to the subject at an effective dose of 10 to about 200 mg/kg, or about 20 to about 120 mg/kg.
  • the dosage form of the oral route can be a tablet, capsule, Powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates
  • the dosage form for the extragastrointestinal route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal Intratumoral, transdermal, and transmucosal dosage forms.
  • prostaglandin receptor (PGE2) inhibitor is administered once or twice daily; or every 2, 3, 4, 5, 6, 7, 8, 9, 10 days or
  • the prostaglandin receptor (PGE2) inhibitor is administered once every 1, 2 or 3 weeks; or once a day for 5 consecutive days per week followed by 2 days apart.
  • the prostaglandin receptor PGE2
  • PGE2 is present in adults at about 20 mg/day to about 2000 mg/day, about 30 mg/day to about 1600 mg/day, about 60 mg/day to about A dose range of 1200 mg/day, about 100 mg/day to about 1000 mg/day is administered.
  • the prostaglandin receptor (PGE2) inhibitor is administered to the subject at an effective dose of about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg.
  • the extra-digestive route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, Intratumoral, percutaneous penetration, transmucosal administration.
  • the PD-1 inhibitor is formulated into a solution, a lyophilized preparation, and a powder injection.
  • PD-1 inhibitor is administered at an effective dose per kg.
  • the tumor/cancer is selected from a PIK3CA mutated cancer.
  • the tumor/cancer is selected from the group consisting of: head and neck squamous cell carcinoma, head and neck cancer, brain cancer, glioma, glioblastoma multiforme, neuroblastoma cell tumor, central nervous system cancer, neuroendocrine tumor, throat cancer, nasopharyngeal cancer, esophageal cancer, thyroid cancer, malignant pleural mesothelioma, lung cancer, breast cancer, liver cancer, hepatocellular tumor, hepatobiliary cancer, pancreatic cancer, gastric cancer, Gastrointestinal cancer, bowel cancer, colon cancer, colorectal cancer, kidney cancer, clear cell renal cell cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, melanoma , leukemia, lymphoma, bone cancer, chondrosarcoma, myeloma, multiple myeloma, myelodysplastic
  • the present invention also provides a pharmaceutical composition and/or pharmaceutical combination comprising a PI3K inhibitor, a prostaglandin receptor (PGE2) inhibitor and a PD-1 inhibitor, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition and/or pharmaceutical combination comprising a PI3K inhibitor, a prostaglandin receptor (PGE2) inhibitor and a PD-1 inhibitor, and a pharmaceutically acceptable carrier.
  • the PI3K inhibitor is selected from the group consisting of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K ⁇ subtype inhibitors.
  • the PI3K inhibitor is selected from Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leliolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib, Bimiralisib, GDC-0084, ACP-319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003 or any combination thereof.
  • the PI3K inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • prostaglandin receptor (PGE2) inhibitor is selected from EP-1, EP-2, EP-3 and EP-4 inhibitors.
  • the EP-4 inhibitor is selected from compounds having formula (II) or pharmaceutically acceptable salts thereof.
  • the PD-1 inhibitor is selected from: PD-1 antibody, PD-L1 antibody and PD-L2 antibody; preferably, wherein the PD-1 inhibitory
  • the agent is selected from the group consisting of Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, toripalizumab, sintilimab, tislelizumab, camrelizumab, or any combination thereof.
  • PI3K inhibitor in the pharmaceutical composition and/or pharmaceutical combination of the present invention, wherein the PI3K inhibitor, prostaglandin receptor (PGE2) inhibitor and PD-1 inhibitor may be in the same and/or separate dosage form .
  • PGE2 prostaglandin receptor
  • the dosage form of the oral route can be are tablets, capsules, powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates
  • the dosage forms for the extragastrointestinal route can be intravenous, intraperitoneal, intradermal, subcutaneous
  • the dosage forms for intramuscular, intracranial, intrathecal, intratumoral, percutaneous penetration, and transmucosal administration can be, for example, solutions, powder injections or lyophilized preparations.
  • the PI3K inhibitor can be formulated into a dosage form of oral, buccal or extra-digestive route
  • the dosage form of the oral route can be tablet, capsule, Powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates
  • the dosage form for the extragastrointestinal route may be intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal
  • the dosage forms for intratumoral, percutaneous penetration and transmucosal administration can be, for example, solutions, powder injections or lyophilized preparations.
  • the prostaglandin receptor (PGE2) inhibitor can be formulated into a dosage form of oral, buccal or extra-digestive route, such as the dosage form of the oral route It can be in the form of tablets, capsules, powders, pills, granules, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates, for example, the dosage form for the extragastrointestinal route can be intravenous, intraperitoneal, intradermal, subcutaneous , intramuscular, intracranial, intrathecal, intratumoral, transdermal, and transmucosal administration dosage forms, such as solutions, powder injections or lyophilized preparations.
  • the dosage form for the extragastrointestinal route can be intravenous, intraperitoneal, intradermal, subcutaneous , intramuscular, intracranial, intrathecal, intratumoral, transdermal, and transmucosal administration dosage forms, such as solutions, powder injections or lyophilized preparations.
  • the extra-digestive route can be intravenous, intraperitoneal, intradermal, Subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, percutaneous penetration, transmucosal administration, such as solution, powder injection or lyophilized preparation.
  • each unit dosage form comprises a dose of 1-1000 mg of a PI3K inhibitor, such as 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120 , 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000mg or any two values above value between.
  • a PI3K inhibitor such as 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120 , 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000mg or any two values above value between.
  • each unit dosage form comprises a dose of 1-1000 mg of a prostaglandin receptor (PGE2) inhibitor, such as 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90 , 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000mg or a value between any two of the above.
  • PGE2 prostaglandin receptor
  • each unit dosage form comprises a dose of 1-5000 mg of PD-1 inhibitor, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175, 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2400, 2500, 2600, 2700, 2750, 2800, 3000, 3500, 4000, 4500, 5000 mg or a value between any two of the above.
  • PD-1 inhibitor such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175,
  • the present invention also provides a pharmaceutical composition and/or pharmaceutical combination for treating tumor/cancer and/or generating a memory immune response against tumor/cancer.
  • the present invention also provides the use of a pharmaceutical composition and/or a pharmaceutical combination for preparing a medicament for treating tumors/cancers and/or generating a memory immune response against tumors/cancers.
  • the present invention also provides a kit comprising the pharmaceutical composition and/or pharmaceutical combination of the present invention, and instructions for use, wherein the PI3K inhibitor, prostaglandin receptor (PGE2) inhibitor
  • PGE2 prostaglandin receptor
  • the agent and the PD-1 inhibitor can be in the same and/or separate containers.
  • FIG. 1 Tumor growth curves of individual EMT6 tumors treated with different drug combinations of AN2025, AN0025, and PD-1 antibodies. 8 mice per group. AN2025 dosing: 30 mg/kg orally (PO) once a day. AN0025 dosing: 150 mg/kg orally (PO) once a day. PD-1 antibody administration: 10 mg/kg, intraperitoneal injection (IP) twice a week.
  • IP intraperitoneal injection
  • FIG. 1 Tumor growth curves of individual CT-26 tumors treated with different drug combinations of AN2025, AN0025, and PD-1 antibodies. 8 mice per group. AN2025 dosing: 30 mg/kg orally (PO) once a day. AN0025 dosing: 100 mg/kg once a day orally (PO). PD-1 antibody administration: 10 mg/kg, intraperitoneal injection (IP) twice a week.
  • IP intraperitoneal injection
  • FIG. 1 Growth curves of PIK3CA mutant tumor HCT116 treated with different drug combinations of AN2025, AN0025 and PD-1 antibodies in humanized mice.
  • AN2025 dosing 37.5 mg/kg once a day orally (PO).
  • AN0025 dosing 30 mg/kg orally (PO) once a day.
  • PD-1 antibody administration 10 mg/kg, intraperitoneal injection (IP) twice a week.
  • PI3K inhibitor refers herein to phosphatidylinositol 3-kinases, a family of highly conserved enzymes that are important components of the intracellular PI3K-Akt-mTOR signaling axis.
  • PI3K inhibitors include, but are not limited to, PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K ⁇ subtype inhibitors.
  • Specific examples include, but are not limited to, Idelalisib, Copanlisib, Duvelisib, Alpelisib, Seletalisib, Gedatolisib, Rigosertib sodium, Leliolisib, Umbralisib, Buparlisib (AN2025), AMG-319, GM-604, Acalisib, Bimiralisib, GDC-0084, ACP- 319, Tenalisib, serabelisib, SF-1126, Nemiralisib, Fimepinostat, LY-3023414, Voxtalisib, Dactolisib, Parsaclisib, GSK-2636771, AZD-8186, ASN-003, and any combination thereof Preferred examples include, but are not limited to, as taught herein Compounds of formula I and pharmaceutically acceptable salts thereof (also referred to herein as AN2025)
  • EP-4 inhibitor refers herein to a compound that inhibits or blocks cell signaling triggered by the interaction of PGE2 with the EP-4 receptor.
  • EP-4 inhibitors include, but are not limited to, ER-819762, MK-2894, MF498, ONO-AE3-208, Evatanepag, ONO-AE2-227, CJ-042794, EP4A, BGC201531, CJ-023423, ONO-AE3 -240, GW627368 and AH23848, for example, are listed in the IUPHAR database as inhibitors of the EP-4 receptor.
  • Other examples include, but are not limited to, compounds of formula II as taught herein and pharmaceutically acceptable salts thereof (also referred to herein as AN0025).
  • PD-1 inhibitor has the same meaning as “PD-1 and/or PD-L1 antibody” and refers to programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) antibody.
  • exemplary antibodies include, but are not limited to, those shown in Patent Nos. US7,029,674, US7,488,802, US7,521,051, US8,008,449, US8,354,509, US8,617,546, and US8,709,417.
  • PD-1/PD-L1 inhibitors also include Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, toripalimab, sintilimab, tislelizumab, camrelizumab monoclonal antibody or any combination thereof.
  • Treatment refers to alleviating, inhibiting and/or reversing the development of a disease (eg, tumor/cancer) in a subject in need thereof.
  • treatment includes any indication of successful treatment or amelioration of the disease, including any objective or subjective parameter, such as alleviation; alleviation; reduction of symptoms or making the subject more tolerant of the injury, pathology or condition; delaying or slowing the rate of progression, and the like. Measures of treatment or improvement can be based, for example, on the results of physical, pathological, and/or diagnostic tests known in the art.
  • treating cancer in the context of the present invention refers to the use of a combination of a PI3K inhibitor, a PGE2 receptor inhibitor, and a PD-1 inhibitor of the present invention for cancer or a subject diagnosed with cancer. , to achieve at least one positive therapeutic outcome, such as a reduction in the number of cancer cells, a reduction in tumor size, a reduction in the rate of tumor cell infiltration into peripheral organs, or a reduction in the rate of tumor metastasis or tumor growth.
  • Treatment can also refer to reducing the onset or risk of onset of the disease, or reducing the recurrence of the disease (eg, prolonging the time to recurrence), as compared to what would have occurred if the measure had not been taken. In the medical field, this treatment is also called "prevention".
  • an “effective amount” or “therapeutically effective amount” refers to an amount effective to treat a disease as documented by clinical testing and evaluation, patient observation, and the like.
  • An “effective amount” can further mean an amount that causes a detectable change in biological or chemical activity. Detectable changes can be detected and/or further quantified by those skilled in the art familiar with the relevant mechanisms or methods.
  • an “effective amount” can mean an amount that maintains a desired physiological state (ie, reduces or prevents significant decline and/or promotes amelioration of a disorder).
  • An “effective amount” can further refer to a therapeutically effective amount.
  • the PI3K inhibitor is administered to the subject in an effective amount.
  • An effective amount is usually 0.01 mg/kg body weight to 500 mg/kg body weight per day.
  • pharmaceutically acceptable compositions can be formulated such that 0.01 mg/kg to 200 mg/kg of body weight or 0.01 mg/kg to 100 mg/kg of body weight per day can be administered to a subject receiving these compositions Dosage of compound (eg 0.75 mg to 7.5 g or 15 g based on a 75 kg human).
  • the active pharmaceutical ingredient of the present invention is formulated to provide a dose of 0.01 mg/kg to 70 mg/kg (eg, a dose of 0.75 mg to 5.25 g based on a 75 kg human).
  • the effective dose of the PI3K inhibitor is about 0.5 to about 250 mg/kg, 1 to about 250 mg/kg, about 2 to about 200 mg/kg, about 3 to about 120 mg/kg, about 5 to about 250 mg/kg kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg.
  • an effective dose includes about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 8 mg/kg, 10 mg/kg, 20 mg/kg , 25mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 75mg/kg, 100mg/kg, 120mg/kg, 150mg/kg, 175mg/kg, 200mg/kg, 225mg/kg, 250mg/kg and 300mg /kg.
  • Dosage forms can take various suitable forms, such as tablets or capsules, and an effective dose can be presented in one or more unit dosage forms (eg, tablets, capsules) and provided 1, 2, or 3 times per day, or in doses of, for example, 4 , 8 or 12 hour intervals are available throughout the day.
  • Tablets or capsules may, for example, contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100 or 1,250 mg of the compound.
  • administering a PI3K inhibitor to a human subject can include a daily dose of the PI3K inhibitor in the range of 100-1,250, 150-1,000, 200-800, or 250-750 mg, the daily dose The whole can be administered once a day, or divided into several portions at regular intervals throughout the day. Liquid preparations can also be prepared so that any dose can be dispensed easily and conveniently.
  • the EP-4 inhibitor is administered to the subject in an effective amount.
  • An effective amount is usually 0.01 mg/kg body weight to 500 mg/kg body weight per day.
  • pharmaceutically acceptable compositions can be formulated such that 0.01 mg/kg to 200 mg/kg of body weight or 0.01 mg/kg to 100 mg/kg of body weight per day can be administered to a subject receiving these compositions Dosage of compound (eg 0.75 mg to 7.5 g or 15 g based on a 75 kg human).
  • the active pharmaceutical ingredient of the present invention is formulated to provide a dose of 0.01 mg/kg to 70 mg/kg (eg, a dose of 0.75 mg to 5.25 g based on a 75 kg human).
  • the effective dose of the EP-4 inhibitor is about 0.5 to about 250 mg/kg, 1 to about 250 mg/kg, about 2 to about 200 mg/kg, about 3 to about 120 mg/kg, about 5 to about 250 mg/kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg.
  • an effective dose includes about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 8 mg/kg, 10 mg/kg, 20 mg/kg , 25mg/kg, 40mg/kg, 50mg/kg, 60mg/kg, 75mg/kg, 100mg/kg, 120mg/kg, 150mg/kg, 175mg/kg, 200mg/kg, 225mg/kg, 250mg/kg and 300mg /kg.
  • Dosage forms can take various suitable forms, such as tablets or capsules, and an effective dose can be presented in one or more unit dosage forms (eg, tablets, capsules) and provided 1, 2, or 3 times per day, or in doses of, for example, 4 , 8 or 12 hour intervals are available throughout the day.
  • Tablets or capsules may, for example, contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, or 1,250 mg of the compound.
  • administering an EP-4 inhibitor to a human subject can include a daily dose of the EP-4 inhibitor in the range of 100-1,250, 150-1,000, 200-800, or 250-750 mg, where The daily dose may be administered all at once a day, or divided into divided portions administered at regular intervals throughout the day. Liquid preparations can also be prepared so that any dose can be dispensed easily and conveniently.
  • Antibodies will typically be mixed with a pharmaceutically acceptable non-toxic carrier material (eg, physiological saline or phosphate buffered saline) prior to administration, and can be administered using any medically appropriate procedure, including, but not limited to, Limited to intravenous or intraarterial administration and injection into cerebrospinal fluid. In certain circumstances, intraperitoneal, intradermal, intraluminal, intrathecal, or direct administration to the tumor or arteries supplying blood to the tumor may be beneficial.
  • a pharmaceutically acceptable non-toxic carrier material eg, physiological saline or phosphate buffered saline
  • the effective dose of the antibody is about 5 to about 250 mg/kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg. In some embodiments, effective doses include 5 mg/kg, 10 mg/kg, 20 mg/kg, 25 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 75 mg/kg, 100 mg/kg, 120 mg/kg, 150 mg /kg, 175 mg/kg, 200 mg/kg, 225 mg/kg, 250 mg/kg and 300 mg/kg. Dosage forms can take the form of, for example, tablets or capsules, and an effective dose can be presented in one or more tablets, capsules, etc., once a day or at intervals of, for example, 4, 8, or 12 hours throughout the day.
  • a tablet or capsule may, for example, contain, for example, 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1,000 mg of antibody.
  • Liquid preparations can also be prepared so that any dose can be dispensed easily and conveniently.
  • the antibody is administered to a subject in an effective amount.
  • An effective amount is usually 0.01 mg/kg body weight to 500 mg/kg body weight per day.
  • pharmaceutically acceptable compositions can be formulated such that 0.01 mg/kg to 200 mg/kg of body weight or 0.01 mg/kg to 100 mg/kg of body weight per day can be administered to patients receiving these compositions Dosage of compound (eg 0.75 mg to 7.5 g or 15 g based on a 75 kg human).
  • the compositions of the present invention are formulated to provide a dose of 0.01 mg/kg to 70 mg/kg (eg, a dose of 0.75 mg to 5.25 g based on a 75 kg human).
  • An effective amount of the antibody can be, for example, 0.05 mg/kg, 0.1 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg or 8 mg/kg per dose (eg a dose of 3.75 mg to 600 mg based on a 75 kg human).
  • Doses of the antibody may be administered once, twice, three times, four times, five times or more per week, once per week, once every two weeks, or even once every three weeks during the course of treatment.
  • the dosing schedule can be once a day, once every two days, once every three days, once every four days, once every five days, once a week, once every two weeks, or once every three weeks.
  • Formulations containing the antibody can be prepared such that any dose can be dispensed easily and conveniently.
  • subject refers to mammalian subjects, and particularly human subjects, including male or female subjects, and including neonatal, infant, toddler, juvenile, adult or elderly subjects, and further including various races and ethnicities, such as Caucasian, African and Asian.
  • the subject has a tumor/cancer.
  • whether the tumor patient expresses PD-L1 is irrelevant.
  • the tumor patient is a PD-L1 positive tumor patient.
  • salts refers to relatively non-toxic inorganic or organic acid salts of compounds of Formula I or Formula II of the present invention. These salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in free form with a suitable organic or inorganic acid, respectively, and isolating the salt so formed.
  • Representative acid salts include, but are not limited to, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate , borate, d-camphorsulfonate, citrate, cyclosulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconic acid Salt, Glucuronate, Hexafluorophosphate, Hebenzate, Hydrochloride/Chloride, Hydrobromide/Bromide, Hydroiodide/Iodide, Isethionate, Lactic Acid salt, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotic acid Salt, Oxalate, Palmitate, Pamoate, P
  • tumors and cancer are used interchangeably herein to refer to an uncontrolled abnormal proliferation of local tissue in the body. Without timely medical intervention, tumors/cancers can grow uncontrollably and have the potential to metastasize to other locations in the body, ultimately causing death.
  • cancer can include cancers caused by genetically inherited mutations.
  • examples of such cancers include, but are not limited to, breast cancer, cancers that may be associated with Lee-Frauming syndrome (eg, childhood sarcoma, leukemia, and brain cancer), cancers that may be associated with Lynch syndrome, such as colon cancer, bile duct cancer, Cancers of the brain, endometrial, kidney, ovary, pancreas, small intestine, stomach and ureter, lung, melanoma, prostate, retinoblastoma, thyroid and uterus.
  • Lee-Frauming syndrome eg, childhood sarcoma, leukemia, and brain cancer
  • Lynch syndrome such as colon cancer, bile duct cancer
  • cancer can be the result of acquired mutations (eg, mutations caused by diet, environment, and/or lifestyle) or somatic mutations.
  • cancers may include, but are not limited to, adrenal cancer, adrenocortical cancer, bladder cancer, brain cancer, primary brain cancer, glioma, glioblastoma, breast cancer, cervical cancer, colon cancer (Non-limiting examples include colorectal cancer, such as colon adenocarcinoma and colon adenoma), endometrial cancer, epithelial cancer, esophageal cancer, gallbladder cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer (non- Limiting examples include adenocarcinoma, small cell lung cancer, and non-small cell lung cancer), lymphomas (non-limiting examples include B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma) , meltheli
  • exocrine pancreatic cancer prostate cancer, renal cell carcinoma, skin cancer (except Cancers other than those previously mentioned (e.g. squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, follicular thyroid cancer, Wilm's tumor, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, hairy cell lymphoma, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, promyelocytic Leukemia, chronic myeloid leukemia, acute myeloid leukemia, fibrosarcoma, rhabdomyosarcoma, astrocytoma, neuroblastoma, rhabdomyosarcoma, schwannoma, Kaposi's sarcoma, polycythemia vera, essential platelets
  • Metal cancer refers to cancer in which cancer cells from one organ or body part have spread (by “metastasis") to another non-adjacent organ or body part. Cancer at a non-adjacent organ or body part (“secondary tumor” or “metastatic tumor”) includes cancer cells originating from an organ or body part from which the cancer or cancer cells have spread from the organ or body part. Sites where secondary tumors can occur include, but are not limited to, lymph nodes, lung, liver, brain, and/or bone.
  • PIK3CA mutant cancer refers to the amino acid change of the PIK3CA gene in cancer cells due to nucleic acid base mutation, which ultimately leads to abnormal PI3K cell signaling, and the mutation sites include but are not limited to H1047R, E542K and E545K.
  • pharmaceutically acceptable and “pharmaceutically acceptable” are used interchangeably and refer to the types generally accepted by those skilled in the art of pharmacy.
  • pharmaceutically acceptable salts pharmaceutically acceptable carriers and the like.
  • Oral dosage form refers to a pharmaceutical formulation prepared for administration to an individual by the oral route of administration.
  • known oral dosage forms include, but are not limited to, tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates, and the like.
  • powders, pills, granules, capsules, and tablets can be coated with suitable polymers or conventional coating materials to achieve, for example, greater stability in the gastrointestinal tract or to achieve a desired release rate.
  • the capsule shells of the powders, pills or granules are further coated. Tablets can be scored to facilitate splitting of administration.
  • a compound of formula I or formula II according to the present invention When a compound of formula I or formula II according to the present invention is administered as an oral formulation, it is preferably coated with a film.
  • Suitable membranes are known in the art and are commercially available or can be manufactured according to known methods.
  • the film coating material is a hydrophilic polymer such as polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, and the like.
  • the film coating composition ingredients may include conventional amounts of plasticizers, such as polyethylene glycol, triethyl citrate, diethyl phthalate, propylene glycol, glycerin; and opacifiers, such as titanium dioxide, and colorants, such as oxides Iron, aluminum lake, etc.
  • plasticizers such as polyethylene glycol, triethyl citrate, diethyl phthalate, propylene glycol, glycerin
  • opacifiers such as titanium dioxide
  • colorants such as oxides Iron, aluminum lake, etc.
  • the film coating material is applied, for example, in an amount that provides a film coating in the range of 1% to 6% of the solid oral dosage form.
  • a compound of formula I or formula II of the present invention When a compound of formula I or formula II of the present invention is administered as an oral formulation, it may optionally further comprise at least one pharmaceutically acceptable carrier for use in medicine.
  • pharmaceutically acceptable carrier refers to any pharmaceutically inert material that is substantially biologically inactive and that constitutes a substantial part of the formulation. Examples of such carriers include, but are not limited to, diluents and fillers, disintegrants, glidants, binders, stabilizers, colorants, flavor enhancers, and preservatives.
  • diluents for example, but not limited to: microcrystalline cellulose, mannitol, powdered sugar, compressible sugar, dextran, dextrin, strobilose, lactose, cellulose powder, sorbitol, sucrose and Talc or a combination thereof.
  • the diluent may be 5% to 90%, preferably 10% to 80%, 20%-70%, 30%-60%, 40%-50%, based on the total weight of the oral preparation.
  • disintegrants for example but not limited to: cellulose, alginates, gums, cross-linked polymers such as crospovidone or crospovidone, croscarmellose sodium , croscarmellose calcium, soybean polysaccharide, sodium starch glycolate, guar gum or any combination thereof.
  • the diluent may be present in an amount of about 1% to 15%, preferably 2% to 10%, based on the total weight of the oral formulation.
  • binders for example but not limited to starch, cellulose or derivatives thereof, such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, Spin sugar, corn syrup, polysaccharide, gelatin, or any combination thereof.
  • the binder may be present in an amount of 0.01 to 10%, preferably 1% to 10%, based on the total weight of the formulation.
  • glidants for example, but not limited to, colloidal silicon dioxide, magnesium trisilicate, cellulose powder, talc, or combinations thereof may be selected. Glidants may be present in an amount of 0.1% to 10%, preferably 0.1% to 0.5%, based on the total weight of the composition.
  • biotherapeutics refers to biomolecules, such as antibodies or fusion proteins, that block ligand/receptor properties in any biological pathway that supports tumor maintenance and/or growth or inhibits tumor immune responses.
  • biological therapeutics include, but are not limited to: alemtuzumab, bevacizumab, belemtuzumab vedotin, catuximab, cetuximab, denosumab, gemtuzumab Monoclonal antibody, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumumab, trastuzumab, nivolumab, Tecilizumab, durvalumab, avelumab.
  • chemotherapeutic agents are chemical compounds that can be used in cancer treatment, including but not limited to alkylating agents, antimetabolites, kinase inhibitors, spindle toxin phytoalkaloids, cytotoxic/antitumor biotins, topoisomeric Constructive enzyme inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, antisense oligonucleotides that inhibit the expression of genes involved in abnormal cell proliferation or tumor growth Nucleotides.
  • chemotherapeutic agents include, but are not limited to, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, Cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, Vinorelbine, Paclitaxel, Docetaxel, Topotecan, Irinotecan, Etoposide, Trabectedin, Dactomycin, Doxorubicin, Epirubicin, Daunomycin, Mitoxantrone , bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonarelin analogues, megestrol
  • the choice of dosage regimen for the combination therapy of the present invention depends on a number of factors, such as: entity serum or tissue turnover rate, symptom level, overall immunogenicity and accessibility of target cells, tissues or organs in the subject being treated.
  • the dosage regimen maximizes the amount of each therapeutic agent delivered to the patient within acceptable levels of side effects.
  • the dosage and frequency of administration of each biotherapeutic agent and chemotherapeutic agent in combination therapy depends in part on the particular therapeutic agent, the severity of the cancer being treated, and the characteristics of the patient.
  • the combination therapy of the present invention may be administered before or after surgery to remove the tumor, and may also be administered before, during, or after radiation therapy.
  • WO2007084786 specifically describes the compounds of formula I of the present invention, the compounds or pharmaceutically acceptable salts thereof and processes for their preparation are disclosed in the Examples of WO2007084786, which is incorporated herein by reference in its entirety.
  • WO2012039972 specifically describes the compound of formula II of the present invention, the compound or a pharmaceutically acceptable salt thereof and a process for its preparation are disclosed in the Examples of WO2012/039972, which is incorporated herein by reference in its entirety.
  • administration of a PI3K inhibitor, an EP-4 inhibitor, and a PD-1 inhibitor in combination results in a potentiation of the PD-1 inhibitor, such that, for example, smaller doses or longer intervals of PD-1 inhibitor are effective for Treatment may be effective.
  • Antibody includes all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof, which are suitable for the medical uses disclosed herein.
  • Antibodies can be monoclonal or polyclonal, and can be of any species origin, including, for example, mouse, rat, rabbit, horse, or human.
  • Antibody fragments that retain specific binding to the protein or epitope (PD-L1 or PD-1) to which the antibodies used in the present invention bind are included within the scope of the term "antibody”. Such fragments can be produced by known techniques.
  • Antibodies can be chimeric or humanized, especially when they are used for therapeutic purposes. Antibodies can be obtained or prepared using methods known in the art.
  • Example 1 Combination therapy of compound of formula I (AN2025), compound of formula II (AN0025) and PD-1 antibody in the treatment of EMT6, CT26 tumors in mice
  • AN0025 was purchased from Shanghai Kalulan Technology Co., Ltd.; AN2025 was purchased from CSNpharm.
  • Antibody against mouse PD-1 (clone number: RMP1-14) was purchased from BioXcell.
  • mice mouse colon cancer CT26 cells (CRL-2638) and breast cancer EMT6 cells (CRL-2755) were purchased from American Tissue Culture Center. All cells were cultured in RPMI-1640 (CT26) or Waymouth's (1x) MB 752/1 (EMT6) medium supplemented with 10% fetal bovine serum in an incubator at 37°C and 5% carbon dioxide and weekly Subculture twice until the necessary number of cells are obtained for inoculating mice.
  • mice 6-8 week old BalB/c female mice were purchased from Shanghai Slack Laboratory Animal Technology Co., Ltd. Animals were housed in micro-isolator cages of up to 5 per cage on a 12h light/dark cycle. Cages were changed twice a week. Animals were observed weekly and clinical signs recorded.
  • PD-1 antibody administration 10 mg/kg, intraperitoneal injection (IP) twice a week; for CT26 model, AN2025 administration: 30 mg/kg, oral (PO) once a day. AN0025 dosing: 100 mg/kg once a day orally (PO).
  • Example 2 Combination therapy of AN2025, AN0025 and PD-1 antibody in the treatment of HCT116 tumor in PBMC immune system humanized mice
  • AN0025 was purchased from Shanghai Kalulan Technology Co., Ltd.; AN2025 was purchased from CSNpharm.
  • the antibody against human PD-1 was provided by Finok Biotechnology Co., Ltd.
  • human PBMC was purchased from Miaoshun (Shanghai) Biotechnology Co., Ltd.
  • HCT116 human colon cancer cells were purchased from the Cell Bank of the Chinese Academy of Sciences. Cells were grown in McCoy's 5a medium supplemented with 10% fetal bovine serum in an incubator at 37°C and 5% carbon dioxide and subcultured twice a week until the necessary number of cells were obtained for inoculating mice.
  • mice 6-8 week old NPSG female mice were purchased from PNK. Animals were housed in IVC isolation cages, 5 per cage, on a 12-h light/dark cycle. Temperature 20 ⁇ 26 °C, humidity 30-70%.
  • mice were injected IV with human PBMC 5x10 6 /100ul.
  • HCT116 cells were subcutaneously inoculated on the right shoulder of the mice at an inoculation amount of 1 ⁇ 10 6 /mice.
  • tumor volume and body weight were measured once a week, and the proportion of hCD45+ cells in the blood of mice was measured when the average tumor volume reached about 80-100 mm 3 .
  • AN2025 dosing 37.5 mg/kg once a day orally (PO).
  • AN0025 dosing 30 mg/kg orally (PO) once a day.
  • PD-1 antibody administration 10 mg/kg, intraperitoneal injection (IP) twice a week.
  • IP intraperitoneal injection
  • mice were measured for body weight and tumor volume twice a week.
  • T-Test analysis was used, and for comparisons between three or more groups, one-way analysis of variance (One-Way ANOVA) was used for analysis.
  • One-Way ANOVA was used for comparison of potential synergistic effects.
  • two-way analysis of variance was used for comparison of potential synergistic effects. All data use SPSS 24.0. A p-value less than 0.05 was considered to be significantly different.
  • AN0025 and PD-1 antibody and the combination of AN2025 and PD-1 antibody showed a certain anti-tumor activity in the humanized mouse HCT116 tumor of the PBMC immune system; but the combination of the three, namely AN2025, AN0025 and PD
  • the anti-tumor activity of triple combination of -1 antibody was significantly better than that of AN0025 and PD-1 antibody (p ⁇ 0.05) and the double combination of AN2025 and PD-1 antibody (p ⁇ 0.01).

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Abstract

一种用于治疗PIK3CA突变癌症的组合物疗法，包括向有需要的对象施用PI3K抑制剂、前列腺素受体（PGE2）抑制剂和PD-1抑制剂。三种联合用药方法所带来的抗肿瘤活性显著优于PI3K抑制剂和PD-1抑制剂以及前列腺素受体（PGE2）与PD-1抑制剂两种联合用药的活性。

Description

用于治疗PIK3CA突变癌症的组合疗法
本申请要求于2020年11月30日提交中国专利局、申请号为202011379205.7、发明名称为“用于治疗PIK3CA突变癌症的组合疗法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种组合治疗方法及药物组合物和/或药物组合，包括向有需要的对象施用PI3K抑制剂、前列腺素受体(PGE2)抑制剂和PD-1抑制剂。
背景技术
使用抗CTLA4抗体和抗PD(L)1抗体的免疫检查点抑制剂(ICI)给癌症免疫治疗带来了深刻的变革。自从2001年第一个免疫检查点抑制剂(ICI)获批以来，这一系列的药物由于在复杂癌症上持久的临床效果引起了广泛的关注。然而，仍然有大量的癌症患者对于ICI治疗不响应。到目前为止经ICI治疗的癌症患者的响应率约为20％，所以找到一种更加有效的免疫治疗方式来进一步利用免疫系统治疗癌症是非常有必要的。
泛I型P13K抑制剂
PI3K-AKT-mTOR信号通路失调在癌症患者中的发生率很高，其主要调控细胞生长，增殖，代谢等关键的细胞过程，在癌症患者中能够促进癌症细胞的存活，扩张和传播。由PIK3CA基因编码的PI3K异构体p110α是人类癌症中排名第二的最容易突变的原癌基因。
PI3K家族中，PI3Kβ同样也参与了肿瘤发生，但PI3Kα起着主要作用，除此之外，另外两个异构体PI3Kγ和PI3Kδ则对免疫系统起着重要调控作用。PI3Kδ能够调控并维持调节性T细胞(Treg)的功能，PI3Kγ不仅能够募集抑制性的髓系细胞到癌症微环境中，而且能够增强它们对于T细胞抗癌症作用的抑制能力。
式I结构的化合物(AN2025)及其药学上可接受的盐是口服泛I型PI3K抑制剂，目前已经在临床三期研发阶段，其适应症为头颈鳞癌。它不仅能够抑制野生型的PI3α，而且能够抑制突变型的P13Kα，突变位点包括(H1047R,E542K  and E545K)。同时，其对于其他PI3K异构体(PI3Kβ,PI3Kγ,PI3Kδ)也具有抑制活性。AN2025已经在临床上证实了其对于PI3K/PIK3CA突变导致乳腺癌的发生是有效的，其响应率最高的患者都具有PIK3CA突变(Campone M et al.Eur J Cancer.2018；103:147-154)。AN2025同样可以通过抑制PI3Kδ和PI3Kγ来下调Tregs和抑制性髓系细胞功能以及其进入肿瘤微环境的能力(O'Donnell JS et al.Semin Cancer Biol.2018；48:91-103.Borazanci et al.The Oncol.2020)。
Figure PCTCN2021134189-appb-000001
EP-4抑制剂
在癌症中，前列腺素E2(PGE2)和其亚型4受体(EP-4)组成的信号通路，不仅能够促进癌症的发生，而且能够形成促进癌症发展，免疫抑制的癌症微环境。T细胞中PGE2/EP-4信号通路激活产生的cAMP能够激活cAMP-PKA信号通路，这个过程能够有效地抑制T细胞的功能。PGE2/EP-4信号通路也能够负调控DC的成熟，诱导包括M2巨噬细胞以及髓系抑制细胞(MDSC)在内的多种免疫抑制细胞的形成(
Figure PCTCN2021134189-appb-000002
S et al.Front Immunol.2019；10:475)。
式(II)结构的化合物(AN0025)及其药学上可接受的盐是一种具有高度选择性的，针对E型前列腺素受体4的小分子抑制剂。在临床前研究中，AN0025通过抑制PGE2/EP-4信号通路，能够在肿瘤微环境中有效的减少免疫抑制细胞。AN0025已经运用到多个临床策略中。在针对多种晚期实体瘤FIH(first in human)I期临床实验中，AN0025已经展现出了一定的单药药效；并且在结直肠癌的新辅助治疗中，AN0025与放化疗联用表现出很强的临床药效(Wyrwicz et.al,Poster#540,ESMO2019)。目前，AN0025与抗PD-1抗体(pembrolizumab)已经在多个实体瘤中进入临床1b/2阶段(NCT04432857)。临床前以及早期临床数据支持AN0025作为一个免疫调节剂，通过调控M2巨噬细胞，MDSC以及T细胞来对 抗免疫抑制的癌症微环境。
Figure PCTCN2021134189-appb-000003
PD-(L)1抗体
PD-1和PD-L1信号通路在调节T细胞激活过程中起到关键作用。PD-L1主要在免疫细胞以及大多数的人癌症细胞中表达。在肿瘤微环境中，癌症PD-L1与T细胞上的PD-1相互作用，最终抑制T细胞的癌症细胞杀伤活性。大量抗PD-(L)1治疗的成功案例，使得它成为现代肿瘤免疫治疗的基石。
AN2025和AN0025能够系统性地调节免疫抑制的肿瘤微环境，这与抗PD(L)1治疗杀伤癌症的机制是互补的。通过AN2025靶向PIK3CA突变能够增加额外的作用机制，使得病人能够获益于这种三联组合带来的免疫调节活性。这种三联组合为大多数晚期实体瘤患者，特别是PIK3CA突变的晚期实体瘤患者提供了理想的治疗选择。
发明内容
本发明所要解决的技术问题在于，解决现有技术中经ICI治疗的癌症患者的响应率低的问题。本发明的目的在于提供了一种更加有效的免疫治疗方式来进一步利用免疫系统治疗癌症。
鉴于此，本发明提供了一种PI3K抑制剂、前列腺素受体(PGE2)抑制剂以及PD-1抑制剂三者联用来治疗癌症的方法，所述方法的抗肿瘤活性显著优于任意两两组合。
具体而言，本发明提供了如下技术方案：
一种在有此需要的对象治疗肿瘤/癌症和/或产生针对肿瘤/癌症的记忆免疫应答的方法，包括向所述对象施用有效量的PI3K抑制剂、前列腺素受体(PGE2)抑制剂以及PD-1抑制剂，其中，所述PI3K抑制剂、前列腺素受体(PGE2)抑制 剂和所述PD-1抑制剂可以作为单一制剂(Dosage form)同时、分开或者顺序施用。
在本发明的一个实施方案中，其中所述PI3K抑制剂选自PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ亚型抑制剂。
在本发明的一个实施方案中，其中所述PI3K抑制剂选自Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003或其任意组合。
在本发明的一个实施方案中，其中所述PI3K抑制剂是具有式(I)的化合物或者其药学上可接受的盐，
Figure PCTCN2021134189-appb-000004
在本发明的一个实施方案中，其中所述前列腺素受体(PGE2)抑制剂选自EP-1，EP-2，EP-3和EP-4抑制剂。
在本发明的一个实施方案中，其中所述EP-4抑制剂选自具有式(II)的化合物或者其药学上可接受的盐。
Figure PCTCN2021134189-appb-000005
在本发明的一个实施方案中，其中所述PD-1抑制剂包括PD-1/PD-L1抗体疗法。
在本发明的一个实施方案中，其中所述PD-1抑制剂选自：PD-1抗体、PD-L1抗体和PD-L2抗体；优选地，其中所述PD-1抑制剂选自Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗或其任意组合物。
在本发明的一个实施方案中，其中以经口服、口含或经消化道外途径的剂型施用所述PI3K抑制剂，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。
在本发明的一个实施方案中，其中每天施用所述PI3K抑制剂1次或2次；或者每2、3、4、5、6、7、8、9、10天或每1、2或3周施用1次所述PI3K抑制剂；或者每周连续5天每天施用1次所述PI3K抑制剂，然后间隔2天。
在本发明的一个实施方案中，其中所述PI3K抑制剂在成年人中以约20mg/天-约200mg/天、约30mg/天-约160mg/天、约60mg/天-约120mg/天的剂量范围施用。
在本发明的技术方案中，其中以约0.5至约250mg/kg、1至约250mg/kg、约2至约200mg/kg、约3至约120mg/kg、约5至约250mg/kg、约10至约200mg/kg、或约20至约120mg/kg的有效剂量向所述对象施用所述PI3K抑制剂。
在本发明的一个实施方案中，其中以经口服、口含或经消化道外途径的剂型施用所述前列腺素受体(PGE2)抑制剂，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。
在本发明的一个实施方案中，其中每天施用所述前列腺素受体(PGE2)抑制剂1次或2次；或者每2、3、4、5、6、7、8、9、10天或每1、2或3周施用1次所述前列腺素受体(PGE2)抑制剂；或者每周连续5天每天施用1次所述前列 腺素受体(PGE2)抑制剂，然后间隔2天。
在本发明的一个实施方案中，其中所述前列腺素受体(PGE2)在成年人中以约20mg/天-约2000mg/天、约30mg/天-约1600mg/天、约60mg/天-约1200mg/天、约100mg/天-约1000mg/天的剂量范围施用。
在本发明的一个实施方案中，其中以约0.5至约250mg/kg、1至约250mg/kg、约2至约200mg/kg、约3至约120mg/kg、约5至约250mg/kg、约10至约200mg/kg、或约20至约120mg/kg的有效剂量向所述对象施用所述前列腺素受体(PGE2)抑制剂。
在本发明的一个实施方案中，其中以消化道外途径施用所述PD-1抑制剂，例如所述消化道外途径可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药。
在本发明的一个实施方案中，其中所述PD-1抑制剂配制成溶液剂、冻干剂、粉针剂。
在本发明的一个实施方案中，其中以0.05mg/kg、0.1mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg或8mg/kg的有效剂量施用所述PD-1抑制剂。
在本发明的一个实施方案中，其中所述肿瘤/癌症选自PIK3CA突变的癌症。
在本发明的一个实施方案中，其中所述肿瘤/癌症选自：头和颈鳞状细胞癌、头和颈癌、脑癌、神经胶质瘤、多形性成胶质细胞瘤、神经母细胞瘤、中枢神经系统癌、神经内分泌肿瘤、咽喉癌、鼻咽癌、食管癌、甲状腺癌、恶性胸膜间皮瘤、肺癌、乳腺癌、肝癌、肝细胞瘤、肝胆癌、胰腺癌、胃癌、胃肠道癌、肠癌、结肠癌、结肠直肠癌、肾癌、透明细胞肾细胞癌、卵巢癌、子宫内膜癌、子宫颈癌、膀胱癌、前列腺癌、睾丸癌、皮肤癌、黑色素瘤、白血病、淋巴瘤、骨癌、软骨肉瘤、骨髓瘤、多发性骨髓瘤、骨髓异常增生综合征、骨髓增生性肿瘤、鳞状细胞癌、尤因氏肉瘤、全身性轻链淀粉样变性和梅克尔细胞癌；更 优选的，所述淋巴瘤选自：霍奇金淋巴瘤、非霍奇金淋巴瘤、弥漫性大B-细胞淋巴瘤、滤泡性淋巴瘤、原发性纵隔大B-细胞淋巴瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤、富含T-细胞/组织细胞的大B-细胞淋巴瘤和淋巴浆细胞性淋巴瘤，所述肺癌选自：非小细胞肺癌和小细胞肺癌，所述白血病选自：慢性髓细胞样白血病、急性髓细胞样白血病、淋巴细胞白血病、成淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病和髓样细胞白血病。
除此之外，本发明还提供了一种药物组合物和/或药物组合，其包含PI3K抑制剂、前列腺素受体(PGE2)抑制剂和PD-1抑制剂，以及可药用载体。
在本发明的药物组合物和/或药物组合中，其中所述PI3K抑制剂选自括PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ亚型抑制剂。
在本发明的药物组合物和/或药物组合中，其中所述PI3K抑制剂选自Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003或其任意组合。
在本发明的药物组合物和/或药物组合中，其中所述PI3K抑制剂是具有式(I)的化合物或者其药学上可接受的盐，
Figure PCTCN2021134189-appb-000006
在本发明的药物组合物和/或药物组合中，其中所述前列腺素受体(PGE2)抑制剂选自EP-1，EP-2，EP-3和EP-4抑制剂。
在本发明的药物组合物和/或药物组合中，其中所述EP-4抑制剂选自具有式(II)的化合物或者其药学上可接受的盐。
Figure PCTCN2021134189-appb-000007
在本发明的药物组合物和/或药物组合中，其中所述PD-1抑制剂选自：PD-1抗体、PD-L1抗体和PD-L2抗体；优选地，其中所述PD-1抑制剂选自Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗或其任意组合物。
在本发明的药物组合物和/或药物组合中，其中所述PI3K抑制剂、前列腺素受体(PGE2)抑制剂和PD-1抑制剂可以处于同一和/或分开的剂型(dosage form)中。
在本发明的药物组合物和/或药物组合中，其中所述药物组合物和/或药物组合可以配制成以经口服、口含或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型，例如可以是溶液剂、粉针剂或冻干剂。
在本发明的药物组合物和/或药物组合中，所述PI3K抑制剂可以配制成以经口服、口含或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型，例如可以是溶液剂、粉针剂或冻干剂。
在本发明的药物组合物和/或药物组合中，其中所述前列腺素受体(PGE2)抑制剂可以配制成以经口服、口含或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、 乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型，例如可以是溶液剂、粉针剂或冻干剂。
在本发明的药物组合物和/或药物组合中，其中所述PD-1抑制剂可以配制成以消化道外途径施用的剂型，例如所述消化道外途径可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药，例如可以是溶液剂、粉针剂或冻干剂。
在本发明的药物组合物和/或药物组合中，其中每单位剂型(unit dosage form)中包含1-1000mg剂量的PI3K抑制剂，例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000mg或以上任意两个数值之间的值。
在本发明的药物组合物和/或药物组合中，其中每单位剂型(unit dosage form)中包含1-1000mg剂量的前列腺素受体(PGE2)抑制剂，例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000mg或以上任意两个数值之间的值。
在本发明的药物组合物和/或药物组合中，其中每单位剂型中包含1-5000mg剂量的PD-1抑制剂，例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000、1100、1200、1300、1400、1500、1600、1700、1800、1900、2000、2200、2400、2500、2600、2700、2750、2800、3000、3500、4000、4500、5000mg或以上任意两个数值之间的值。
除此之外，本发明还提供一种药物组合物和/或药物组合，其用于治疗肿瘤/癌症和/或产生针对肿瘤/癌症的记忆免疫应答。
除此之外，本发明还提供药物组合物和/或药物组合用于制备治疗肿瘤/癌症和/或产生针对肿瘤/癌症的记忆免疫应答的药物的用途。
除此之外，本发明还提供了一种药盒，其包含本发明所述的药物组合物和/或药物组合，以及使用说明，其中所述PI3K抑制剂、前列腺素受体(PGE2)抑制剂和PD-1抑制剂可以处于同一和/或分开的容器中。
附图说明
图1用AN2025、AN0025以及PD-1抗体的不同药物组合治疗单个EMT6肿瘤的肿瘤生长曲线。每组8只小鼠。AN2025给药：30mg/kg，每天口服(PO)一次。AN0025给药：150mg/kg，每天口服(PO)一次。PD-1抗体给药：10mg/kg，每周腹腔注射(IP)两次。
图2用AN2025、AN0025以及PD-1抗体的不同药物组合治疗单个CT-26肿瘤的肿瘤生长曲线。每组8只小鼠。AN2025给药：30mg/kg，每天口服(PO)一次。AN0025给药：100mg/kg，每天口服(PO)一次。PD-1抗体给药：10mg/kg，每周腹腔注射(IP)两次。
图3在人源化小鼠上，用AN2025、AN0025以及PD-1抗体的不同药物组合治疗PIK3CA突变型肿瘤HCT116的生长曲线。AN2025给药：37.5mg/kg，每天口服(PO)一次。AN0025给药：30mg/kg，每天口服(PO)一次。PD-1抗体给药：10mg/kg，每周腹腔注射(IP)两次。
具体实施方式
术语定义：
除非本文中另外指出，本文所用术语具有在其所属领域的常规含义。
术语“PI3K抑制剂剂”在本文中是指磷脂酰肌醇3-激酶，是一类高度保守的酶家族，是胞内PI3K-Akt-mTOR信号轴的重要组成部分。PI3K抑制剂的实例包括但不限于PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ亚型抑制剂。具体的实施例包括但不 限于Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003和其任意组合优选的实例包括但不限于如本文所教导的式I化合物及其药学上可接受的盐(本文中又称AN2025)
Figure PCTCN2021134189-appb-000008
术语“EP-4抑制剂剂”在本文中是指抑制或阻断通过PGE2与EP-4受体的相互作用而触发的细胞信号传导的化合物。EP-4抑制剂的实例包括但不限于ER-819762、MK-2894、MF498、ONO-AE3-208、Evatanepag、ONO-AE2-227、CJ-042794、EP4A、BGC201531、CJ-023423、ONO-AE3-240、GW627368和AH23848，例如作为EP-4受体的抑制剂列举在IUPHAR数据库中的。其它实例包括但不限于如本文所教导的式II化合物及其药学上可接受的盐(本文中又称AN0025)。
Figure PCTCN2021134189-appb-000009
在本文中，术语“PD-1抑制剂”与“PD-1和/或PD-L1抗体”具有相同的含义，是指针对程序性死亡蛋白1(PD-1)/程序性死亡蛋白配体1(PD-L1)的抗体。示例性抗体包括但不限于如专利号US7,029,674、US7,488,802、US7,521,051、US8,008,449、US8,354,509、US8,617,546和US8,709,417中所示的抗体。PD-1/PD-L1抑制剂的具体实例还包括Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗或其任意组合物。
“治疗”、“处理”和“医治”是指在有需要的对象中减轻、抑制和/或逆转疾病(如肿瘤/癌症)的发展。术语“治疗”包括疾病的成功治疗或改善的任何迹象， 包括任何客观或主观参数，例如减轻；缓和；症状减少或使受试对象更容易容忍损伤、病理或病症；延迟或减缓发展速率等。治疗或改善的测量可基于例如所属领域已知的身体检查、病理学检查和/或诊断检查的结果。例如，在一个实施方案中，本发明所涉及的“治疗”癌症是指对癌症或被诊断患有癌症的对象使用本发明的PI3K抑制剂、PGE2受体抑制剂与PD-1抑制剂联合治疗，以实现至少一项阳性治疗结果，例如癌细胞数量减少、肿瘤大小减小、肿瘤细胞浸润外周器官的速率减少或肿瘤转移或肿瘤生长速率减小。
治疗也可指与在不采取该措施的情况下将会发生的相比，减少疾病的发病或发作风险，或减少疾病复发(例如延长复发时间)。在医学领域，这种治疗也被称为“预防”。
术语“有效量”或“治疗有效量”是指如通过临床测试和评估、患者观察等所记录的，可有效治疗疾病的量。“有效量”可进一步表示引起生物或化学活性的可检测到的变化的量。可检测到的变化可以由熟悉相关机制或方法的所属领域技术人员检测和/或进一步定量。此外，“有效量”可表示维持期望生理状态(即减少或预防显著的衰退和/或促进病症的改善)的量。“有效量”可进一步指治疗有效量。
在一些实施方案中，PI3K抑制剂以有效量施予对象。有效量通常是每天0.01mg/kg体重至500mg/kg体重。在一些实施方案中，药学上可接受的组合物可经过配制，使得可以向接受这些组合物的对象施用每天0.01mg/kg体重至200mg/kg体重或0.01mg/kg体重至100mg/kg体重的化合物的剂量(例如基于75kg的人，剂量为0.75mg至7.5g或15g)。在某些实施方案中，本发明的活性药物成分经过配制，以提供0.01mg/kg至70mg/kg的剂量(例如基于75kg的人，剂量为0.75mg至5.25g)。
在一些实施方案中，PI3K抑制剂的有效剂量为约0.5至约250mg/kg、1至约250mg/kg、约2至约200mg/kg、约3至约120mg/kg、约5至约250mg/kg、约10至约200mg/kg、或约20至约120mg/kg。在一些实施方案中，有效剂量包括约0.5mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、8mg/kg、10mg/kg、20mg/kg、25mg/kg、40mg/kg、50mg/kg、60mg/kg、75mg/kg、100mg/kg、120mg/kg、150mg/kg、175mg/kg、200mg/kg、225mg/kg、250mg/kg和300mg/kg。剂型可以采取各种合适的形式，例如片剂或胶囊，并且有效剂量可以在一个或多个单位剂型(如片剂、胶囊)中提供，并且每天提供1、2或3次，或以例如4、8或12小时的时间间隔全天提供。片剂或胶囊例如可以含有例如10、25、50、75、100、150、200、250、300、350、400、450、500、600、700、800、 900、1,000、1,100或1,250mg化合物。举例来说，在一些实施方案中将PI3K抑制剂施予人类对象可以包括在100-1,250、150-1,000、200-800或250-750mg范围的PI3K抑制剂的每日剂量，所述每日剂量可以每天一次全部施用，或者分多份以一定的时间间隔全天施用。也可以制备成液体制剂，使得可以容易地且便利地分配任何剂量。
在一些实施方案中，EP-4抑制剂以有效量施予对象。有效量通常是每天0.01mg/kg体重至500mg/kg体重。在一些实施方案中，药学上可接受的组合物可经过配制，使得可以向接受这些组合物的对象施用每天0.01mg/kg体重至200mg/kg体重或0.01mg/kg体重至100mg/kg体重的化合物的剂量(例如基于75kg的人，剂量为0.75mg至7.5g或15g)。在某些实施方案中，本发明的活性药物成分经过配制，以提供0.01mg/kg至70mg/kg的剂量(例如基于75kg的人，剂量为0.75mg至5.25g)。
在一些实施方案中，EP-4抑制剂的有效剂量为约0.5至约250mg/kg、1至约250mg/kg、约2至约200mg/kg、约3至约120mg/kg、约5至约250mg/kg、约10至约200mg/kg、或约20至约120mg/kg。在一些实施方案中，有效剂量包括约0.5mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、8mg/kg、10mg/kg、20mg/kg、25mg/kg、40mg/kg、50mg/kg、60mg/kg、75mg/kg、100mg/kg、120mg/kg、150mg/kg、175mg/kg、200mg/kg、225mg/kg、250mg/kg和300mg/kg。剂型可以采取各种合适的形式，例如片剂或胶囊，并且有效剂量可以在一个或多个单位剂型(如片剂、胶囊)中提供，并且每天提供1、2或3次，或以例如4、8或12小时的时间间隔全天提供。片剂或胶囊例如可以含有例如10、25、50、75、100、150、200、250、300、350、400、450、500、600、700、800、900、1,000、1,100或1,250mg化合物。举例来说，在一些实施方案中将EP-4抑制剂施予人类对象可以包括在100-1,250、150-1,000、200-800或250-750mg范围的EP-4抑制剂的每日剂量，所述每日剂量可以每天一次全部施用，或者分多份以一定的时间间隔全天施用。也可以制备成液体制剂，使得可以容易地且便利地分配任何剂量。
抗体通常将在施用前与药学上可接受的无毒载体物质(例如生理盐水或磷酸盐缓冲盐水)混合，并且可以使用任何医学上适当的程序施用，所述医学上适当的程序例如包括但不限于静脉内或动脉内施用和注射到脑脊髓液中。在某些情况下，腹膜内、皮内、腔内、鞘内或直接施予肿瘤或为肿瘤供血的动脉可能是有利的。
在一些实施方案中，抗体的有效剂量是约5至约250mg/kg、约10至约 200mg/kg、或约20至约120mg/kg。在一些实施方案中，有效剂量包括5mg/kg、10mg/kg、20mg/kg、25mg/kg、40mg/kg、50mg/kg、60mg/kg、75mg/kg、100mg/kg、120mg/kg、150mg/kg、175mg/kg、200mg/kg、225mg/kg、250mg/kg和300mg/kg。剂型可以采取例如片剂或胶囊的形式，并且有效剂量可以在一个或多个片剂、胶囊等中提供，并且每天提供一次或以例如4、8或12小时的时间间隔全天提供。片剂或胶囊例如可以含有例如10、25、50、75、100、150、200、250、300、350、400、450、500、600、700、800、900或1,000mg抗体。也可以制备液体制剂，使得可以容易地且便利地分配任何剂量。
在一些实施方案中，抗体以有效量施予受试对象。有效量通常是每天0.01mg/kg体重至500mg/kg体重。在一些实施方案中，药学上可接受的组合物可经过配制，使得可以向接受这些组合物的患者施用每天0.01mg/kg体重至200mg/kg体重或0.01mg/kg体重至100mg/kg体重的化合物的剂量(例如基于75kg的人，剂量为0.75mg至7.5g或15g)。在某些实施方案中，本发明的组合物经过配制，以提供0.01mg/kg至70mg/kg的剂量(例如基于75kg的人，剂量为0.75mg至5.25g)。
抗体的有效量可以是例如每剂量0.05mg/kg、0.1mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg或8mg/kg(例如基于75kg的人，剂量为3.75mg至600mg)。
抗体的剂量可以在治疗过程中每周一次、两次、三次、四次、五次或更多次、每周一次、每两周一次、或甚至每三周一次施用。给药时间可以是每天一次、每两天一次、每三天一次、每四天一次、每五天一次、每周一次、每两周一次或每三周一次。可以制备包含抗体的制剂，使得可以容易地且便利地分配任何剂量。
术语“对象”是指哺乳动物对象，并且尤其是人类对象，包括雄性或雌性对象，并且包括新生儿、婴儿、幼儿、青少年、成人或老年人对象，并且进一步包括各种人种和种族，例如高加索人种、非洲人种和亚洲人种。本文中，所述对象患有肿瘤/癌症。在一个实施方案中，不考虑所述肿瘤患者是否表达PD-L1。在另一个实施方案中，所述肿瘤患者是PD-L1表达阳性的肿瘤患者。
术语“可药用盐”是指本发明式I或式II化合物的相对无毒的无机或有机酸盐。这些盐可以在化合物的最终分离和纯化期间原位制备，或者通过将游离形态的经纯化化合物分别与合适的有机酸或无机酸反应并分离如此形成的盐而制备。代表性的酸盐包括(但不限于)乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、右旋樟脑磺酸盐、柠 檬酸盐、环磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖酸盐、硬脂酸盐、琥珀酸盐、丹宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐和昔萘酸盐。在一个实施方案中，药学上可接受的盐是盐酸盐/氯化物盐。
术语“肿瘤”和“癌症”在本文中可互换使用，表示机体局部组织的失控的异常增生。如果不及时进行医疗介入，肿瘤/癌症可以不受控制地生长，并有可能转移到机体其他位置，最终造成机体死亡。
术语“癌症”可以包括由遗传继承的突变引起的癌症。此类癌症的实例包括但不限于乳腺癌、可能与李弗劳明综合征相关的癌症(例如儿童肉瘤、白血病和脑癌)、可能与林奇综合征相关的癌症例如结肠癌、胆管癌、脑癌、子宫内膜癌、肾癌、卵巢癌、胰腺癌、小肠癌、胃癌和输尿管癌、肺癌、黑素瘤、前列腺癌、视网膜母细胞瘤、甲状腺癌和子宫癌。
此外，癌症可以是获得性突变(例如由饮食、环境和/或生活方式引起的突变)或体细胞突变的结果。此类癌症的实例可以包括(但不限于)肾上腺癌、肾上腺皮质癌、膀胱癌、脑癌、原发性脑癌、神经胶质瘤、胶质母细胞瘤、乳腺癌、宫颈癌、结肠癌(非限制性实例包括结肠直肠癌，例如结肠腺癌和结肠腺瘤)、子宫内膜癌、上皮癌、食管癌、胆囊癌、泌尿生殖道癌、头颈癌、肾癌、肝癌、肺癌(非限制性实例包括腺癌、小细胞肺癌和非小细胞肺癌)、淋巴瘤(非限制性实例包括B细胞淋巴瘤、T细胞淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤)、黑素瘤、恶性黑素瘤、恶性类癌、恶性胰腺胰岛素瘤、骨髓瘤、多发性骨髓瘤、卵巢癌、胰腺癌(例如外分泌胰腺癌)、前列腺癌、肾细胞癌、皮肤癌(除了先前提到的癌症以外，例如鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、甲状腺滤泡状癌、威尔姆氏瘤、绒毛膜癌、蕈样肉芽肿病、恶性高钙血症、颈椎增生、白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、毛细胞淋巴瘤、伯基特氏淋巴瘤、急性骨髓性白血病、慢性骨髓性白血病、骨髓增生异常综合征、早幼粒细胞性白血病、慢性粒细胞白血病、急性粒细胞白血病、纤维肉瘤、横纹肌肉瘤、星形细胞瘤、神经母细胞瘤、横纹肌肉瘤、神经鞘瘤、卡波西氏肉瘤、真性红细胞增多症、原发性血小板增多症、霍奇金氏病、非霍奇金氏淋巴瘤、软组织肉瘤、骨源性肉瘤、原发性巨球蛋白血症、精原细胞瘤、畸胎癌、骨肉 瘤、着色性干皮病、角化棘皮瘤和视网膜母细胞瘤。
“转移性癌症”是指其中来自一个器官或身体部分的癌细胞已经(通过“转移”)扩散到另一个非相邻器官或身体部分的癌症。非相邻器官或身体部分处的癌症(“继发性肿瘤”或“转移性肿瘤”)包括来源于癌症或癌细胞已经从该器官或身体部分扩散的器官或身体部分的癌细胞。可以发生继发性肿瘤的部位包括(但不限于)淋巴结、肺、肝、脑和/或骨头。
“PIK3CA突变癌症”是指癌症细胞中PIK3CA基因由于核酸碱基突变导致的氨基酸变化，这一变化最终导致PI3K细胞传导信号的异常，突变位点包括但不限于H1047R,E542K and E545K。
本文中，术语“可药用”和“药学上可接受”可互换使用，是指制药领域技术人员一般接受的类型。例如可药用盐、可药用载体等。
“口服剂型”是指经制备用于通过口服施用途径用于个体的药物制剂。已知的口服剂型的实例包括但不限于片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂等。在一些方法，粉末、丸剂、颗粒、胶囊和片剂可经适宜聚合物或常用包衣材料包被以达到(例如)在胃肠中的更高稳定性或达到期望释放速率。此外，粉末、丸剂或颗粒的胶囊壳经进一步包被。片剂可以刻痕以促进给药分割。
本发明所述的式I或式II化合物作为口服制剂施用时，其优选地被膜包被。适宜膜为本领域已知且可自市场购得或可根据已知方法来制造。通常，膜衣材料是亲水聚合物，例如聚乙二醇、聚乙烯吡咯啶酮、聚乙烯醇、羟丙基纤维素、羟甲基纤维素和羟丙基甲基纤维素等。膜衣组合物成份可包括常用量的增塑剂，例如聚乙二醇、柠檬酸三乙酯、邻苯二甲酸二乙酯、丙二醇、甘油；以及遮光剂，例如二氧化钛和着色剂，例如氧化铁，铝色淀等。通常，膜衣材料是以例如可提供介于固体口服剂剂型的1％至6％范围内的膜衣的量来施加。
本发明式I或式II化合物作为口服制剂施用时，可任选地进一步包含至少一种用于药物的药学上可接受的载体。“药学上可接受的载体”是指实质上不具有生物活性且构成制剂的实质性部分的任何药学上的惰性材料。这些载体的实例包括但不限于稀释剂和填充剂、崩解剂、助流剂、黏合剂、稳定剂、着色剂、增味剂和防腐剂。
作为稀释剂，可以选择的是例如但不限于：微晶纤维素、甘露醇、粉糖、可压制糖、葡聚糖、糊精、石旋糖、乳糖、纤维素粉末、山梨醇、蔗糖和滑石粉或其组合。其中，稀释剂可以基于口服制剂总重量的5％至90％，优选为10％ 至80％，20％-70％，30％-60％，40％-50％。
作为崩解剂，可以选择的是例如但不限于：纤维素、藻酸盐、树胶、交联聚合物，例如交联聚乙烯吡咯啶酮或交聚维酮、交联羧甲基纤维素钠、交联羧甲基纤维素钙、大豆多糖、淀粉羟乙酸钠、瓜尔胶或其任意组合。
其中，稀释剂可以基于口服制剂总重量约1％至15％，优选为2％至10％的量存在。
作为黏合剂，可以选择的是例如但不限于淀粉、纤维素或其衍生物，例如微晶纤维素、羟丙基纤维素、羟乙基纤维素和羟丙基甲基纤维素、蔗糖、右旋糖、玉米糖浆、多糖、明胶或其任意组合。其中，黏合剂可以基于制剂总重量的0.01至10％，优选为1％-10％的量存在。
作为助流剂，可以选择的是例如但不限于胶体二氧化硅、三硅酸镁、纤维素粉末、滑石粉或其组合。助流剂可以基于组合物的总重量的0.1％至10％，优选为0.1％-0.5％的量存在。
除非另有说明，否则如本文所用术语“包含”和“包括”具有开放性和非限制性含义。例如，除本发明的PI3K抑制剂、PGE2受体抑制剂与PD-1抑制剂所形成的药物组合之外，还可以包含其它治疗剂，例如“生物治疗剂”、“化学治疗剂”。
其中，“生物治疗剂”是指生物分子，例如抗体或融合蛋白，其在支持肿瘤维持和/或生长或抑制肿瘤免疫应答的任何生物通路中阻断配体/受体性。例如“生物治疗剂”包括但不限于：阿仑单抗、贝伐单抗、贝伦妥单抗维多汀、卡妥索单抗、西妥昔单抗、地诺单抗、吉妥珠单抗、伊匹单抗、尼妥珠单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、纳武利尤单抗、阿替珠单抗、度伐单抗、阿维单抗。
其中，“化学治疗剂”是可以用于癌症治疗的化学化合物，包括但不限于烷化剂、抗代谢物、激酶抑制剂、纺锤体毒素植物生物碱、细胞毒性/抗肿瘤生物素、拓扑异构酶抑制剂、光敏剂、抗雌激素和选择性雌激素受体调节剂、芳香酶抑制剂、EGFR抑制剂、VEGF抑制剂、抑制与细胞增殖异常或肿瘤生长有关的基因表达的反义寡核苷酸。例如，化学治疗剂的实例包括但不限于苯丁酸氮芥、美法仑、环磷酰胺、异环磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲佐菌素、顺铂、卡铂、奥沙利铂、达卡巴嗪、替莫唑胺、丙卡巴肼、甲氨蝶呤、氟尿嘧啶、阿糖胞苷、吉西他滨、巯基嘌呤、氟达拉滨、长春碱、长春新碱、长春瑞滨、紫杉醇、多西紫杉醇、拓扑替康、伊立替康、依托泊苷、曲贝替定、更生霉素、多柔比星、表柔比星、道诺霉素、米托蒽醌、博来霉素、丝裂霉素C、 伊沙匹隆、他莫昔芬、氟他胺、戈那瑞林类似物、甲地孕酮、强的松、地塞米松、甲泼尼龙、沙利度胺、干扰素α、亚叶酸钙、西罗莫司、西罗莫司脂化物、依维莫司、阿法替尼、alisertib、amuvatinib、阿帕替尼、阿西替尼、硼替佐米、波舒替尼、布立尼布、卡博替尼、西地尼布、crenolanib、克卓替尼、达拉菲尼、达可替尼、达努塞替、达沙替尼、多维替尼、厄洛替尼、foretinib、ganetespib、吉非替尼、依鲁替尼、埃克替尼、伊马替尼、iniparib、拉帕替尼、lenvatinib、linifanib、linsitinib、马赛替尼、momelotinib、莫替沙尼、来那替尼、尼罗替尼、niraparib、oprozomib、olaparib、帕唑帕尼、pictilisib、普纳替尼、quizartinib、瑞格菲尼、rigosertib、rucaparib、鲁索利替尼、塞卡替尼、saridegib、索拉非尼、舒尼替尼、替拉替尼、tivantinib、替沃扎尼、托法替尼、曲美替尼、凡德他尼、维利帕尼、威罗菲尼、维莫德吉、volasertib。
对于本发明的联合治疗的剂量方案的选择取决于多个因素，例如：受治疗的个体的实体血清或组织翻转率、症状水平、整体免疫原性和靶细胞、组织或器官的可接近程度。优选地，剂量方案将递送至患者的每种治疗剂的量最大化，符合可接受的副作用水平。因此，联合治疗中每种生物治疗剂和化学治疗剂的剂量和给药频率部分取决于具体的治疗剂、受治疗的癌症的严重程度和患者的表征。
本发明的联合治疗可以在移除肿瘤的手术前或后施用，也可以在放射治疗之前、期间、或之后施用。
WO2007084786具体阐述了本发明的式I化合物，该化合物或其药学上可接受的盐和其制备工艺公开于WO2007084786的实施例中，其以全文引用方式并入本文中。
WO2012039972具体阐述了本发明的式II化合物，该化合物或其药学上可接受的盐和其制备工艺公开于WO2012/039972的实施例中，其以全文引用方式并入本文中。
以下通过实施例来进一步阐述本发明，但实施例不意味着对本发明的保护范围做任何限定。
在一些实施方案中，PI3K抑制剂、EP-4抑制剂与PD-1抑制剂组合施用导致所述PD-1抑制剂增强，使得例如更小剂量或者更长时间间隔的PD-1抑制剂对于治疗可能是有效的。
“抗体”包括所有类型的免疫球蛋白，包括IgG、IgM、IgA、IgD和IgE或其片段，其可适用于本文所公开的医学用途。抗体可以是单克隆的或多克隆的， 并且可以属于任何物种来源，包括例如小鼠、大鼠、兔、马或人。与本发明中使用的抗体所结合的蛋白质或表位(PD-L1或PD-1)保持特异性结合的抗体片段包括在术语“抗体”的范围内。此类片段可以通过已知技术产生。抗体可以是嵌合的或人源化的，尤其当其用于治疗目的时。抗体可以使用所属领域中已知的方法获得或制备。
为了可以更充分地理解本文中描述的发明，列出以下实施例。应理解这些实施例仅用于说明性目的，而不应解释为以任何方式限制本发明。
具体实施例
实施例1：式I化合物(AN2025)、式II化合物(AN0025)与PD-1抗体的组合疗法治疗小鼠EMT6，CT26肿瘤
材料和方法
试剂和仪器：AN0025购买自上海喀露蓝科技有限公司；AN2025购买自CSNpharm。针对小鼠的PD-1的抗体(克隆号：RMP1-14)购买自BioXcell。
细胞系：小鼠结肠癌CT26细胞(CRL-2638)、乳腺癌EMT6细胞(CRL-2755)购自美国组织培养中心。所有细胞都在补充有10％胎牛血清的RPMI-1640(CT26)或者Waymouth’s(1x)MB 752/1(EMT6)培养基中在培养箱中以37℃和5％二氧化碳条件培养，并每周传代培养两次，直至获得必需数量的用于接种小鼠的细胞。
动物：6-8周的BalB/c雌性小鼠购自上海斯莱克实验动物技术有限公司。动物被圈养在微型隔离笼中，每笼最多5只，执行12h光/暗循环。笼每周更换两次。每周观察一次动物并记录临床征象。
动物研究：收获体外培养的癌细胞，分别以2.0×10 5细胞(CT26)/ml的细胞浓度和2.5×10 5细胞(EMT6)/ml的细胞浓度悬浮于100μl磷酸盐缓冲盐水中，并使用注射器在右侧前肢背部皮下(sc)注入小鼠体内。在细胞植入后的6-7天，基于肿瘤大小随机分配小鼠，对于EMT6模型，采用AN2025给药：30mg/kg，每天口服(PO)一次。AN0025给药：150mg/kg，每天口服(PO)一次。PD-1抗体给药：10mg/kg，每周腹腔注射(IP)两次的方式进行给药；对于CT26模型，采用AN2025给药：30mg/kg，每天口服(PO)一次。AN0025给药：100mg/kg， 每天口服(PO)一次。PD-1抗体给药：10mg/kg，每周腹腔注射(IP)两次的方式进行给药。在各个研究中被分配到治疗组的动物在所有组别中都具有接近的平均肿瘤重量。用数显卡尺每周2-3次测量肿瘤大小，并使用公式(l×w 2)/2＝mm 3计算体积，其中l和w是指在每次测量中收集的较大和较小正交尺寸。使用GraphPad Prism 6软件绘制群组肿瘤大小(平均±SEM)对比时间的曲线图。使用Independent Sample t检验进行分析进行统计分析。
实验结果
如图1，图2所示，尽管AN0025和PD-1抗体联用以及AN2025与PD-1抗体联用在小鼠乳腺癌EMT6模型和小鼠结直肠癌CT26模型上都体现出了一定的抗肿瘤活性；但是三者联用，即AN2025，AN0025和PD-1抗体三联所带来的抗肿瘤活性显著优于AN0025和PD-1抗体(p<0.05)以及AN2025与PD-1抗体(p<0.05)二联活性。
实施例2：AN2025、AN0025与PD-1抗体的组合疗法治疗PBMC免疫系统人源化小鼠HCT116肿瘤
材料和方法
试剂和仪器：AN0025购买自上海喀露蓝科技有限公司；AN2025购买自CSNpharm。针对人的PD-1的抗体(Pembrolizumab)由菲诺克生物科技有限公司提供。human PBMC购买自妙顺(上海)生物科技有限公司。
细胞系：HCT116人结肠癌细胞购自中科院细胞库。细胞在补充有10％胎牛血清的McCoy's 5a培养基中在培养箱中以37℃和5％二氧化碳条件培养，并每周传代培养两次，直至获得必需数量的用于接种小鼠的细胞。
动物：6-8周的NPSG雌性小鼠购自PNK。动物被圈养在IVC隔离笼中，每笼5只，执行12h光/暗循环。温度20～26℃，湿度30-70％。
动物研究：NPSG小鼠以human PBMC 5x10 6/100ul的接种量，IV注射。接种6天后，在小鼠右侧肩部皮下接种HCT116细胞，接种量1×10 6/mice。接种后，每周1次测量肿瘤体积及体重，当平均肿瘤体积达到约80-100mm 3时测量小鼠 血液中hCD45+细胞比例。依据肿瘤体积和小鼠血液中hCD45+细胞比例，将小鼠分别随机分为6组，每组10只。分组时肿瘤体积变异系数CV应≤30％(CV＝标准偏差/平均值)。分组后即开始给药。AN2025给药：37.5mg/kg，每天口服(PO)一次。AN0025给药：30mg/kg，每天口服(PO)一次。PD-1抗体给药：10mg/kg，每周腹腔注射(IP)两次。给药开始后，小鼠每周2次测量体重及肿瘤体积。每周1次流式监控小鼠血液中hCD45+细胞比例。在各个研究中被分配到治疗组的动物在所有组别中都具有接近的平均肿瘤重量。肿瘤大小使用公式(l×w 2)/2＝mm 3计算体积，其中l和w是指在每次测量中收集的较大和较小正交尺寸。对于两两两比较，采用T-Test分析方法，对于三个以上的组相互比较，采用单因素方差分析(One-Way ANOVA)方法进行分析。对于比较潜在的协同效应，采用双因素方差分析(Two-Way ANOVA)。所有的数据使用SPSS 24.0。p值小于0.05视为有显著差异。
实验结果
尽管AN0025和PD-1抗体联用以及AN2025与PD-1抗体联用在PBMC免疫系统人源化小鼠HCT116肿瘤体现出了一定的抗肿瘤活性；但是三者联用，即AN2025、AN0025和PD-1抗体三联所带来的抗肿瘤活性显著优于AN0025和PD-1抗体(p<0.05)以及AN2025与PD-1抗体(p<0.01)二联活性。

Claims (38)

  1. 一种在有此需要的对象中治疗肿瘤/癌症和/或产生针对肿瘤/癌症的记忆免疫应答的方法，包括向所述对象施用有效量的PI3K抑制剂、前列腺素受体(PGE2)抑制剂以及PD-1抑制剂，其中，所述PI3K抑制剂、前列腺素受体(PGE2)抑制剂和所述PD-1抑制剂可以作为单一制剂(Dosage form)同时、分开或者顺序施用。
  2. 如权利要求1所述的方法，其中所述PI3K抑制剂选自PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ亚型抑制剂。
  3. 如权利要求1或2所述的方法，其中所述PI3K抑制剂选自Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003和其任意组合。
  4. 如权利要求1-3任意一项所述的方法，其中所述PI3K抑制剂是具有式(I)的化合物或者其药学上可接受的盐，
    Figure PCTCN2021134189-appb-100001
  5. 如权利要求1-4任意一项所述的方法，其中所述前列腺素受体(PGE2)抑制剂包括EP-1，EP-2，EP-3和EP-4抑制剂。
  6. 如权利要求1-5任意一项所述的方法，其中所述前列腺素受体(PGE2)选自具有式(II)的化合物或者其药学上可接受的盐，
    Figure PCTCN2021134189-appb-100002
  7. 如权利要求1-6任意一项所述的方法，其中所述PD-1抑制剂包括PD-1/PDL-1抗体疗法。
  8. 如权利要求1-7任意一项所述的方法，其中所述PD-1抑制剂选自：PD-1抗体、PD-L1抗体和PD-L2抗体；优选地，其中所述PD-1抑制剂选自Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗和其任意组合物。
  9. 如权利要求1-8任意一项所述的方法，其中以经口服、口含或经消化道外途径的剂型施用所述PI3K抑制剂，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。
  10. 如权利要求1-9任意一项所述的方法，其中每天施用所述PI3K抑制剂1次或2次；或者每2、3、4、5、6、7、8、9或10天或每1、2或3周施用1次所述PI3K抑制剂；或者每周连续5天每天施用1次所述PI3K抑制剂，然后间隔2天。
  11. 如权利要求1-10任意一项所述的方法，其中所述PI3K抑制剂在成年人中以约20mg/天-约200mg/天、约30mg/天-约160mg/天、约60mg/天-约120mg/天的剂量范围施用。
  12. 如权利要求1-11任意一项所述的方法，其中以约0.5至约250mg/kg、1至约250mg/kg、约2至约200mg/kg、约3至约120mg/kg、约5至约250mg/kg、约10至约200mg/kg、或约20至约120mg/kg的有效剂量向所述对象施用所述PI3K抑制剂。
  13. 如权利要求1-12任意一项所述的方法，其中以经口服、口含或经消化道外途径的剂型施用所述前列腺素受体(PGE2)抑制剂，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型。
  14. 如权利要求1-13任意一项所述的方法，其中每天施用所述前列腺素受体(PGE2)抑制剂1次或2次；或者每2、3、4、5、6、7、8、9或10天或每1、2或3周施用1次所述前列腺素受体(PGE2)抑制剂；或者每周连续5天每天施用1次所述前列腺素受体(PGE2)抑制剂，然后间隔2天。
  15. 如权利要求1-14任意一项所述的方法，其中所述前列腺素受体(PGE2)在成年人中以约20mg/天-约2000mg/天、约30mg/天-约1600mg/天、约60mg/天-约1200mg/天或约100mg/天-约1000mg/天的剂量范围施用。
  16. 如权利要求1-15任意一项所述的方法，其中以约0.5至约250mg/kg、1至约250mg/kg、约2至约200mg/kg、约3至约120mg/kg、约5至约250mg/kg、约10至约200mg/kg或约20至约120mg/kg的有效剂量向所述对象施用所述前列腺素受体(PGE2)抑制剂。
  17. 如权利要求1-16任意一项所述的方法，其中以消化道外途径施用所述PD-1抑制剂，例如所述消化道外途径可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药。
  18. 如权利要求1-17任意一项所述的方法，其中所述PD-1抑制剂配制成溶液剂、冻干剂、粉针剂。
  19. 如权利要求1-18任意一项所述的方法，其中以0.05mg/kg、0.1mg/kg、1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg或8mg/kg的有效剂量施用所述PD-1抑制剂。
  20. 如权利要求1-19任意一项所述的方法，其中所述肿瘤/癌症选自PIK3CA突 变的癌症。
  21. 如权利要求1-20任意一项所述的方法，其中所述肿瘤/癌症选自：头和颈鳞状细胞癌、头和颈癌、脑癌、神经胶质瘤、多形性成胶质细胞瘤、神经母细胞瘤、中枢神经系统癌、神经内分泌肿瘤、咽喉癌、鼻咽癌、食管癌、甲状腺癌、恶性胸膜间皮瘤、肺癌、乳腺癌、肝癌、肝细胞瘤、肝胆癌、胰腺癌、胃癌、胃肠道癌、肠癌、结肠癌、结肠直肠癌、肾癌、透明细胞肾细胞癌、卵巢癌、子宫内膜癌、子宫颈癌、膀胱癌、前列腺癌、睾丸癌、皮肤癌、黑色素瘤、白血病、淋巴瘤、骨癌、软骨肉瘤、骨髓瘤、多发性骨髓瘤、骨髓异常增生综合征、骨髓增生性肿瘤、鳞状细胞癌、尤因氏肉瘤、全身性轻链淀粉样变性和梅克尔细胞癌；更优选的，所述淋巴瘤选自：霍奇金淋巴瘤、非霍奇金淋巴瘤、弥漫性大B-细胞淋巴瘤、滤泡性淋巴瘤、原发性纵隔大B-细胞淋巴瘤、套细胞淋巴瘤、小淋巴细胞性淋巴瘤、富含T-细胞/组织细胞的大B-细胞淋巴瘤和淋巴浆细胞性淋巴瘤，所述肺癌选自：非小细胞肺癌和小细胞肺癌，所述白血病选自：慢性髓细胞样白血病、急性髓细胞样白血病、淋巴细胞白血病、成淋巴细胞性白血病、急性成淋巴细胞性白血病、慢性淋巴细胞性白血病和髓样细胞白血病。
  22. 一种药物组合物和/或药物组合，其包含PI3K抑制剂、前列腺素受体(PGE2)抑制剂和PD-1抑制剂，以及可药用载体。
  23. 如权利要求22所述的药物组合物和/或药物组合，其中所述PI3K抑制剂选自PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ亚型抑制剂。
  24. 如权利要求22或23所述的药物组合物和/或药物组合，其中所述PI3K抑制剂选自Idelalisib、Copanlisib、Duvelisib、Alpelisib、Seletalisib、Gedatolisib、Rigosertib sodium、Leniolisib、Umbralisib、Buparlisib(AN2025)、AMG-319、GM-604、Acalisib、Bimiralisib、GDC-0084、ACP-319、Tenalisib、serabelisib、SF-1126、Nemiralisib、Fimepinostat、LY-3023414、Voxtalisib、Dactolisib、Parsaclisib、GSK-2636771、AZD-8186、ASN-003或其任意组合。
  25. 如权利要求22-24任意一项所述的药物组合物和/或药物组合，其中所述PI3K抑制剂是具有式(I)的化合物或者其药学上可接受的盐，
    Figure PCTCN2021134189-appb-100003
  26. 如权利要求22-25任意一项所述的药物组合物和/或药物组合，其中所述的前列腺素受体(PGE2)抑制剂选自EP-1，EP-2，EP-3和EP-4抑制剂。
  27. 如权利要求22-26任意一项所述的药物组合物和/或药物组合，其中所述EP-4抑制剂是具有式(II)的化合物或者其药学上可接受的盐。
    Figure PCTCN2021134189-appb-100004
  28. 如权利要求22-27任意一项所述的药物组合物和/或药物组合，其中所述PD-1抑制剂选自：PD-1抗体、PD-L1抗体和PD-L2抗体；优选地，其中所述PD-1抑制剂选自Nivolumab、Pembrolizumab、Atezolizumab、Avelumab、Durvalumab、Tremelimumab、特瑞普利单抗、信迪利单抗、替雷利珠单抗、卡瑞利珠单抗或其任意组合物。
  29. 如权利要求22-28任意一项所述的药物组合物和/或药物组合，其中所述PI3K抑制剂、前列腺素受体(PGE2)抑制剂和PD-1抑制剂可以处于同一和/或分开的剂型(dosage form)中。
  30. 如权利要求22-29任意一项所述的药物组合物和/或药物组合，其中所述的PI3K抑制剂可以配制成以经口服、口含或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、 腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型，例如可以是溶液剂、粉针剂或冻干剂。
  31. 如权利要求22-30任意一项所述的药物组合物和/或药物组合，其中所述的前列腺素受体(PGE2)抑制剂可以配制成以经口服、口含或经消化道外途径的剂型，例如所述口服途径的剂型可以是片剂、胶囊、粉末、丸剂、颗粒、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂，例如所述消化道外途径的剂型可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药的剂型，例如可以是溶液剂、粉针剂或冻干剂；和/或
  32. 如权利要求22-31任意一项所述的药物组合物和/或药物组合，其中所述PD-1抑制剂可以配制成以消化道外途径施用的剂型，例如所述消化道外途径可以是静脉内、腹膜内、皮内、皮下、肌肉、颅内、鞘内、瘤内、经皮渗透、经粘膜给药，例如可以是溶液剂、粉针剂或冻干剂。
  33. 如权利要求22-32任意一项所述的药物组合物和/或药物组合，其中每单位剂型(unit dosage form)中包含1-1000mg剂量的PI3K抑制剂，例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000mg或以上任意两个数值之间的值。
  34. 如权利要求22-33任意一项所述的药物组合物和/或药物组合，其中每单位剂型(unit dosage form)中包含1-1000mg剂量的前列腺素受体(PGE2)抑制剂，例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000mg或以上任意两个数值之间的值。
  35. 如权利要求22-34任一项所述的药物组合物和/或药物组合，其中每单位剂型 中包含1-5000mg剂量的PD-1抑制剂，例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、75、80、90、100、110、120、125、130、140、150、160、170、175、180、190、200、250、300、350、400、450、500、600、700、750、800、900、1000、1100、1200、1300、1400、1500、1600、1700、1800、1900、2000、2200、2400、2500、2600、2700、2750、2800、3000、3500、4000、4500、5000mg或以上任意两个数值之间的值。
  36. 如权利要求22-35任意一项所述的药物组合物和/或药物组合，其用于治疗肿瘤/癌症和/或产生针对肿瘤/癌症的记忆免疫应答。
  37. 如权利要求22-35任意一项所述的药物组合物和/或药物组合用于制备治疗肿瘤/癌症和/或产生针对肿瘤/癌症的记忆免疫应答的药物的用途。
  38. 一种药盒，其包含权利要求22-35任意一项所述的药物组合物和/或药物组合，以及使用说明，其中所述PI3K抑制剂、前列腺素受体(PGE2)抑制剂和PD-1抑制剂可以处于同一和/或分开的容器中。
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