Classifications

• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • 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
• • 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
  • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—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
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/66—Microorganisms or materials therefrom
  • A61K35/74—Bacteria
  • A61K35/741—Probiotics
  • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2803—Immunoglobulins [IG], 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 [IG], 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

Definitions

• the present invention relates to a combination drug for the treatment of cancer.
• Probiotics are defined as "live microorganisms that have a positive effect on the host's health by improving the balance of intestinal flora," and there are active attempts to apply them in practical clinical applications in the medical field.
• probiotics when used in combination with chemotherapy such as anticancer drugs, will improve the therapeutic effects of cancer patients.
• Patent Document 1 describes that the therapeutic effect of immune checkpoint inhibitors can be enhanced by administering immune checkpoint inhibitors and Clostridium butyricum MIYAIRI 588 (FERM BP-2789) to cancer patients.
• the objective of the present invention is to provide a novel combination drug for cancer treatment.
• the inventors have surprisingly found that the antitumor effect can be improved by combining Clostridium butyricum MIYAIRI 588 (FERM BP-2789) with a tyrosine kinase inhibitor. Based on this finding, the present invention has been completed.
• a combination drug for cancer treatment contains a tyrosine kinase inhibitor and Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof.
• 1 is a graph showing the change in tumor volume over time in each group in Test Example 1.
• 1 is a graph showing the tumor volume at each observation time point (4th day, 8th day, 11th day, 15th day, and 18th day) in each group of Test Example 1.
• 1 is a graph showing a Kaplan-Meier curve in Test Example 1, in which a tumor volume of 1000 mm3 was defined as an event.
• X-Y means "X or more and Y or less.”
• operations and measurements of physical properties are performed at room temperature (20-25°C) and a relative humidity of 40-50% RH.
• CBM588 Clostridium butyricum MIYAIRI 588 (FERM BP-2789)
• the first aspect of the present invention is a combination drug for treating cancer, comprising a tyrosine kinase inhibitor and CBM588 or a culture thereof.
• a second aspect of the present invention is a method for treating cancer, comprising administering to a subject a combination of an effective amount of a tyrosine kinase inhibitor and an effective amount of CBM588 or a culture thereof.
• a third aspect of the present invention is a pharmaceutical composition for use in treating cancer, comprising a combination of a tyrosine kinase inhibitor and CBM588 or a culture thereof.
• the fourth aspect of the present invention is a pharmaceutical composition for treating cancer, comprising CBM588 or a culture thereof, administered in combination with a tyrosine kinase inhibitor.
• the fifth aspect of the present invention is a pharmaceutical composition for treating cancer, comprising a tyrosine kinase inhibitor administered in combination with CBM588 or a culture thereof.
• the sixth aspect of the present invention is a kit for treating cancer, comprising a tyrosine kinase inhibitor and CBM588 or a culture thereof.
• the seventh aspect of the present invention is CBM588 or a culture thereof for use in combination with a tyrosine kinase inhibitor in a method for treating cancer.
• An eighth aspect of the present invention is a tyrosine kinase inhibitor for use together with CBM588 or a culture thereof in a method for treating cancer.
• a ninth aspect of the present invention is the use of a tyrosine kinase inhibitor and/or CBM588 or a culture thereof in a medicament for use in a method for treating cancer comprising administering to a subject a tyrosine kinase inhibitor and CBM588 or a culture thereof.
• the antitumor effect particularly the effect of reducing tumor volume, can be improved compared to administering a tyrosine kinase inhibitor alone, thereby significantly increasing the survival rate of the subject.
• the tyrosine kinase inhibitor of the present invention is used in combination with Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof for the treatment of cancer.
• Tyrosine kinase inhibitors are drugs that exert antitumor effects by inhibiting cellular tyrosine kinases, enzymes involved in many cellular functions, including cell signaling, growth, and division.
• the tyrosine kinase inhibitor according to the present invention is not particularly limited, and any conventionally known tyrosine kinase inhibitor can be used.
• the tyrosine kinase inhibitor is preferably at least one selected from the group consisting of EGFR tyrosine kinase inhibitors, c-kit receptor tyrosine kinase inhibitors, BCR-ABL tyrosine kinase inhibitors, and multikinase inhibitors, and is more preferably a multikinase inhibitor.
• tyrosine kinase inhibitors include, but are not limited to, at least one selected from the group consisting of imatinib, dasatinib, nilotinib, afatinib, erlotinib, osimertinib, gefitinib, axitinib, cabozantinib, sunitinib, sorafenib, pazopanib, regorafenib, and lenvatinib, and more preferably at least one selected from the group consisting of axitinib, cabozantinib, sunitinib, sorafenib, pazopanib, regorafenib, and lenvatinib.
• Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof according to the present invention is used in combination with a tyrosine kinase inhibitor for the treatment of cancer.
• CBM588 is spore-forming, and when in a spore state, it is resistant to various external environments. Therefore, when CBM588 is orally administered to humans or animals in the form of spores, even when it comes into contact with digestive fluids such as gastric acid, intestinal fluids, and bile acid, CBM588 does not die completely, but instead reaches the fermentation sites from the lower small intestine to the large intestine, where it is able to grow.
• digestive fluids such as gastric acid, intestinal fluids, and bile acid
• CBM588 is widely sold commercially as a probiotic, feed additive, and food product, and has been shown to cause no side effects even when administered over long periods of time to humans, livestock, and other mammals, ensuring a high level of safety.
• CBM588 was deposited on May 1, 1981 at the Microbial Industrial Technology Institute, Agency of Industrial Science and Technology, Ministry of International Trade and Industry (currently the Patent Organism Depositary Center, National Institute of Technology and Evaluation, Japan) (Room 120, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, 292-0818, Japan) under the accession number FERM BP-2789, and on March 6, 1990, it was transferred to an international depository institution under the Budapest Treaty, where it is deposited under the accession number FERM BP-2789.
• CBM588 is commercially available from Miyarisan Pharmaceutical Co., Ltd. as a live bacteria agent, and has no side effects even when administered to humans or animals for a long period of time.
• CBM588 is a live bacteria.
• the culture of CBM588 refers to the culture medium in which Clostridium butyrim is cultured, the residue containing the bacteria obtained by centrifuging the culture medium, and the dried product of the residue.
• a culture of CBM588 can be obtained by a known method for culturing a microorganism, for example, the method disclosed in JP-A-08-252088.
• One embodiment of the method is shown below: CBM588 is inoculated into a medium containing 1.0 (w/v)% peptone, 1.0 (w/v)% yeast extract, 1.0 (w/v)% corn starch, and 0.2 (w/v)% precipitated calcium carbonate to a concentration of 10 to 10 cells/mL, and then subjected to static culture at 37°C for 48 hours to obtain a "culture solution of CBM588".
• the resulting culture solution is centrifuged (2,000 to 6,000 g x 10 to 30 minutes) to separate the "residue containing bacteria obtained by centrifuging the culture solution", and this residue is dried by air drying or the like at 0 to 80°C, preferably 10 to 20°C, for 1 to 24 hours, preferably 5 to 18 hours, or dried under reduced pressure at 0 to 80°C, preferably 10 to 20°C, 0.05 to 500 Torr (7 Pa to 66.7 kPa), preferably 1 to 100 Torr (133 Pa to 13.3 kPa), for 1 to 24 hours, preferably 2 to 15 hours, to obtain a "dried product of the residue".
• spray drying, freeze drying, etc. may be used.
• the medium used for culturing CBM588 according to the present invention may be either a synthetic medium or a natural medium, so long as it contains a carbon source that CBM588 can assimilate, an appropriate amount of a nitrogen source, inorganic salts, and other nutrients such as vitamins.
• examples of carbon sources used in the medium according to the present invention are not particularly limited as long as they are carbon sources that can be assimilated by CBM588.
• the carbon source is not necessarily limited to sugar, but in consideration of the growth of the bacterial cells, a sugar or a sugar-containing source that can be used by CBM588 is preferably used.
• Specific examples of carbon sources that can be used, in consideration of assimilation, include cellobiose, glucose, fructose, galactose, lactose, maltose, mannose, melibiose, raffinose, salicin, starch, sucrose, trehalose, xylose, dextrin, and molasses.
• carbon sources starch, glucose, fructose, sucrose, and molasses are preferably used.
• concentration of the carbon source added varies depending on the type of carbon source used and the medium composition other than the carbon source, but is usually 0.5 to 5 (w/v)%, preferably 2 to 4 (w/v)%.
• nitrogen sources and vitamins examples include meat extract, peptone, yeast extract, seasoning liquid and other soybean and wheat hydrolysates, soybean powder, milk casein, casamino acids, various amino acids, corn steep liquor, other organic nitrogen compounds such as hydrolysates of animals, plants and microorganisms, and ammonium salts such as ammonium sulfate.
• peptone, yeast extract, meat extract, corn steep liquor and seasoning liquid are preferably used.
• One or more of the above-mentioned nitrogen sources and vitamins may be selected and used to improve the growth of CBM588.
• the concentration of the nitrogen source added varies depending on the type of strain and nitrogen source used, and the medium composition other than the nitrogen source of the medium used, but when using peptone containing a large amount of nitrogen source, it is usually 0.5 to 4 (w/v)%, preferably 1 to 3 (w/v)%, when using seasoning liquid or corn steep liquor containing a large amount of nitrogen source and vitamins, it is usually 0.5 to 5 (w/v)%, preferably 1 to 4 (w/v)%, and when using yeast extract or meat extract containing a large amount of vitamins, it is usually 0.5 to 4 (w/v)%, preferably 1 to 3 (w/v)%.
• inorganic salts one or more selected from phosphates, hydrochlorides, sulfates, butyrates, propionates, acetates, etc. of magnesium, manganese, calcium, sodium, potassium, molybdenum, strontium, boron, copper, iron, tin, zinc, etc. can be used.
• antifoaming agents, vegetable oils, surfactants, blood and blood components, drugs such as antibiotics, physiologically active substances such as plant or animal hormones, etc. may be appropriately added to the medium as necessary.
• the culture conditions must be such that it is cultured under anaerobic conditions without aeration, or by aerating nitrogen or carbon dioxide, or by adding a reducing agent to the medium to lower the redox potential.
• the culture conditions are appropriately selected depending on the composition of the medium and the culture method used, and are not particularly limited as long as they allow CBM588 to grow.
• the culture temperature is usually 20 to 42°C, preferably 35 to 40°C.
• the growth of CBM588 is promoted by neutralizing the acid produced during the culture with an alkali
• the amount of calcium carbonate added is usually 0.1 to 4 (w/v)%, preferably 0.2 to 2.5 (w/v)%.
• the "set pH” means the pH of the culture medium that is set in advance during the culture period
• the “set pH range” means the pH range that is acceptable during the culture period, and is generally expressed as the set pH ⁇ tolerance.
• the set pH is usually set within the range of 5.0 to 7.5, preferably 5.5 to 6.5
• the set pH range is the set pH ⁇ 0.5, preferably the set pH ⁇ 0.2.
• the pH of the medium during cultivation is near neutral when CBM588 is inoculated, and more preferably 6.5 to 7.5.
• the initial culture concentration of CBM588 is not particularly limited as long as it is within the range in which CBM588 can grow, and specifically, it is usually 10 4 to 10 7 cells/mL, preferably 10 5 to 10 6 cells/mL.
• the CBM588 culture obtained in this way can be used in combination with a tyrosine kinase inhibitor to improve the antitumor effect.
• a tyrosine kinase inhibitor and CBM588 or a culture thereof can be used in combination with an immune checkpoint inhibitor to treat cancer.
• Immune checkpoint inhibitors block the function of immune checkpoint receptors or ligands, and examples of such inhibitors include antagonists for inhibitory receptors and agonists for costimulatory immune checkpoint receptors.
• antagonist includes various substances that interfere with receptor activation through the binding of a receptor to a ligand. Examples include substances that bind to a receptor and interfere with receptor-ligand binding, and substances that bind to a ligand and interfere with receptor-ligand binding.
• antagonists against inhibitory immune checkpoints include antagonistic antibodies that bind to inhibitory immune checkpoint molecules (inhibitory receptors or ligands for said receptors), soluble polypeptides that do not activate receptors and are designed based on inhibitory immune checkpoint ligands, or vectors capable of expressing said polypeptides.
• the immune checkpoint inhibitor according to the present invention is not particularly limited, and any conventionally known immune checkpoint inhibitor can be used.
• the immune checkpoint inhibitor is preferably at least one selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4 inhibitors, and more preferably a PD-1 inhibitor.
• immune checkpoint inhibitors include, but are not limited to, at least one selected from the group consisting of nivolumab, ipilimumab, pembrolizumab, semipilimab, durvalumab, daclizumab, avelumab, and atezolizumab, and more preferably at least one selected from the group consisting of nivolumab, pembrolizumab, and semipilimab.
• the present invention includes the following embodiments: A combination drug for treating cancer comprising a tyrosine kinase inhibitor, CBM588, and an immune checkpoint inhibitor; A method for treating cancer, comprising administering to a subject in combination an effective amount of a tyrosine kinase inhibitor, an effective amount of CBM588 or a culture thereof, and an effective amount of an immune checkpoint inhibitor; A pharmaceutical composition comprising a combination of a tyrosine kinase inhibitor, CBM588 or a culture thereof, and an immune checkpoint inhibitor for use in the treatment of cancer; A pharmaceutical composition for treating cancer, comprising CBM588 or a culture thereof administered in combination with a tyrosine kinase inhibitor and an immune checkpoint inhibitor; a pharmaceutical composition for treating cancer comprising CBM588 or a culture thereof and a tyrosine kinase inhibitor administered in combination with an immune checkpoint inhibitor; A kit for treating cancer, comprising a tyrosine kinase inhibitor,
• the type of "cancer" to be treated is not particularly limited.
• cancer include oral cancer, pharyngeal cancer, esophageal cancer, gastric cancer, liver cancer, gallbladder cancer, biliary tract cancer, spleen cancer, colon cancer, small intestine cancer, duodenal cancer, colon cancer, colon adenocarcinoma, rectal cancer, pancreatic cancer, liver cancer, bladder cancer, renal cell cancer, non-small cell lung cancer, small cell lung cancer, malignant melanoma, sarcoma, lymphoma, breast cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, prostate cancer, head and neck cancer, and metastatic cancers thereof.
• the cancer is preferably at least one type selected from the group consisting of colon cancer, metastatic renal cell carcinoma (mRCC), non-small cell lung cancer, melanoma, sarcoma, lymphoma, breast cancer, bladder cancer, cervical cancer, head and neck cancer, liver cancer, gastric cancer, and rectal cancer.
• mRCC metastatic renal cell carcinoma
• non-small cell lung cancer melanoma
• sarcoma lymphoma
• breast cancer bladder cancer
• cervical cancer cervical cancer
• head and neck cancer liver cancer
• gastric cancer gastric cancer
• rectal cancer rectal cancer
• effective amount means the amount of active ingredient (i.e., tyrosine kinase inhibitor, CBM588 or immune checkpoint inhibitor) that is at least required to exert the desired effect, such as the treatment of cancer, particularly the improvement of antitumor effect.
• active ingredient i.e., tyrosine kinase inhibitor, CBM588 or immune checkpoint inhibitor
• the "subject” is not particularly limited, but refers to a mammal or a bird, preferably a mammal or a bird that is suffering from or has the potential to suffer from cancer.
• mammals include both primates such as humans, monkeys, gorillas, chimpanzees, and orangutans, as well as non-human mammals such as mice, rats, hamsters, guinea pigs, rabbits, dogs, cats, pigs, cows, horses, sheep, camels, and goats.
• Birds include chickens, quails, and pigeons. Of these, humans are preferred.
• a tyrosine kinase inhibitor CBM588 or a culture thereof, and optionally an immune checkpoint inhibitor, are administered in combination (concomitant administration) to a subject.
• Combined administration includes simultaneous administration of each component, and sequential administration of each component at predetermined intervals over the course of treatment (combination therapy).
• the route and means of administration of each component administered in combination may be the same or different.
• the dosage and method of administration of the tyrosine kinase inhibitor, CBM588 or a culture thereof, and the immune checkpoint inhibitor can be appropriately determined taking into consideration the type of cancer, symptoms, age, sex, weight, and condition of the subject, etc.
• the dosage of the tyrosine kinase inhibitor is, for example, about 1 to about 2400 mg/kg body weight/day of the active ingredient.
• the tyrosine kinase inhibitor can be administered 1 to 6 times per day, every day, every other day, or every few days.
• the method of administration of the tyrosine kinase inhibitor is not particularly limited, and examples include oral administration, intravenous injection, intraarterial injection, subcutaneous injection, intradermal injection, intraperitoneal injection, intramuscular injection, intrathecal injection, transdermal administration, parenteral administration such as transdermal absorption, etc., and oral administration is preferred.
• the dosage of the tyrosine kinase inhibitor is 3 mg/kg body weight/day (5 times a week), and the administration method is oral administration.
• the dosage of CBM588 or a culture thereof is, for example, 0.1 to 1000 mg/kg body weight/day as an active ingredient.
• CBM588 or a culture thereof can be administered 1 to 6 times per day, every day, every other day, or every few days.
• the method of administration of CBM588 or a culture thereof is not particularly limited, and includes oral administration, intravenous injection, intraarterial injection, subcutaneous injection, intradermal injection, intraperitoneal injection, intramuscular injection, intrathecal injection, parenteral administration such as percutaneous administration or percutaneous absorption, and the like, and is preferably oral administration.
• the dosage of CBM588 is about 43 mg/kg body weight/day (1 ⁇ 10 8 cfu (about 1.3 mg)/100 ⁇ L/animal), and the method of administration is oral administration.
• the dosage of the immune checkpoint inhibitor is, for example, 0.1 to 20 mg/kg body weight/day of active ingredient, preferably 2 to 3 mg/kg body weight/day.
• the immune checkpoint inhibitor can be administered 1 to 6 times per day, every day, every other day, or every few days.
• the method of administration of the immune checkpoint inhibitor is not particularly limited, and includes oral administration, intravenous injection, intraarterial injection, subcutaneous injection, intradermal injection, intraperitoneal injection, intramuscular injection, intrathecal injection, transdermal administration, parenteral administration such as transdermal absorption, etc., and is preferably intraperitoneal administration or intravenous injection.
• the dosage of the immune checkpoint inhibitor is 10 mg/kg body weight/day (5 times every 3 days), and the administration method is intraperitoneal administration.
• the tyrosine kinase inhibitor, CBM588 or a culture thereof, and the immune checkpoint inhibitor may be in the form of a combined drug, or each may be in the form of a separate drug (or pharmaceutical composition).
• the combination medicine may be in the form of a combination preparation in which each component is contained in the same composition, or in the form of a single package in which each component is prepared separately and suitable for administration in combination (i.e., in the form of a kit).
• additives that are acceptable for formulation can be further used.
• additives include excipients, stabilizers, preservatives, wetting agents, emulsifiers, lubricants, sweeteners, colorants, flavorings, buffers, antioxidants, pH adjusters, binders, thickeners, dispersants, suspending agents, disintegrants, bacteriostatic agents, surfactants, etc.
• the dosage forms of the combination drug, pharmaceutical composition, tyrosine kinase inhibitor, CBM588 or a culture thereof, and immune checkpoint inhibitor are not particularly limited and may be appropriately set, and may be, for example, tablets, powders, fine granules, granules, capsules, pills, sustained release agents, solutions, suspensions, emulsions, lotions, injections, drips, external preparations, suppositories, patches, etc.
• a combination drug for cancer treatment comprising a tyrosine kinase inhibitor and Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof.
• Clostridium butyricum MIYAIRI 588 FERM BP-2789
• tyrosine kinase inhibitor is at least one selected from the group consisting of an EGFR tyrosine kinase inhibitor, a c-kit receptor tyrosine kinase inhibitor, a BCR-ABL tyrosine kinase inhibitor, and a multikinase inhibitor.
• [4] The combination drug for cancer treatment according to any one of [1] to [3], wherein the tyrosine kinase inhibitor is at least one selected from the group consisting of imatinib, dasatinib, nilotinib, afatinib, erlotinib, osimertinib, gefitinib, axitinib, cabozantinib, sunitinib, sorafenib, pazopanib, regorafenib, and lenvatinib.
• the immune checkpoint inhibitor is at least one selected from the group consisting of nivolumab, ipilimumab, pembrolizumab, semipilimab, durvalumab, daclizumab, avelumab, and atezolizumab.
• mRCC metastatic renal cell carcinoma
• a method for treating cancer comprising administering to a subject a combination of an effective amount of a tyrosine kinase inhibitor and an effective amount of Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof.
• a pharmaceutical composition for use in the treatment of cancer comprising a combination of a tyrosine kinase inhibitor and Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof.
• a pharmaceutical composition for cancer treatment comprising Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof, administered in combination with a tyrosine kinase inhibitor.
• a pharmaceutical composition for treating cancer comprising a tyrosine kinase inhibitor administered in combination with Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof.
• a kit for treating cancer comprising a tyrosine kinase inhibitor and Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof.
• Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof for use together with a tyrosine kinase inhibitor in a method for treating cancer.
• a tyrosine kinase inhibitor and/or Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof in a medicament for use in a method for treating cancer comprising administering to a subject a tyrosine kinase inhibitor and Clostridium butyricum MIYAIRI 588 (FERM BP-2789) or a culture thereof.
• mice Animal experiments using mice were conducted with the approval of the Animal Experiment Committee of the Osaka International Cancer Institute (approval number: 23022121).
• mice 7 weeks old, male/female, purchased from CLEA Japan, SPF) were subjected to a 7-day quarantine and acclimation period, and it was confirmed that all mice were in good health and had no weight loss before being used in the study.
• the mice were reared in a 12-hour lighting environment with a temperature of 20-26°C and humidity of 30-70%, and were allowed to freely consume food and water.
• TKI tyrosine kinase inhibitors
• ICI immune checkpoint inhibitors
• mice were euthanized as a humane endpoint 28 days after the start of administration, or when the tumor minor axis reached 10 mm or the tumor mass reached 10% of the body weight. Mice with tumor volumes exceeding 1500 mm3 by 11 days after the start of administration were excluded.
• TKI Regorafenib (#R0142, Tokyo Chemical Industry Co., Ltd.) 30 ⁇ g/g, 100 ⁇ L (maximum amount 1000 ⁇ L) once a day for 9 days orally administered.
• ICI Anti-CD279 antibody (J43; BE-00332, Iwai Chemicals Co., Ltd.) 5 ⁇ g/g, 100 ⁇ L (maximum amount 1600 ⁇ L) intraperitoneally administered every 3 days (continue until the end of the observation period).
• CBM MiyaBM original powder (Miyarisan Pharmaceutical Co., Ltd.) 1 x 10 8 cfu/100 ⁇ L, 100 ⁇ L was orally administered three times a week.
• Tumor volume (mm 3 ) 1 ⁇ 2 ⁇ tumor minor axis ⁇ tumor minor axis ⁇ tumor major axis.
• the Kaplan-Meier curve in which a tumor volume of 1000 mm3 is defined as an event, is shown in Figure 3.
• the log-rank test shows that the TKI+CBM group exhibits a significantly higher progression-free rate than the control group and the TKI group.

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