WO2021143799A1 - Utilisation d'un anticorps anti-pd-1 en combinaison avec du fruquintinib dans la préparation de médicaments pour le traitement du cancer - Google Patents

Utilisation d'un anticorps anti-pd-1 en combinaison avec du fruquintinib dans la préparation de médicaments pour le traitement du cancer Download PDF

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WO2021143799A1
WO2021143799A1 PCT/CN2021/071996 CN2021071996W WO2021143799A1 WO 2021143799 A1 WO2021143799 A1 WO 2021143799A1 CN 2021071996 W CN2021071996 W CN 2021071996W WO 2021143799 A1 WO2021143799 A1 WO 2021143799A1
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cancer
antibody
fruquintinib
use according
seq
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Chinese (zh)
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闫洪滨
王斯斯
谢帆
戴秋曦
陈文会
王倩
郭倩
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嘉和生物药业有限公司
和记黄埔医药（上海）有限公司
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Priority to CN202180008488.0A priority Critical patent/CN115003332A/zh
Publication of WO2021143799A1 publication Critical patent/WO2021143799A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to the field of medicine, and more specifically, to the use of an anti-PD-1 antibody or an antigen-binding fragment thereof and fruquintinib or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating cancer.
  • Vascular endothelial cell growth factor (vascular endothelial cell growth factor, VEGF) is currently found to be one of the main inducers related to tumor angiogenesis. Combining with VEGF receptor (VEGFR) can activate angiogenesis, leading to continuous tumor growth and metastasis diffusion. Blocking the VEGF/VEGFR signal transduction pathway can inhibit angiogenesis, thereby inhibiting tumor growth and achieving anti-tumor effects.
  • VEGF vascular endothelial cell growth factor
  • VEGF/VEGFR inhibitors including monoclonal antibody drug bevacizumab and small molecule kinase inhibitor drugs sunitinib, sorafenib, lenvatinib, regofini, and A Xitinib, Fruquintinib and so on.
  • Patent number CN101575333B discloses the VEGFR small molecule inhibitor Fruquintinib (Fruquintinib), the chemical name is 6-(6,7-dimethoxyquinazoline-4-oxo)-N,2-dimethylbenzene Difuran-3-carboxamide, the molecular formula is C 21 H 19 N 3 O 5 , and its structural formula is shown in the following formula:
  • Fruquintinib is a highly selective tumor angiogenesis inhibitor. Its main targets are VEGFR kinase family VEGFR1, VEGFR2 and VEGFR3. It can inhibit VEGFR phosphorylation, thereby inhibiting tumor angiogenesis, and ultimately inhibiting tumor growth. .
  • Programmed death receptors (Programmed Death-1, PD-1) and its ligands PD-L1/L2 are important T-cell negative regulatory immune checkpoints, which regulate the body’s peripheral immune tolerance, which is important for peripheral immunity.
  • Balance plays an important role. Cancer cells can inhibit immune cell activation by highly expressing PD-L1 and binding to the PD-1 receptor on the surface of T-cells, and induce tumor immune tolerance.
  • PD-1/PD-L1 plays a role in tumor immune escape and tumor microenvironment formation. To an important role.
  • the monoclonal antibody drugs represented by targeting PD-1 and its ligand PD-L1 block the PD1/PD-L1 negative immune check site to activate and proliferate T-cells, which can reverse the tumor immunosuppressive microenvironment and enhance resistance Tumor immune response to achieve tumor immunotherapy, thereby effectively inhibiting tumor growth.
  • the anti-PD-1 antibody of Jiahe Biopharmaceutical Industry (CN106573052A discloses the antibody and its preparation method, also referred to as GB226 hereinafter), is currently in clinical phase II, has good safety, and has effective anti-tumor effects.
  • the therapeutic effect of single administration has certain limitations, the drug effect is not obvious, and drug resistance is easy to develop.
  • patients with metastatic colorectal cancer and EGFR-TKI-resistant non-small cell lung cancer who have failed standard treatments are currently treated with very limited treatment options.
  • New treatment methods and drugs are urgently needed to improve the efficacy and prolong the survival of patients.
  • WO2015119930 discloses the use of an anti-PD-1 antibody in combination with axitinib
  • WO2015088847 discloses the use of an anti-PD-1 antibody in combination with pazopanib
  • CN105960415A discloses an anti-PD-1 antibody Use in combination with axitinib.
  • the present invention provides the use of an anti-PD-1 antibody or an antigen-binding fragment thereof and fruquintinib or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating cancer.
  • the aforementioned anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain CDR1 (LCDR1) sequence, which is an amino acid sequence as shown in SEQ ID NO:1, or is similar to the sequence shown in SEQ ID NO:1
  • the amino acid sequence has at least 80% homology, the light chain CDR2 (LCDR2) sequence, which is the amino acid sequence shown in SEQ ID NO: 2, or has at least 80% of the amino acid sequence shown in SEQ ID NO: 2
  • the light chain CDR3 (LCDR3) sequence which is the amino acid sequence shown in SEQ ID NO: 3, or has at least 80% homology with the amino acid sequence shown in SEQ ID NO: 2.
  • Chain CDR1 (HCDR1) sequence, which is the amino acid sequence shown in SEQ ID NO: 4, or has at least 80% homology with the amino acid sequence shown in SEQ ID NO: 4, heavy chain CDR2 (HCDR2) sequence , which is the amino acid sequence shown in SEQ ID NO: 5, or has at least 80% homology with the amino acid sequence shown in SEQ ID NO: 5, and the heavy chain CDR3 (HCDR3) sequence, which is shown in SEQ
  • the amino acid sequence shown in ID NO: 6 or the amino acid sequence shown in SEQ ID NO: 6 has at least 80% homology.
  • the aforementioned anti-PD-1 antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof.
  • the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region sequence, which is an amino acid sequence as shown in SEQ ID NO: 7, or an amino acid sequence as shown in SEQ ID NO: 7
  • the sequence has at least 80% homology.
  • the aforementioned anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence, which is the amino acid sequence shown in SEQ ID NO: 8, or is the same as the amino acid sequence shown in SEQ ID NO: 8 Have at least 80% homology.
  • the heavy chain sequence of the aforementioned anti-PD-1 antibody is the sequence shown in SEQ ID NO: 9, and the light chain sequence is the sequence shown in SEQ ID NO: 10.
  • the aforementioned cancer has one or more of the following characteristics:
  • PD-L1 high microsatellite instability (MSI-H), mismatch repair defect (dMMR) and high tumor mutational burden (TMB).
  • MSI-H high microsatellite instability
  • dMMR mismatch repair defect
  • TMB tumor mutational burden
  • the above-mentioned cancer is lymphoma, leukemia, melanoma, glioma, breast cancer, lung cancer, bowel cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, liver cancer, stomach cancer, testicular cancer, salivary gland cancer, Thyroid cancer, thymus cancer, epithelial cancer, head and neck cancer, pancreatic cancer, prostate cancer, or kidney cancer.
  • the above-mentioned bowel cancer is colon cancer, rectal cancer, large intestine cancer, small intestine cancer or colorectal cancer.
  • the above-mentioned bowel cancer is colorectal cancer.
  • the aforementioned colorectal cancer is metastatic colorectal cancer.
  • the above-mentioned colorectal cancer is microsatellite stable (MSS) and/or mismatch repair function intact or high degree of microsatellite instability and/or mismatch repair defect.
  • MSS microsatellite stable
  • the aforementioned lung cancer is non-small cell lung cancer.
  • the aforementioned non-small cell lung cancer is recurrent or metastatic non-small cell lung cancer with EGFR sensitive mutations.
  • the recurrence or metastatic non-small cell lung cancer of the above-mentioned EGFR-sensitive mutation of the EGFR-sensitive mutation is the failure of EGFR-TKI treatment.
  • the aforementioned non-small cell lung cancer has one or more of the following characteristics:
  • Exon 19 deletion (19DEL), exon 21 point mutation (L858R/L861Q), exon 18 point mutation (G719X) and exon 20 point mutation (S768I).
  • the single administration dose of the aforementioned anti-PD-1 antibody is 0.1-40 mg/kg individual body weight or a single fixed dose of 100-400 mg.
  • the single administration dose of the above-mentioned anti-PD-1 antibody is 3 mg/kg individual body weight or a single fixed dose of 210 mg.
  • the above-mentioned anti-PD-1 antibody is administered once every two weeks.
  • the single administration dose of the above-mentioned anti-PD-1 antibody is 5 mg/kg individual body weight. Preferably, it is administered twice a week.
  • the above-mentioned anti-PD-1 antibody is GB226, and its dosage is 3 mg/kg administered according to the patient's body weight or a fixed dose of 210 mg, administered once every two weeks.
  • the single administration dose of Fruquintinib is 0.1-10 mg/kg individual body weight or a single fixed dose of 0.1-20 mg.
  • the single administration dose of Fruquintinib is 1 mg/kg, 2 mg/kg of individual body weight, or a single fixed dose of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg.
  • Fruquintinib is administered in a single fixed dose of 2 mg, 3 mg, 4 mg or 5 mg.
  • Fruquintinib is administered once a day. More preferably, the drug is administered for three weeks and the drug is stopped for one week, or the drug is administered for two weeks and the drug is stopped for one week.
  • a single fixed dose of 2 mg of Fruquintinib is administered once a day for three weeks and the drug is stopped for one week.
  • a single fixed dose of 3 mg of Fruquintinib is administered once a day for three weeks and the drug is stopped for one week.
  • a single fixed dose of Fruquintinib is 4 mg, which is administered once a day for three weeks, and the drug is stopped for one week.
  • a single fixed dose of Fruquintinib is administered at 5 mg, once a day for three weeks, and the drug is stopped for one week.
  • the anti-PD-1 antibody or its antigen-binding fragment and fruquintinib or its pharmaceutically acceptable salt are administered in the same administration cycle.
  • the single administration dose of PD-1 antibody or antigen-binding fragment thereof is 3 mg/kg individual body weight, and the administration frequency is every two weeks.
  • the drug is administered once; and a single fixed dose of Fruquintinib is 3 mg, the frequency of administration is once a day for three consecutive weeks, and the drug is stopped for one week.
  • the single administration dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 3 mg/kg individual body weight, and the administration frequency is It is administered once every two weeks; and the single fixed dose of Fruquintinib is 4 mg, and the frequency of administration is once a day for three consecutive weeks, and the drug is stopped for one week.
  • the fixed dose of anti-PD-1 antibody or its antigen-binding fragment is 210 mg for a single administration .
  • the frequency of administration is once every two weeks; and a single fixed dose of fruquintinib is 5 mg, and the frequency of administration is once a day for three consecutive weeks, and the drug is stopped for one week.
  • the present invention also provides a kit containing the above-mentioned anti-PD-1 antibody or antigen-binding fragment thereof and fruquintinib or a pharmaceutically acceptable salt thereof.
  • the present invention also provides an anti-PD-1 antibody or an antigen-binding fragment thereof combined with fruquintinib or a pharmaceutically acceptable salt thereof as a therapeutic preparation for treating tumors.
  • the present invention also provides the above-mentioned anti-PD-1 antibody or its antigen-binding fragment in combination with fruquintinib or its pharmaceutically acceptable salt as a medicine for reducing adverse drug reactions, the adverse reactions of the above-mentioned drugs are selected from those caused by anti-PD-1 antibodies or Caused by Fruquintinib or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the above-mentioned anti-PD-1 antibody or its antigen-binding fragment in combination with fruquintinib or a pharmaceutically acceptable salt thereof as a single administration dose reduction of anti-PD-1 antibody and/or fruquintinib or its pharmaceutically acceptable salt.
  • the received salt is administered with a dose of drug alone.
  • the present invention also provides a method for reducing the dose of anti-PD-1 antibody or its antigen-binding fragment alone and/or the dose of Fruquintinib or its pharmaceutically acceptable salt alone, comprising administering the above-mentioned anti-PD-1 antibody to a patient.
  • PD-1 antibody combined with Fruquintinib or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for treating tumor/cancer, comprising administering the above-mentioned anti-PD-1 antibody or antigen-binding fragment thereof and fruquintinib or a pharmaceutically acceptable salt thereof to a patient.
  • the present invention also provides a kit containing the above-mentioned anti-PD-1 antibody or antigen-binding fragment thereof and fruquintinib or a pharmaceutically acceptable salt thereof.
  • Figure 1 shows the growth curve of a mouse colorectal cancer MC38 model after the start of treatment.
  • This figure illustrates the effect of the anti-PD-1 antibody of the present invention and furquintinib alone or in combination on the tumor volume of the mouse colorectal cancer MC38 model It can be seen from the figure that at the end of the control group (PG-D17), the tumor growth inhibition rate of the GB226 group, Fruquintinib high-dose group, Fruquintinib low-dose group, GB226+Fruquintinib high-dose group, and GB226+Fruquintinib low-dose group They were 90%, 73%, 56%, 94%, 93%.
  • the tumor volume of each treatment group was significantly lower than that of the control group (p ⁇ 0.05).
  • Figure 2 shows the weight change curve of experimental animals after the start of treatment.
  • This figure illustrates the weight change curve of experimental animals after the anti-PD-1 antibody of the present invention and fruquintinib are administered alone or in combination. It can be seen from the figure during the treatment period
  • the tumor-bearing mice showed good tolerance to the test drugs Fruquintinib, GB226 and their combination.
  • the mice in each group had normal body weight, no abnormal performance, and were generally in good condition.
  • Figure 3 shows the percentage of weight change of experimental animals after the start of treatment, which illustrates the percentage of weight change of experimental animals after the anti-PD-1 antibody of the present invention and fruquintinib are administered alone or in combination. It can be seen from the figure that during the treatment period, the tumor-bearing mice showed good tolerance to the test drugs Fruquintinib, GB226 and their combination. The mice in each group had normal body weight, no abnormal performance, and were generally in good condition.
  • the above-mentioned cancer is a cancer that expresses PD-L1.
  • the aforementioned cancers include, but are not limited to, lymphoma, leukemia, melanoma, glioma, breast cancer, lung cancer, bowel cancer, bone cancer, ovarian cancer, bladder cancer, kidney cancer, liver cancer, testicular cancer, salivary gland cancer , Thyroid cancer, thymus cancer, epithelial cancer, head and neck cancer, stomach cancer, pancreatic cancer, prostate cancer, kidney cancer or a combination thereof.
  • the above-mentioned colon cancer is colorectal cancer.
  • the aforementioned colorectal cancer is metastatic colorectal cancer.
  • the aforementioned lung cancer is non-small cell lung cancer (NSCLC).
  • the above-mentioned non-small cell lung cancer is epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment failure of EGFR sensitive mutation recurrence or metastatic non-small cell lung cancer (NSCLC).
  • the term “comprising” or “including” means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps.
  • the term “comprises” or “includes” when used, unless otherwise specified, it also encompasses the situation consisting of the stated elements, integers or steps.
  • an antibody variable region that "comprises” a specific sequence when referring to an antibody variable region that "comprises” a specific sequence, it is also intended to encompass the antibody variable region composed of that specific sequence.
  • antibody is used in the broadest sense and refers to a protein containing an antigen-binding site, covering natural and artificial antibodies of various structures, including but not limited to intact antibodies and antigen-binding fragments of antibodies.
  • dose is the amount of a drug that induces a therapeutic effect. Unless otherwise stated, the dosage is related to the amount of the free form of the drug. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased in proportion to the amount of the drug in the free form. For example, the dosage will be stated on the product packaging or product information sheet.
  • administration refers to the physical introduction of each active ingredient of the drug of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art.
  • the route of administration of each active ingredient in the medicine of the present invention includes oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local or other parenteral administration way.
  • parenteral administration refers to methods of administration other than gastrointestinal and topical administration, usually via intravenous, and without limitation includes intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrasaccular , Intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injection and infusion, and in vivo electroporation.
  • each active ingredient in the medicine of the present invention can be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes or suppositories, etc.
  • continuous administration refers to daily administration.
  • the drug may be administered one or more times a day, for example, the drug may be administered at a frequency of once a day, twice a day, or three times a day, preferably at a frequency of once a day.
  • treatment includes administering the drug of the present invention to an individual in need to achieve the purpose of curing the disease or having an effect on the regression of the disease or delaying the progression of the disease.
  • treatment refers to alleviating the disease (ie, slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof), preventing or delaying the onset or development or progression of the disease.
  • pharmaceutically acceptable salt refers to a salt of fruquintinib that is non-toxic, biologically tolerable, or otherwise biologically suitable for the administration of fruquintinib for the treatment or prevention of diseases.
  • acid addition salt or base addition salt for example: acid addition salt formed by furquintinib and inorganic acid, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate , Sulfates, sulfites, nitrates, etc.; and acid addition salts formed by furquintinib and organic acids, such as formate, acetate, malate, maleate, fumarate, Tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and The salt of alkane dicarboxylic acid of the formula HO
  • the single administration dose of anti-PD-1 antibody may be 0.1-40 mg/kg, preferably 0.5-20 mg/kg, more preferably 1-10 mg/kg, most preferably 3 mg/kg or 5 mg/kg;
  • a fixed dose may also be used, such as 100-400 mg, preferably 150-300 mg, and most preferably 210 mg.
  • the frequency of administration of the anti-PD-1 antibody may be once every 1 to 3 weeks, preferably once every 2 weeks.
  • the single administration dose of Fruquintinib may be 0.1-10 mg/kg, preferably 0.5-5 mg/kg.
  • a fixed dose may be used, for example 0.1-20 mg, preferably 1-10 mg, more preferably 1 mg, 2 mg, 3 mg, 4 mg or 5 mg.
  • the frequency of administration of Fruquintinib can be once a day, more preferably three weeks of continuous administration, and one week of withdrawal.
  • the anti-PD-1 antibody is preferably administered by injection, such as subcutaneous or intravenous injection, and the anti-PD-1 antibody needs to be formulated into an injectable form before injection.
  • the injectable form of the anti-PD-1 antibody may be an injection or a lyophilized powder injection, which contains an anti-PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant.
  • the buffer can be selected from one or more of acetate, citrate, succinate, and phosphate.
  • the stabilizer may be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose, maltose.
  • the surfactant is selected from polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, preferably the above-mentioned polyoxyethylene sorbitan fatty acid esters are polysorbate 20, 40, 60 or 80, Polysorbate 20 is most preferred.
  • the most preferred injectable form of anti-PD-1 antibody contains anti-PD-1 antibody, acetate buffer, trehalose and polysorbate 20.
  • Fruquintinib is preferably administered orally, for example, it can be formulated into tablets or capsules for administration.
  • “combination” is a mode of administration, which includes various situations in which two drugs are administered sequentially or simultaneously.
  • the so-called “simultaneous” herein refers to the administration of anti-PD- in the same administration cycle. 1 Antibody and Fruquintinib, for example, two drugs are given within 2 days or 1 day.
  • the so-called “sequential” administration includes the administration of anti-PD-1 antibody and Fruquintinib in different administration cycles.
  • the anti-PD-1 antibody when used in combination with fruquintinib, it can reduce the adverse drug reaction caused by the anti-PD-1 antibody and/or fruquintinib.
  • the aforementioned adverse reactions can be selected from vascular-related adverse reactions, glandular hypofunction, skin adverse reactions, respiratory system adverse reactions, liver-related adverse reactions, endocrine-related adverse reactions, digestive system adverse reactions, kidney-related adverse reactions, fatigue, fever;
  • the aforementioned vascular-related adverse reactions can be selected from hemangioma, vasculitis, lymphangioma, and the aforementioned hypothyroidism can be selected from hypothyroidism, hypoparathyroidism, hypopancreatic hypofunction, and prostate hypofunction;
  • the aforementioned skin adverse reactions are optional Self-pruritus, urticaria, skin rash, toxic epidermal necrosis;
  • the above-mentioned respiratory system adverse reaction is selected from pneumonia, bronchitis, chronic obstructive pulmonary disease,
  • the dose of fruquintinib when used in combination with the above-mentioned anti-PD-1, is that of the dose alone. 10%-100% of the dose, preferably 10%-75%, more preferably 75%, 50%, 25%, 12.5%.
  • the dosage of the anti-PD-1 antibody is 10%-100% of the dosage of the anti-PD-1 antibody alone, preferably 10%-50%.
  • microsatellite refers to a DNA sequence repeated in a few nucleotides (mostly 1-6) in the cell genome, also known as short tandem repeats.
  • MMR DNA mismatch repair
  • MSI microsatellite instablity
  • MSI-H MS highly unstable
  • MSI-L MS low unstable
  • MSS MS stable
  • MSI is mostly caused by MMR functional defects caused by the lack of MMR protein expression, so the MSI state can be reflected by detecting the lack of MMR protein.
  • Detection of MMR protein expression and detection of MSI status based on DNA analysis are different methods to evaluate the same biological effects.
  • One method to detect the expression of MMR protein is the IHC method, which uses specific antibodies against MLH1, MSH2, MSH6, and PMS2, respectively, and locates the nucleus to check the positive expression. If all four MMR proteins are positively expressed in the tumor sample, it means that the MMR function is intact (proficient mismatch repair, pMMR); the absence of any MMR protein is dMMR.
  • MSI-H high microsatellite instability
  • dMMR low density multireliable cellular magnetic resonance
  • pMMR complete mismatch repair function
  • MSI-H/dMMR MSI-H/dMMR
  • TMB tumor mutation burden
  • first-line treatment refers to the treatment methods adopted for tumor patients clinically
  • first-line treatment refers to the intervention measures taken for the first treatment of the patient’s condition , Including surgery and chemotherapy drugs.
  • the second-line mainly refers to the failure of the first treatment, or after a period of time after the first treatment, such as chemotherapy patients after six to eight times of chemotherapy, which may cause resistance to chemotherapy drugs, which will not have a therapeutic effect on tumor treatment.
  • second-line treatment options can be considered.
  • For patients who have failed second-line treatment that is, patients who still have disease progression after treatment, consider a third-line treatment plan.
  • the anti-cancer mechanisms used in different number of treatments are different.
  • EGFR-TKI treatment refers to a treatment regimen that uses a tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor (EGFR).
  • TKI tyrosine kinase inhibitor
  • Common EGFR-TKI drugs include gefitinib, erlotinib, icotinib, afatinib and so on.
  • Epidermal growth factor receptor (EGFR) is overexpressed, dysregulated or mutated in many epithelial malignancies, and EGFR activation is important in tumor growth and progression.
  • NSCLC non-small cell lung cancer
  • EGFR has a high frequency of mutations in Asian populations.
  • EGFR-TKI has achieved good results in the treatment of non-small cell lung cancer.
  • Fruquintinib The chemical name is 6-(6,7-dimethoxyquinazoline-4-oxo)-N,2-dimethylbenzofuran-3-carboxamide , The molecular formula is C 21 H 19 N 3 O 5 , and its preparation method is disclosed in the CN101575333B patent.
  • the structural formula is as follows:
  • the anti-PD-1 antibody is prepared according to the method disclosed in CN106573052A, and the heavy and light chain sequences of the anti-PD-1 antibody are shown in SEQID NO: 9 and SEQID NO: 10 of the present invention.
  • Anti-PD-1 antibody (10mg/ml): Use a micropipette to accurately measure 0.3ml sample stock solution into a glass bottle, take another 5.7ml PBS to the glass bottle and mix thoroughly to a final concentration of 0.5mg/ml, for use now Now equipped
  • Fruquintinib accurately weigh 5.6 mg of fruquintinib sample into a glass bottle, measure 28 ml of 0.5% CMC-Na into the glass bottle, vortex for 1-3 minutes and sonicate with an ultrasonic cleaner for 15 minutes , Mix thoroughly to the final concentration of 0.2mg/ml, prepare once a week and sub-package, store at 4°C;
  • Mus Musculus huPD-1 C57BL/6 (mouse, PD-1), 6-8 weeks old, all females, weighing 18-23g, a total of 62 (enrolled in 48); the experimental animal was made by Beijing Weitong Provided by Lihua Laboratory Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016-0011, quality certificate number: 1100111911048361.
  • the experimental animals were kept in a clean room with SPF-grade constant temperature and humidity in a laminar flow, using independent ventilated cages with IVC, one cage for every 4 rats, and the litter changed twice a week. Each cage has a cage label indicating the number of animals , Gender, strain, receiving time, group and start time of experiment.
  • the temperature and humidity are controlled in the range of (23 ⁇ 3)°C/40-70%.
  • SPF rodent feed, sterilized by cobalt 60 irradiation, drinking water is ultrafiltration purified water, and after autoclaving, animals can freely ingest sterile food and drinking water. Animals are numbered by ear punching.
  • MC38 mouse colon cancer cells (YK-CL-256-02) were purchased from Biovector NTCC Inc. (Biovector NTCC Inc.), with inactivated 10% fetal bovine serum, 100U/ml penicillin Cultivate tumor cells in a DEME medium with 100 ⁇ g/ml streptomycin and 2mM glutamine in a 37°C, 5% CO 2 incubator. After the cells are overgrown every 3 to 4 days, the tumor cells will be subcultured. Tumor cells in logarithmic growth phase are used for inoculation of tumors in vivo.
  • the dosage volume is 10 ⁇ l/g based on the animal's body weight, and the dosage can be adjusted when the body weight drops by 15-20%;
  • ip intraperitoneal injection
  • po intragastric administration
  • biw ⁇ 4 administration twice a week for a total of 4 administrations
  • qd ⁇ 18/23/26 administration once a day for a total of 18, 23, 26 days (times).
  • the T/C value was calculated according to the tumor volume, where T is the average value of Relative Tumor Volume (RTV) of each test substance treatment group, and C is the average value of Relative Tumor Volume (RTV) of the control group.
  • mice were euthanized if the tumor volume was greater than 2000 mm 3. Therefore, the mice in the control group were sacrificed at PG-D17; the mice in the low-dose group of Fruquintinib were sacrificed at PG-D22; the GB226 group, the high-dose Fruquintinib group, the GB226+Fruquintinib high-dose group, and the GB226+Furaquinib All mice in the quintinib low-dose group were killed at PG-D25. After the mice were euthanized, the tumors were taken and weighed.
  • the tumor weight inhibition rate calculation formula is 1-the ratio of the tumor weight between the administration group and the control group.
  • the tumor weight in the control group is based on the tumor weight at PG-D17, and the tumor weight in the low-dose fruquintinib group is based on PG-D22 , Other groups are subject to PG-D25 tumor weight. See Table 6 for the measurement results.
  • the tumor volume (see Table 5), the growth curve of the mouse colorectal cancer MC38 model after the start of treatment (see Figure 1) and the tumor weight (see Table 6), the results show that when the control group ends (PG-D17), GB226
  • the tumor growth inhibition rates of the Fruquintinib group, Fruquintinib high-dose group, Fruquintinib low-dose group, GB226+Fruquintinib high-dose group, and GB226+Fruquintinib low-dose group were 90%, 73%, 56%, 94%, 93%, respectively.
  • the tumor volume was significantly lower than the control group (p ⁇ 0.05).
  • Tumor weight changes (see Table 6): mouse tumor weight in GB226 group, Fruquintinib high-dose group, Fruquintinib low-dose group, GB226+Fruquintinib high-dose group, GB226+Fruquintinib low-dose group, tumor weight inhibition rates were 40.1%, 19.35, respectively %, 10.57%, 83.33%, 83.30%. Through the inhibition rate of tumor weight, it can be found that the combination medication has a significant synergistic effect.
  • mice in the Vehicle control group and Fruquintinib low-dose (1mg/kg) group ended early on PG-D17 and PG-D22 due to excessive tumor growth.
  • mice The body weight changes of experimental animals after the start of treatment (see Figure 2 and Figure 3). The results showed that during the treatment period, the tumor-bearing mice showed good tolerance to the test substances Fruquintinib, GB226 and their combination. The mice in each group had normal body weight, no abnormal performance, and were generally in good condition.
  • test drugs GB226 (5mg/kg), Fruquintinib high-dose (2mg/kg), GB226+ Fruquintinib high-dose (2mg/kg), GB226+ Fruquintinib low-dose (1mg/kg) for PD- 1
  • Humanized MC38 mouse tumor models have significant anti-tumor effects, effectively inhibiting tumor growth, and the anti-tumor effect of the combination of furquintinib and GB226 is significantly better than the corresponding single-agent therapy.
  • Treatment failure refers to disease progression or intolerable toxicity after receiving ⁇ 1 cycle of treatment; or recurrence during adjuvant chemotherapy/neoadjuvant therapy or within 6 months after the end of treatment;
  • Blood routine requires hemoglobin ⁇ 90g/L (blood transfusion is not allowed within 14 days before baseline blood routine examination), and neutrophils ⁇ 1.5 ⁇ 10 9 /L (recombinant human granulocyte colonies are not used within 14 days before baseline blood routine examination Stimulating factor support therapy), platelets ⁇ 100 ⁇ 10 9 /L (recombinant human thrombopoietin or blood transfusion was not used for supportive therapy in the 14 days before the baseline blood routine examination);
  • urine protein ⁇ 2+ or ⁇ 1.0g/L at baseline a 24-hour urine protein quantitative test should be performed and must be ⁇ 1.0g/L before they can be selected;
  • Thyroid function indicators Thyroid-stimulating hormone (TSH) and free thyroxine (FT3/FT4) are in the normal range; if TSH is not in the normal range and FT3/FT4 is in the normal range, you can join the group;
  • Patients can be followed up on schedule, can communicate well with the investigator, and can complete the study in accordance with the research regulations.
  • Active central nervous system (CNS) metastases including symptomatic brain metastases or meningeal metastases or spinal cord compression, etc.; asymptomatic brain metastases can be included in the group (at least 4 weeks after radiotherapy, no progression and/or no after surgical resection Neurological symptoms or signs do not require treatment with glucocorticoids, antiepileptic drugs, anticonvulsants or mannitol);
  • autoimmune diseases including but not limited to systemic lupus erythematosus, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Hashimoto's thyroiditis, etc., except: Type I Diabetes, hypothyroidism that can be controlled only by hormone replacement therapy, skin diseases that do not require systemic treatment (such as vitiligo, psoriasis), and controlled celiac disease;
  • anti-PD-1 antibody anti-PD-L1 antibody, anti-PD-L2 antibody or anti-CTLA-4 antibody treatment (or any other antibody that acts on T cell co-stimulation or checkpoint pathway);
  • the image shows signs of tumor invasion of large blood vessels, including the tumor has completely approached, surrounded or invaded the lumen of large blood vessels (such as pulmonary artery or superior vena cava);
  • gastrointestinal disorders that will significantly affect the absorption of oral drugs or conditions that may cause gastrointestinal bleeding or perforation (such as duodenal ulcer, intestinal obstruction, acute Crohn’s disease, ulcerative colitis, large-area stomach And small bowel resection, etc.). Patients with chronic Crohn's disease and ulcerative colitis (except for total colon and rectal resection) should be excluded even in the inactive period. People with hereditary non-polyposis colorectal cancer or familial adenomatous polyposis syndrome. Those who have a history of intestinal perforation and intestinal fistula, but have not recovered after surgical treatment;
  • HBV-Ab Human immunodeficiency virus antibody
  • active syphilis active syphilis
  • hepatitis C antibody HCV-Ab
  • HCV-RNA hepatitis B surface antigen
  • HBV-DNA copy Number upper limit of normal value of detection unit
  • the GB226 preparation is a colorless to light yellow liquid, the specification is 70mg/7ml/bottle, GB226 (that is, the anti-PD-1 antibody with heavy and light chain sequences as shown in SEQ ID NO: 9 and SEQ ID NO: 10 of the present invention) Prepared in 100ml of 0.9% sodium chloride solution, the concentration of administration must be controlled at 1mg/ml ⁇ 10mg/ml, and the infusion is completed within 60 minutes ⁇ 10 minutes after the first application. If there is no infusion reaction, it can be adjusted to ⁇ 30 minutes later.
  • Fruquintinib capsules two sizes, 1mg or 5mg, orally on an empty stomach, once a day.
  • MTD ⁇ Maximum tolerated dose
  • RDE recommended dose for extended period
  • the evaluation indicators of clinical effectiveness include objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS)
  • the pharmacokinetic parameters of GB226 include T max , C max , C ss, min , R C, trough, etc.
  • the pharmacokinetic parameters of Fruquintinib include T max , C max , AUC 0-24h , Rauc etc.
  • ⁇ Immunogenicity of GB226 the number and percentage of subjects who produced anti-GB226 antibodies (ADA) and neutralizing antibodies (NAb)
  • Clopper-pearson method is used to estimate ORR and DCR and provide the corresponding 90% confidence interval. If the number of subjects in the dose group exceeds 10, the Kaplan-Meier method is used to analyze PFS and DOR, and the median and 90% confidence interval are provided.
  • Blood drug concentration (c)-time (t) data analysis PK concentration set is used to draw individual and average ct curves; the number of cases, mean, standard deviation, median, maximum, and maximum value of blood drug concentration at time points are listed. Minimum value and coefficient of variation, etc.
  • PK parameter analysis The PK parameter analysis set is used to calculate the pharmacokinetic parameters of each subject from the non-compartmental model, including GB226 T max , C max , C ss, min , R C, trough, etc., Fruquintinib T max , C max , AUC 0-24h , Rauc and so on. Calculate the number of cases, arithmetic mean, standard deviation, coefficient of variation, quartile, maximum, minimum and geometric mean of each parameter at the same time.
  • the study is in the dose-escalation phase, and a total of 15 subjects were enrolled. As shown in Table 8, 3 subjects were enrolled in the first dose group, 6 subjects were enrolled in the second dose group, and 6 subjects were enrolled in the third dose group. In this study, there were 11 cases of colon cancer and 4 cases of rectal cancer.
  • MSS/pMMR type MSS/pMMR type, second-line treatment failed, ECOG score 1 point.
  • the subject showed a progressive reduction in the therapeutic effect, but an immune rash appeared after 6 months of study medication.
  • Hormone therapy was stopped for 2 months.
  • the tumor was evaluated as PR, and the tumor was reduced from 32mm to 20mm, a reduction of 37.5%. It lasts for 4 months and is currently under study.
  • the main adverse reactions in the subjects in this study were: hypertension, proteinuria, abnormal liver function (increased transaminase and bilirubin), abnormal thyroid function (hypothyroidism, hyperthyroidism, decreased T4, decreased TSH, etc.), hands and feet Syndrome, skin rash.
  • adverse events such as dysphonia, tinnitus, abdominal pain, diarrhea, fatigue, loss of appetite, weight loss, etc., all of which have been identified risks for GB226 and Fruquintinib, and no new safety events and toxicity have occurred. Security incidents.
  • the trial population was relapsed or metastatic NSCLC patients with EGFR-sensitive mutations who failed EGFR-TKI treatment.
  • PD-L1 Programmed cell death protein ligand-1
  • MSI microsatellite instability
  • dMMR mimetics of tumor tissues of patients with recurrent or metastatic NSCLC with EGFR-sensitive mutations that have failed EGFR-TKI treatment
  • TMB tumor mutation burden
  • the subject must have at least one measurable target lesion (lesions with longest diameter ⁇ 10 mm, or lymph nodes with short diameter ⁇ 15 mm) that can be examined by CT or MRI;
  • the EGFR-TKI treatment has been completed for more than 2 weeks before the trial drug;
  • the corticosteroid medication prednisone>10mg/day or equivalent dose used systemically has been discontinued for at least 2 weeks;
  • AST Aspartate aminotransferase
  • ALT alanine aminotransferase
  • Urine protein ⁇ 2+ or ⁇ 1.0g/L Urine protein ⁇ 2+ or ⁇ 1.0g/L.
  • a 24-hour urine protein quantitative test should be performed and must be ⁇ 1.0g/L before they can be selected;
  • APTT Activated partial thromboplastin time
  • PT prothrombin time
  • Thyroid function indicators Thyroid-stimulating hormone (TSH) and free thyroxine (FT3/FT4) are in the normal range; if TSH is not in the normal range, FT3/FT4 can be included in the normal range;
  • Subjects need to provide tissue samples and are willing to undergo tissue biopsy when needed.
  • Imaging shows that the tumor focus is less than 5 mm from the large blood vessels, or there is a central type tumor that invades the local large blood vessels; or it shows that there are obvious cavitation or necrotic tumors in the lung;
  • Active central nervous system (CNS) metastasis including symptomatic brain metastasis or meningeal metastasis or spinal cord compression, etc.; asymptomatic brain metastasis can be included in the group (at least 4 weeks after radiotherapy, no progression and/or no after surgical resection There are neurological symptoms or signs that do not require treatment with glucocorticoids, anticonvulsants or mannitol);
  • a history of active and known autoimmune diseases including but not limited to systemic lupus erythematosus, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Hashimoto’s thyroiditis, etc., except: Type I Diabetes, hypothyroidism that can be controlled only by hormone replacement therapy, skin diseases that do not require systemic treatment (such as vitiligo, psoriasis), and controlled celiac disease.
  • HBV-Ab Human immunodeficiency virus antibody
  • active syphilis active syphilis
  • hepatitis C antibody HCV-Ab
  • HCV-RNA hepatitis B surface antigen
  • HBV-DNA copy Number upper limit of normal value of detection unit
  • Live vaccines or attenuated vaccines are expected to be given 4 weeks before administration, during treatment, or 5 months after the last administration;
  • the GB226 preparation is a colorless to light yellow liquid, the specification is 70mg/7ml/bottle, GB226 (that is, the anti-PD-1 antibody with heavy and light chain sequences as shown in SEQ ID NO: 9 and SEQ ID NO: 10 of the present invention) Prepared in 100ml of 0.9% sodium chloride solution, the concentration of administration must be controlled at 1mg/ml ⁇ 10mg/ml, and the infusion is completed within 60 minutes ⁇ 10 minutes after the first application. If there is no infusion reaction, it can be adjusted to ⁇ 30 minutes later.
  • Fruquintinib capsules two sizes, 1mg or 5mg, orally on an empty stomach, once a day.
  • AE adverse events
  • SAE serious adverse events
  • MTD ⁇ Maximum tolerated dose
  • RDE recommended dose for extended period
  • PK evaluation indicators including: peak concentration (C max ), peak time (T max ), area under the plasma concentration-time curve (AUC 0-t and AUC 0- ⁇ ) , Apparent volume of distribution (V d ), mean residence time (MRT), total clearance (CL); and the area under the plasma concentration-time curve (AUC 0- ⁇ ) and average steady-state plasma concentration during the interval between medications (C avg ), minimum blood concentration (C min ) and steady-state clearance (CL ss )
  • ⁇ Efficacy evaluation indicators include: objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS)
  • ⁇ Immunogenicity of GB226 the number and percentage of subjects who produced anti-GB226 antibodies (ADA) and neutralizing antibodies (NAb)
  • PD-L1 Programmed cell death protein ligand-1 (PD-L1) protein expression, microsatellite instability (MSI)/mismatch repair defect (dMMR), tumor mutational burden (TMB) and efficacy (ORR, DOR, DCR, PFS, OS) relevance.
  • MSI microsatellite instability
  • dMMR tumor mutational burden
  • ORR efficacy
  • Clopper-pearson method is used to estimate ORR and DCR and provide the corresponding 90% confidence interval. If the number of subjects in the dose group exceeds 10, the Kaplan-Meier method is used to analyze PFS and DOR, and the median and 90% confidence interval are provided.
  • adverse reactions with an incidence of ⁇ 10% include: decreased white blood cell count, gum pain, hypoproteinemia, abnormal liver function, hyperuricemia, hypertension, increased conjugated bilirubin, cough, skin ulcers , Peripheral edema, pleural effusion, increased blood bilirubin, decreased platelet count, sinus tachycardia, epistaxis, hyperglycemia, hypothyroidism, hyperthyroidism, decreased thyroxine, blood in the urine, palpitations , Elevated blood thyroid stimulating hormone, skin rash, elevated blood alkaline phosphatase adverse reactions.
  • GB226 combined with Fruquintinib in the treatment of EGFR-TKI failed EGFR-TKI treatment of EGFR-sensitive mutation recurrence or metastatic non-small cell lung cancer clinical research safety risk is controllable, and has obtained preliminary efficacy, the study will select the third dose group As the recommended dose for the expansion phase, the subsequent dose expansion phase is carried out.

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Abstract

Utilisation d'un anticorps anti-PD-1 ou de son fragment de liaison à l'antigène en combinaison avec du fruquintinib ou son sel pharmaceutiquement acceptable dans la préparation de médicaments pour le traitement du cancer. L'administration combinée de l'anticorps anti-PD-1 et du fruquintinib a un certain effet synergique. Par comparaison avec l'administration unique correspondante, l'effet d'inhibition de la croissance tumorale est évident. Pendant l'administration, les animaux de laboratoire ont une bonne tolérance et ne présentent aucune réaction indésirable.
PCT/CN2021/071996 2020-01-17 2021-01-15 Utilisation d'un anticorps anti-pd-1 en combinaison avec du fruquintinib dans la préparation de médicaments pour le traitement du cancer WO2021143799A1 (fr)

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