[go: up one dir, main page]

WO2025223372A1 - Combinaison comprenant un inhibiteur de pd-1 et un composé de pyridine destiné à être utilisé dans le traitement de tumeurs solides - Google Patents

Combinaison comprenant un inhibiteur de pd-1 et un composé de pyridine destiné à être utilisé dans le traitement de tumeurs solides

Info

Publication number
WO2025223372A1
WO2025223372A1 PCT/CN2025/090198 CN2025090198W WO2025223372A1 WO 2025223372 A1 WO2025223372 A1 WO 2025223372A1 CN 2025090198 W CN2025090198 W CN 2025090198W WO 2025223372 A1 WO2025223372 A1 WO 2025223372A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
inhibitor
compound
tumor
day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/090198
Other languages
English (en)
Inventor
Junqing Li
Yuxuan ZHANG
Shizhen SU
Jianjia ZHENG
Ruyong WANG
Guangming Chen
Xinshan Kang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujian Haixi Pharmaceuticals Co Ltd
Original Assignee
Fujian Haixi Pharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujian Haixi Pharmaceuticals Co Ltd filed Critical Fujian Haixi Pharmaceuticals Co Ltd
Publication of WO2025223372A1 publication Critical patent/WO2025223372A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • the present disclosure relates to a combination treatment method and pharmaceutical composition, comprising administering to a subject in need a multi-target inhibitor of CSF-1 R, DDRs, and VEGFR2, and a PD-1 inhibitor.
  • TAM Tumor-associated macrophages
  • TAM Tumor-associated macrophages
  • TAM Tumor-associated macrophages
  • TAM has a dominant role in tumor growth and progression, and is a new therapeutic direction with great potential.
  • the tumor-promoting function of TAM is based on the ability to secrete provascular growth factors and growth factors, and the ability to effectively inhibit T cell effector function through the release of immunosuppressive cytokines.
  • the regulation of TAM is very complex and influenced by various mechanisms and the microenvironment of macrophages.
  • colony-stimulating factor 1 is one of the main regulators of the survival, proliferation and differentiation of mononuclear phagocytes/macrophages, which can maintain the pro-tumorigenesis function of TAM.
  • CSF-1 can recruit peripheral blood monocytes to the TME, differentiate into macrophages, bind to the CSF-1 receptor, and polarize macrophages to TAM, which is important in tumor progression, immune escape, and resistance to ICB therapy.
  • TME tumor microenvironment
  • TAMs tumor-associated macrophages
  • M2 subtype TAM promotes tumor development by secreting anti-inflammatory cytokines (such as IL-10, TGF ⁇ )
  • activated M1 subtype TAM promotes immune-mediated tumor killing by producing pro-inflammatory cytokines.
  • existing therapeutic strategies focus on depletion of TAM in the tumor microenvironment and reprogramming of TAM to drive antitumor function (resulting in polarization of M2 to M1) .
  • the macrophage colony-stimulating factor receptor (CSF-1R) kinase is the product encoded by c-fms of the proto-oncogene, which belongs to the class III receptor tyrosine kinase family along with FLT3, c-kit, and PDGFR.
  • CSF-1R binds to its ligand colony-stimulating factor-1 (CSF-1) and interleukin (IL-34) to activate CSF-1 R, thus playing an important role in the proliferation, differentiation and growth of mononuclear macrophages.
  • CSF-1R ligand colony-stimulating factor-1
  • IL-34 interleukin
  • the macrophages When combined with its ligand CSF-1, the macrophages will transform in the direction of tumor promotion, drive immune suppression, and promote the growth of tumor cells. Furthermore, high expression of CSF-1R on tumor cells is associated with poor survival of some cancer patients, TableMing tumor dependency and therefore a potential therapeutic target.
  • the development of CSF-1R/CSF-1 inhibitors for the CSF-1R target can effectively reduce the number of TAM in tumor tissue, promote the generation of tumor inhibitory macrophages and help relieve immunosuppression, and promote the penetration of immune cells including T cells and lymphocytes into the tumor group
  • Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) is the primary responder to VEGF signaling, regulating endothelial cell migration and proliferation. It not only governs vascular normalization but also significantly influences the morphological distribution of tumor-associated macrophages (TAMs) and the infiltration of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) into tumor tissues.
  • TAMs tumor-associated macrophages
  • Tregs regulatory T cells
  • MDSCs myeloid-derived suppressor cells
  • Programmed death molecule 1 (programmed death-l, PD-1) is a protein receptor expressed on the surface of T cells found in 1992 and is involved in the apoptotic process.
  • PD-1 belongs to the CD28 family and has 23%amino acid identity with cytotoxic T lymphocyte antigen 4 (cytotoxic T Iymphocyte antigen 4, CTLA-4) , but its expression is different from CTLA, mainly on activated T cells, B cells and myeloid cells.
  • PD-1 has two ligands, namely PD-L1 and PD-L2.
  • PD-L1 is mainly expressed on T cells, B cells, macrophages and dendritic cells (dendritic cell, DC) , and can be upregulated on cells after activation.
  • PD-L2 is relatively restricted and is mainly expressed on antigen-presenting cells, such as activated macrophages and dendritic cells.
  • Anti-PD-1 monoclonal antibody which can maximize the immune system response to tumor by blocking the binding between PD-L1/PD-1, so as to achieve the purpose of killing tumor cells.
  • the present disclosure provides an innovative method for combining a multi-target small molecule inhibitor targeting CSF-1R/DDRs/VEGFR2 with a PD-1 inhibitor.
  • CSF-1R tumor-associated macrophages
  • TAMs tumor-associated macrophages
  • DDRs and VEGFR2 while inhibiting tumor angiogenesis, it "normalizes” the formation of tumor microvessels, thereby increasing the oxygen supply and changing the direction of drug delivery. In this way, it can inhibit and regulate the immune microenvironment around solid tumors, relieve immune suppression. Meanwhile, through the synergistic effect of the PD-1 antibody, a better tumor suppression effect can be achieved.
  • compositions and/or pharmaceutical combination comprising a CSF-1R/DDRs/VEGFR2 multi-target inhibitor, a PD-1 inhibitor, and a pharmaceutically acceptable carrier.
  • the present disclosure provides the following technical solution: a method for preventing and/or treating solid tumors, comprising administering an effective amount of CSF-1R/DDRs/VEGFR2 target inhibitor and PD-1 inhibitor to an individual in need.
  • the present disclosure provides the following technical solution: a composition and/or pharmaceutical combination comprising CSF-1R/DDRs/VEGFR2 target inhibitor, PD-1 inhibitor, and a pharmaceutically acceptable carrier, for use in the treatment of solid tumors.
  • the present disclosure provides the use of the pharmaceutical composition and/or pharmaceutical combination for the manufacture of a medicament for treating tumor/cancer and/or generating a memory immune response against tumor/cancer.
  • the present disclosure provides the use of the pharmaceutical composition and/or pharmaceutical combination in the treatment of solid tumors.
  • the CSF-1R/DDRs/VEGFR2 target inhibitor is a compound having the structure as shown in Formula I, or a pharmaceutically acceptable salt thereof:
  • the compound of Formula I or a pharmaceutically acceptable salt thereof and a PD-1 inhibitor may be combined to form a single administration unit or be independently formulated as separate administration units, and the active ingredients can be administered simultaneously, separately, or sequentially.
  • the PD-1 inhibitor is selected from an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-PD-L2 antibody.
  • the PD-1 inhibitor is selected from Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Sepalimab, Penpulimab, Serplulimab, Putilimab, Pembrolizumab, Nivolumab, biosimilars thereof, biobetters thereof, bioequivalents thereof, or any combination thereof.
  • the solid tumor is selected from a benign solid tumor or a malignant solid tumor.
  • the benign solid tumor is selected from tenosynovial giant cell tumor, hemangioma, leiomyoma, or adenoma.
  • the malignant solid tumor is selected from skin cancer, brain cancer, cervical cancer, ovarian cancer, esophageal cancer, bladder cancer, testicular cancer, osteosarcoma, colorectal cancer, lung cancer, kidney cancer, liver cancer, cholangiocarcinoma, gastric cancer, prostate cancer, head and neck squamous cell carcinoma, or pancreatic cancer.
  • the malignant solid tumor is selected from colorectal cancer, gastric cancer, esophageal squamous cell carcinoma, pancreatic cancer, head and neck squamous cell carcinoma, or osteosarcoma.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof may be formulated into dosage forms for oral, buccal, or parenteral administration.
  • the oral dosage forms may be selected from tablets, capsules, powders, pills, granules, suspensions, solutions and solution preconcentrates, emulsions and emulsion preconcentrates.
  • the parenteral dosage forms may be selected from intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal, or transmucosal administration, such as solutions, powder injections, or lyophilized preparations.
  • the PD-1 inhibitor is administered via a parenteral route.
  • the parenteral route may be selected from intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal, or transmucosal administration.
  • the PD-1 inhibitor is formulated into a solution, lyophilized preparation, or powder for injection.
  • the compound of Formula I is administered in a dose range of 25 mg/day to 600 mg/day.
  • the compound of Formula I is administered in a dose range of 100 mg/day to 300 mg/day.
  • the PD-1 inhibitor is administered in a dose range of 50 mg/day to 800 mg/day.
  • CSF-1R/DDRs/VEGFR2 target inhibitor refers to an inhibitor that exerts effects on the Colony Stimulating Factor 1 Receptor (CSF-1R) , Discoidin Domain Receptors (DDRs) , and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) targets, including but not limited to compounds represented by Formula I.
  • PD-1 inhibitor refers to "anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-PD-L2 antibodies” , which are antibodies targeting programmed death protein-1 (PD-1) , programmed death ligand-1 (PD-L1) , or programmed death ligand-2 (PD-L2) .
  • the exemplary antibodies include, but are not limited to, those disclosed in U.S. 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 further comprise Nivolumab, Pembrolizumab, Atezolizumab, Avelumab, Durvalumab, Tremelimumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab and any combinations thereof.
  • solid tumor encompasses both benign and malignant solid tumors. Different types of solid tumors are named based on the cell types from which they originate.
  • solid tumor excludes leukemia (blood cancer) .
  • a "sarcoma” refers to cancer arising from connective or supportive tissues (e.g., bone or muscle) .
  • Carcinomas are cancers originating from glandular or epithelial cells lining human tissues. Since these cells are present in most tissues, lymphomas may occur in multiple organs.
  • Exemplary benign solid tumors primarily include hamartomas, leiomyomas, hemangiomas, lymphangiomas, and various adenomas and adenomatous polyps.
  • Malignant solid tumors include, but are not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma, pancreatic cancer, head and neck malignancies, urothelial malignancies, endometrial carcinoma, cervical cancer, osteosarcoma, chondrosarcoma, Ewing's sarcoma, thyroid carcinoma, hepatoblastoma, and nephroblastoma.
  • treat refers to alleviating, suppressing, and/or reversing the progression of diseases (e.g., tumors/cancer) in subjects in need.
  • treatment encompasses any indication of successful therapy or improvement of a disease, including objective or subjective parameters such as mitigation, alleviation, symptom reduction, or enhancing the subject's tolerance to injuries, pathologies, or conditions. It may also involve delaying or slowing the rate of disease progression.
  • the measurement of treatment or improvement can be based on results from physical examinations, pathological tests, and/or diagnostic examinations, as recognized in the relevant medical field.
  • treating cancer refers to administering a combination therapy comprising a CSF-1R/DDRs/VEGFR2 target inhibitor and a PD-1 inhibitor to a subject with cancer.
  • This aims to achieve at least one positive therapeutic outcome, such as reduced cancer cell count, diminished tumor size, decreased tumor cell infiltration into peripheral organs, or slowed tumor metastasis or growth rate.
  • treatment may also involve reducing the risk of disease onset or occurrence, or lowering the likelihood of recurrence (e.g., prolonging relapse-free intervals) compared to outcomes without such intervention. In medical contexts, this approach is termed “prophylaxis" or “preventive care” .
  • the term “effective amount” or “therapeutically effective amount” refers to a quantity that can effectively treat a disease as recorded through clinical testing and evaluation, patient observation, or other scientifically validated methods.
  • the "effective amount” may further denote a measurable change in biological or chemical activity that can be detected and/or quantified by those skilled in the art using established mechanisms or methodologies.
  • the "effective amount” indicates a dosage sufficient to maintain a desired physiological state (i.e., reducing or preventing significant functional decline and/or promoting disease amelioration) . This term may also specifically refer to the therapeutic dosage required for achieving clinically meaningful outcomes.
  • subject refers to a mammalian subject, particularly a human subject, including male or female subjects, and encompasses neonates, infants, children, adolescents, adults, or elderly subjects, further comprising various ethnicities and races such as Caucasian, African, and Asian.
  • the subject is diagnosed with a tumor/cancer.
  • the PD-L1 expression status of the tumor patient is not considered.
  • the tumor patient is PD-L1 -positive.
  • pharmaceutically acceptable salt refers to a relatively non-toxic inorganic or organic acid salt of the compound of Formula I according to the present disclosure. These salts may be prepared in situ during the final isolation and purification of the compound or by reacting the purified free-form compound with a suitable organic or inorganic acid and isolating the resulting salt.
  • Representative acid salts include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, d-camphorsulfonate, citrate, cyclohexylsulfamate, disulfamate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafiuorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • malignant tumor and “cancer” as used herein refer to uncontrolled abnormal proliferation of local tissue cells in the body. Without timely medical intervention, such malignant tumors/cancer may grow uncontrollably and potentially metastasize to other parts of the body, ultimately resulting in systemic organ failure and death.
  • cancer may encompass malignancies arising from inherited genetic mutations.
  • examples of such cancers include, but are not limited to: cancers associated with li-fraumeni syndrome (e.g., pediatric sarcomas, leukemia, and brain tumors) , cancers linked to lynch syndrome, including colorectal cancer, cholangiocarcinoma, glioblastoma, endometrial cancer, renal cell carcinoma, ovarian cancer, pancreatic cancer, small intestinal cancer, gastric cancer, and ureteral carcinoma, lung cancer, melanoma, prostate cancer, retinoblastoma, thyroid cancer, uterine cancer.
  • li-fraumeni syndrome e.g., pediatric sarcomas, leukemia, and brain tumors
  • cancers linked to lynch syndrome including colorectal cancer, cholangiocarcinoma, glioblastoma, endometrial cancer, renal cell carcinoma, ovarian cancer, pancreatic cancer, small intestinal cancer,
  • cancer may result from acquired mutations (e.g., dietary, environmental, or lifestyle-induced) or somatic mutations.
  • Representative examples include: Adrenal cortical carcinoma, bladder cancer, primary brain tumors (e.g., gliomas, glioblastoma) , cervical cancer, colorectal cancer (including adenocarcinoma and adenoma subtypes) , endometrial carcinoma, esophageal cancer, gallbladder carcinoma, genitourinary tract tumors, head and neck cancers, hepatocellular carcinoma, lung cancer subtypes (adenocarcinoma, small cell lung cancer, non-small cell lung cancer) , lymphomas (b-cell, t-cell, hodgkin, non-hodgkin) , malignant melanoma, neuroendocrine tumors (e.g., pancreatic insulinoma) , multiple myeloma, ovarian epithelial cancer, pancreatic exocrine
  • pharmaceutically acceptable and “pharmaceutically suitable” are interchangeable, denoting categories generally recognized by pharmaceutical technical personnel. Representative examples include pharmaceutically acceptable salts and pharmaceutically acceptable carriers.
  • antibody encompasses all immunoglobulin types, including IgG, IgM, IgA, IgD, and IgE, or their fragments, applicable to the medical uses disclosed herein. Antibodies may be monoclonal or polyclonal and may originate from any species, including but not limited to murine, rat, rabbit, equine, or human. The scope of the term “antibody” includes antibody fragments that retain specific binding to proteins or epitopes (e.g., programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) ) targeted by the antibodies employed in the present disclosure.
  • PD-L1 programmed death ligand 1
  • PD-1 programmed cell death protein 1
  • Antibodies may be chimeric or humanized, particularly when intended for therapeutic applications.
  • the antibodies may be obtained or prepared using standard methods known in the art, such as hybridoma technology, phage display, or transgenic animal platforms.
  • biological therapeutic agent refers to biological molecules (e.g., antibodies or fusion proteins) that block ligand/receptor interactions in any biological pathway supporting tumor maintenance/growth or suppressing tumor immune responses.
  • Examples include, but are not limited to: Alemtuzumab, Bevacizumab, Brentuximab vedotin, Catumaxomab, Cetuximab, Denosumab, Gemtuzumab ozogamicin, Ipilimumab, Nimotuzumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, Nivolumab, Atezolizumab, Durvalumab, Avelumab.
  • chemical therapeutic agent denotes chemical compounds used in cancer treatment, including but not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle toxin plant alkaloids, cytotoxic/antineoplastic antibiotics, topoisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs) , aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, antisense oligonucleotides targeting genes associated with aberrant cell proliferation or tumor growth.
  • alkylating agents include antimetabolites, kinase inhibitors, spindle toxin plant alkaloids, cytotoxic/antineoplastic antibiotics, topoisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs) , aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, antisense oligonucleotides targeting genes associated with aberrant cell proliferation or tumor growth
  • T/C (%) refers to an evaluation index of antitumor activity, specifically the relative tumor proliferation rate.
  • Figure 1 Growth inhibitory effect of compound of Formula I on A20 B-cell lymphoma syngeneic graft tumors in BALB/c mice (Mean ⁇ SEM)
  • Figure 2 Effect of compound of Formula I on body weight in a A20 B-cell lymphoma syngeneic graft tumor model using BALB/c mice (Mean ⁇ SEM)
  • Figure 3 Growth inhibitory effect of compound of Formula I on B16-F10 melanoma syngeneic graft tumors in C57BL/6 mice (Mean ⁇ SEM)
  • Figure 4 Effect of compound of Formula I on body weight in a B 16-F 10 melanoma syngeneic graft tumor model using C57BL/6 mice (Mean ⁇ SEM)
  • Figure 5 Growth inhibitory effect of compound of Formula I on MC38 colon cancer syngeneic graft tumors in C57BL/6 mice (Mean ⁇ SEM)
  • Figure 6 Effect of compound of Formula I on body weight in an MC38 colon cancer syngeneic graft tumor model using C57BL/6 mice (Mean ⁇ SEM)
  • the murine B-cell lymphoma A20 cell line was obtained from ATCC.
  • A20 cells were cultured in RPMI 1640 medium (GIBCO, USA) containing 0.05 mM 2-mercaptoethanol and 10%FBS (GIBCO, USA) , under 5%CO2 at 37°C.
  • the murine melanoma B16-F10 cell line was purchased from ATCC.
  • B16-F10 cells were maintained in DMEM medium (GIBCO, USA) with 10%FBS (GIBCO, USA) and cultured at 37°C in a 5%CO2 atmosphere.
  • the murine colon cancer MC38 cell line was acquired from Obio Technology (Shanghai) Co., Ltd. MC38 cells were cultured in DMEM medium (GIBCO, USA) supplemented with 10%FBS (GIBCO, USA) and incubated at 37°C with 5%CO 2 .
  • mice Female BALB/c mice (5 9 weeks old, used in Examples 1) and C57BL/6 mice (5 8 weeks old, used in Examples 2 and 3) were purchased from Vital River Laboratory Animal Technology Co., Ltd. (Shanghai Branch) .
  • mice were inoculated with 1 ⁇ 10 6 cells per animal in a volume of 0.1 mL. When the average tumor volume reached approximately 69 mm 3 , animals with tumors that were excessively large, small, or irregularly shaped were excluded. The remaining mice were stratified into 9 groups (10 mice/group) using a randomized block design based on tumor volume. The day of grouping was designated as Day 0, and dosing commenced according to the average body weight.
  • Example 1 Combination therapy of compound of Formula I and Anti-mPD-1 for mouse B cell lymphoma
  • Example 3 Combination therapy of compound I and Anti-mPD-1 for the treatment of colon cancer in mice
  • the Anti-mPD-1 group As shown in Table 8 and Figure 5, compared with the vehicle group, the Anti-mPD-1 group, different doses of compound of Formula I, and the combination of Anti-mPD-1 with compound of Formula I exhibited significant inhibitory effects on mouse colon cancer.
  • the 5-FU group showed some inhibitory effect on mouse colon cancer, but the T/C ratios were all greater than 40%.
  • Example 4 Safety, tolerability, and efficacy evaluation of compound of Formula I in combination with Sintilimab in patients with advanced malignant solid tumors
  • Sintilimab The administration method of Sintilimab was as follows: a dose of 200 mg every 3 weeks until disease progression or the emergence of intolerable toxicity.
  • Doses are set at l00 mg once daily (QD) , 200 mg QD, and 300 mg QD, using a traditional 3+3 escalation approach.
  • QD dose-limiting toxicity
  • Subsequent dose groups will enroll 3 subjects each until at least 1 DLT occurs; 2) If 1 DLT is observed among the initial 3 subjects in a dose group, 3 additional subjects will be enrolled at the same dose level; 3) Ifno further DLT occurs in the additional 3 subjects (i.e., only 1 DLT in 6 total subjects) , escalate to the next dose group; 4) If ⁇ 2 DLTs occur among the initial 3 subjects or ⁇ 2 DLTs in 6 subjects, stop dose escalation and treat 3 additional subjects at the next lower dose level (if fewer than 6 subjects have been treated at that level) ; 5) Dose escalation within individual subjects is prohibited.
  • Enrollment into a new dose level is permitted only after all 3 subjects in the current dose group complete at least 21 days of treatment; 6) If ⁇ 2 DLTs occur in the first dose group (l00 mg QD) , de-escalate to 50 mg QD or 25 mg QD for further exploration. If the 300 mg QD dose does not reach the maximum tolerated dose (MTD) , the Safety Monitoring Committee (SMC) will evaluate preclinical data, existing safety profiles, preliminary antitumor activity, pharmacokinetic (PK) data, and effective doses observed in domestic and international counterparts to determine whether to escalate to 400 mg QD. Additional dose levels beyond the predefined range may be explored based on comprehensive data analysis.
  • Tumor types included colorectal cancer (7 pts) , non-small cell lung cancer (NSCLC, 2 pts) , and cervical cancer (1 pts) .
  • the median number of prior systemic therapies was 3 (range: 1-7) .
  • Safety and efficacy were evaluated in all patients. No dose-limiting toxicities (DLTs) were observed within the l00-300 mg QD dose range, and the maximum tolerated dose (MTD) was not reached.
  • DLTs dose-limiting toxicities

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne l'utilisation d'un inhibiteur ciblant CSF-1R/DDR/VEGFR2 en combinaison avec un inhibiteur de PD-1 dans le traitement de tumeurs solides. L'inhibiteur ciblant CSF-1R/DDR/VEGFR2 avec un inhibiteur de PD-1 fourni par la présente divulgation est utilisé dans le traitement de tumeurs solides avancées et a de bons effets thérapeutiques.
PCT/CN2025/090198 2024-04-22 2025-04-21 Combinaison comprenant un inhibiteur de pd-1 et un composé de pyridine destiné à être utilisé dans le traitement de tumeurs solides Pending WO2025223372A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410486771.X 2024-04-22
CN202410486771 2024-04-22

Publications (1)

Publication Number Publication Date
WO2025223372A1 true WO2025223372A1 (fr) 2025-10-30

Family

ID=95933707

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/090198 Pending WO2025223372A1 (fr) 2024-04-22 2025-04-21 Combinaison comprenant un inhibiteur de pd-1 et un composé de pyridine destiné à être utilisé dans le traitement de tumeurs solides

Country Status (1)

Country Link
WO (1) WO2025223372A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7029674B2 (en) 2001-04-02 2006-04-18 Wyeth Methods for downmodulating immune cells using an antibody to PD-1
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
US8354509B2 (en) 2007-06-18 2013-01-15 Msd Oss B.V. Antibodies to human programmed death receptor PD-1
US8617546B2 (en) 2008-10-02 2013-12-31 Seoul National University Industry Foundation Anticancer agent comprising anti-PD-1 antibody or anti-PD-L1 antibody
US8709417B2 (en) 2009-09-30 2014-04-29 Memorial Sloan-Kettering Cancer Center Combination immunotherapy for the treatment of cancer
WO2019174601A1 (fr) * 2018-03-15 2019-09-19 Fujian Haixi Pharmaceuticals Co., Ltd Composés hétéroaryle utilisés en tant qu'inhibiteur de kinase
WO2025103436A2 (fr) * 2023-11-17 2025-05-22 Fujian Haixi Pharmaceuticals Co., Ltd. Traitements du sarcome à l'aide d'inhibiteurs multi-cibles csf-1r/pdgfr

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7029674B2 (en) 2001-04-02 2006-04-18 Wyeth Methods for downmodulating immune cells using an antibody to PD-1
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
US7521051B2 (en) 2002-12-23 2009-04-21 Medimmune Limited Methods of upmodulating adaptive immune response using anti-PD-1 antibodies
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
US8354509B2 (en) 2007-06-18 2013-01-15 Msd Oss B.V. Antibodies to human programmed death receptor PD-1
US8617546B2 (en) 2008-10-02 2013-12-31 Seoul National University Industry Foundation Anticancer agent comprising anti-PD-1 antibody or anti-PD-L1 antibody
US8709417B2 (en) 2009-09-30 2014-04-29 Memorial Sloan-Kettering Cancer Center Combination immunotherapy for the treatment of cancer
WO2019174601A1 (fr) * 2018-03-15 2019-09-19 Fujian Haixi Pharmaceuticals Co., Ltd Composés hétéroaryle utilisés en tant qu'inhibiteur de kinase
WO2025103436A2 (fr) * 2023-11-17 2025-05-22 Fujian Haixi Pharmaceuticals Co., Ltd. Traitements du sarcome à l'aide d'inhibiteurs multi-cibles csf-1r/pdgfr

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PRZYSTAL JUSTYNA M. ET AL: "Targeting CSF1R Alone or in Combination with PD1 in Experimental Glioma", CANCERS, vol. 13, no. 10, 1 May 2021 (2021-05-01), CH, pages 2400, XP093296546, ISSN: 2072-6694, Retrieved from the Internet <URL:https://www.mdpi.com/2072-6694/13/10/2400/pdf> DOI: 10.3390/cancers13102400 *
VESSEY BRYNN: "M2-like TAMs tamed by anti-CSF1R and anti-PD-1 combination therapy", 9 May 2018 (2018-05-09), XP093296541, Retrieved from the Internet <URL:https://acir.org/weekly-digests/2018/may/m2-like-tams-tamed-by-anti-csf1r-and-anti-pd-1-combination-therapy> *
YANG YUNPENG ET AL: "Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11)", vol. 15, no. 10, 8 August 2020 (2020-08-08), pages 1636 - 1646, XP055903186, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/article/pii/S1556086420305955/pdfft?md5=747db300df497e7f625b5f5742064a8e&pid=1-s2.0-S1556086420305955-main.pdf> DOI: 10.1016/j.jtho.2020.07.014 *

Similar Documents

Publication Publication Date Title
AU2020388848A1 (en) Use of FAK inhibitor in preparation of drug for treating tumors having NRAS mutation
CN113613674B (zh) 治疗小细胞肺癌的联用药物组合物
RS65474B1 (sr) Primena riluzola, prolekova riluzola ili analoga riluzola sa imunoterapijama za lečenje kancera
KR102088469B1 (ko) Mek 억제제 및 igf1r 억제제의 병용 요법
CN110536703A (zh) 使用抗axl抗体-药物缀合物的组合疗法
CN110730663B (zh) 阿帕替尼和c-Met抑制剂联合在制备治疗肿瘤的药物中的用途
WO2018223923A1 (fr) Utilisation d&#39;un anticorps pd-1 combiné avec un ligand vegf ou un inhibiteur du récepteur vegf dans la préparation d&#39;un médicament pour le traitement d&#39;une tumeur
TW202241440A (zh) 預防或治療抗腫瘤劑相關疾病或病症的方法
CN110636861B (zh) 用于治疗癌症的包含小分子csf-1r抑制剂和特异性地结合cd40的激动性抗体的协同疗法
CN108350080A (zh) 用于癌症的联合疗法
EP4252774A1 (fr) Polythérapie pour traiter un cancer à mutation pik3ca
WO2020249018A1 (fr) Composition pharmaceutique combinée pour le traitement du cancer du poumon positif aux gènes &#34;conducteurs&#34;
CN112168961A (zh) 治疗结直肠癌的联用药物组合物
WO2020233602A1 (fr) Dérivé de quinoléine utilisé pour le traitement combiné du cancer du poumon à petites cellules
BR112021000169A2 (pt) Ministração de inibidor de enzima ativadora de sumo e anticorpos anti-cd20
CN120437288A (zh) 治疗卵巢癌的药物组合
CN112043831A (zh) 用于联合治疗乳腺癌的喹啉类化合物
WO2025223372A1 (fr) Combinaison comprenant un inhibiteur de pd-1 et un composé de pyridine destiné à être utilisé dans le traitement de tumeurs solides
EP3930719B1 (fr) Administration d&#39;inhibiteur d&#39;enzyme d&#39;activation sumo et inhibiteurs de points de contrôle
TW202133848A (zh) 作為bcl-2抑制劑的n-(苯基磺醯基)苯甲醯胺及相關化合物
US20230112450A1 (en) Combined use of ctb006 and ponatinib
US20110129467A1 (en) Therapeutic combination comprising an aurora kinase inhibitor and antiproliferative agents
RU2830077C2 (ru) Введение ингибитора sumo-активирующего фермента и ингибиторов контрольных точек
WO2023078408A1 (fr) Combinaison pharmaceutique contenant un inhibiteur de la tyrosine kinase du récepteur met et son utilisation
CN114470191A (zh) 喹啉衍生物与pd-1单抗的药物组合

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25729042

Country of ref document: EP

Kind code of ref document: A1