WO2024111609A1 - Agent thérapeutique pour un cancer à mutation de kras - Google Patents

Agent thérapeutique pour un cancer à mutation de kras Download PDF

Info

Publication number
WO2024111609A1
WO2024111609A1 PCT/JP2023/041919 JP2023041919W WO2024111609A1 WO 2024111609 A1 WO2024111609 A1 WO 2024111609A1 JP 2023041919 W JP2023041919 W JP 2023041919W WO 2024111609 A1 WO2024111609 A1 WO 2024111609A1
Authority
WO
WIPO (PCT)
Prior art keywords
inhibitor
kras
cancer
sirpα
therapeutic agent
Prior art date
Application number
PCT/JP2023/041919
Other languages
English (en)
Japanese (ja)
Inventor
寛倫 衣斐
雄太 足立
Original Assignee
愛知県
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 愛知県 filed Critical 愛知県
Publication of WO2024111609A1 publication Critical patent/WO2024111609A1/fr

Links

Images

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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P37/04—Immunostimulants
    • 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

Definitions

  • the present invention relates to a therapeutic agent for KRAS mutant cancer, a pharmaceutical composition for treating KRAS mutant cancer, a method for treating KRAS mutant cancer, etc.
  • KRAS also known as K-RAS or K-ras
  • K-RAS gene mutations are one of the most frequently occurring gene mutations in cancer, and are known to be deeply involved in the development, proliferation, and progression of cancer.
  • KRAS gene mutations are found in 5%, 40%, and 90% of lung cancer, colon cancer, and pancreatic cancer, which are the leading causes of cancer deaths by site, respectively.
  • KRAS is a major component of the MAPK (mitogen-activated protein kinase) signaling pathway, but mutations in KRAS lead to cell cancer, and mutated KRAS activates many downstream signaling proteins such as MAPK, promoting the survival and proliferation of tumor cells (Non-Patent Document 1). Therefore, there has been a long awaited need for a therapeutic drug that can suppress tumor cells by targeting KRAS.
  • MAPK mitogen-activated protein kinase
  • sotorasib a specific inhibitor for the KRAS G12C mutation, was approved. Furthermore, adagrasib has also been developed as another KRAS G12C inhibitor, achieving the practical application of KRAS inhibitors, which had previously been described as "undruggable.”
  • the response rate of monotherapy with KRAS inhibitors is less than 50%, and the high efficacy that was previously expected has not been achieved.
  • the response rate of monotherapy with KRAS G12C inhibitors is only about 40%, but the cause and mechanism of this has not been clarified.
  • the object of the present invention is to provide a new combination therapy to improve the therapeutic effect of KRAS inhibitors against KRAS mutant cancers.
  • Non-Patent Document 1 MYC is a transcription factor that is overexpressed in many cancers and has been shown to increase the expression of CD47 (Casey, S. C., et al., Science, 2016, 352(6282):227-231.).
  • CD47 is expressed in blood cells and cancer cells, and binds as a ligand to SIRP ⁇ , a receptor expressed on macrophages.
  • Signals mediated by CD47 and SIRP ⁇ are also known as "Don't eat me" signals because they suppress the phagocytic activity of macrophages and other cells.
  • the present inventors added a KRAS inhibitor to lung cancer cell lines and colon cancer cell lines with KRAS mutations such as KRAS G12C and KRAS G12D, and comprehensively analyzed immune checkpoint-related factors whose expression levels change.
  • KRAS G12C and KRAS G12D KRAS mutations
  • KRAS G12D KRAS G12D
  • comprehensively analyzed immune checkpoint-related factors whose expression levels change As a result, contrary to the above prediction, it was found that the expression level of the CD47 gene was greatly increased in the presence of a KRAS inhibitor. This result suggests that a KRAS inhibitor paradoxically enhances the "Don't eat me signal" mediated by CD47, enabling cancer cells to evade the immune system.
  • the present inventors further discovered that the combined use of a KRAS inhibitor and an anti-CD47 antibody can dramatically improve the therapeutic effect against KRAS mutant cancers, and have completed the present invention.
  • the present invention is based on the above new findings and provides the following.
  • a therapeutic agent for treating KRAS mutant cancer comprising a CD47 inhibitor and/or a SIRP ⁇ inhibitor as an active ingredient, The therapeutic agent for KRAS mutant cancer, wherein the CD47 inhibitor and/or the SIRP ⁇ inhibitor is administered in combination with a KRAS inhibitor.
  • a therapeutic agent for treating KRAS mutant cancer comprising a KRAS inhibitor as an active ingredient, The therapeutic agent for KRAS mutant cancer, wherein the KRAS inhibitor is administered in combination with a CD47 inhibitor and/or a SIRP ⁇ inhibitor.
  • the anti-CD47 antibody is selected from the group consisting of magrolimab, AO-176, IBI188, IMC-002, AK117, ZL-1201, TQB2928, lemzoparimab, SRF231, CC-90002, HX009, IBI322, and PF-07257876.
  • the KRAS mutant cancer therapeutic agent according to (3) wherein the Fc fusion protein is TTI-621, TTI-622, evoluptor, or SL-172154.
  • the anti-SIRP ⁇ antibody is BI-765063/OSE172, GS-189, CC-95251, or ADU-1805.
  • the KRAS mutant cancer therapeutic agent according to any one of (1) to (7), wherein the KRAS inhibitor is selected from the group consisting of a KRAS G12C inhibitor, a KRAS G12D inhibitor, a KRAS G12V inhibitor, a KRAS G13C inhibitor, and a pan-KRAS inhibitor.
  • the KRAS G12C inhibitor is selected from the group consisting of sotrasib, adagrasib, JDQ443, and LY3537982.
  • a pharmaceutical composition for treating KRAS mutant cancer comprising the KRAS mutant cancer therapeutic agent according to any one of (1) to (12).
  • the present invention provides a new combination therapy for improving the therapeutic effect of KRAS inhibitors against KRAS mutant cancers.
  • the results of an analysis of survival time in the pleural dissemination model based on the day of LLC cell line transplantation are shown below.
  • the "*" in the figure indicates a significant difference (P ⁇ 0.001) based on the Log-rank test.
  • a KRAS mutant cancer therapeutic agent comprises a CD47 inhibitor and/or a SIRP ⁇ inhibitor as an active ingredient, and the CD47 inhibitor and/or the SIRP ⁇ inhibitor is administered in combination with a KRAS inhibitor.
  • the KRAS mutant cancer therapeutic agent of the present invention comprises a KRAS inhibitor as an active ingredient, and the KRAS inhibitor is administered in combination with a CD47 inhibitor and/or a SIRP ⁇ inhibitor.
  • treatment refers to the alleviation or elimination of symptoms associated with a disease, and/or the prevention or suppression of the progression of the disease, as well as the cure of the disease.
  • an “antibody” may be an immunoglobulin of any class (e.g., IgG, IgE, IgM, IgA, IgD, and IgY) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) that can specifically bind to and recognize an antigen.
  • An antibody may also be a recombinant antibody, a synthetic antibody, a chimeric antibody, or a humanized antibody.
  • fragment of an antibody refers to an antibody fragment that exhibits immune reactivity to an antigen.
  • fragments include Fab, Fab', F(ab') 2 , Fv fragments, Fv fragments stabilized by disulfide bonds (dsFv), (dsFv) 2 , bispecific dsFv (dsFv-dsFv'), diabodies stabilized by disulfide bonds (dsdiabodies), single-chain antibody molecules (scFv), dimeric scFvs (bivalent diabodies), multispecific antibodies, heavy chain antibodies such as camelized single domain antibodies (camelized antibodies; VHH antibodies), nanobodies, domain antibodies, and bivalent domain antibodies.
  • cancer is not limited, but examples include adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and large cell carcinoma.
  • Specific types of cancer include, for example, malignant melanoma, oral cancer, laryngeal cancer, pharyngeal cancer, thyroid cancer, lung cancer, breast cancer, esophageal cancer, gastric cancer, colorectal cancer (including colon cancer and rectal cancer), small intestine cancer, bladder cancer, prostate cancer, testicular cancer, uterine cancer, cervical cancer, endometrial cancer, ovarian cancer, stomach cancer, kidney cancer, liver cancer, pancreatic cancer, biliary tract cancer (including gallbladder cancer and bile duct cancer), brain tumor, head and neck cancer, mesothelioma, osteosarcoma, soft tissue sarcoma, glioma, pediatric tumors such as neuroblastoma, blood cancer, lymphoma, and myeloma.
  • KRAS mutant cancer includes any cancer that expresses a mutated KRAS protein.
  • the KRAS mutant cancer may be any of the cancers described above, but is preferably a solid cancer.
  • KRAS mutant solid cancers include, but are not limited to, KRAS mutant lung cancer (e.g., non-small cell lung cancer), colon cancer (e.g., colorectal cancer), pancreatic cancer, bile duct cancer, gallbladder cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, and thyroid cancer.
  • KRAS mutations in KRAS mutant cancers are mutations that may cause cancer or promote the survival or proliferation of cancer cells, such as gain-of-function or activation mutations.
  • Known KRAS mutations in KRAS mutant cancers include G12X, G13X, Q61X, and A146X.
  • X refers to any amino acid other than the amino acid residue in the wild-type sequence, and in the example of "G12X", it means that the glycine at codon 12 has been replaced with the amino acid X other than glycine.
  • Specific examples of KRAS G12X mutations include KRAS G12D, KRAS G12C, and KRAS G12V.
  • an example of a KRAS G13X mutation is KRAS G13C
  • an example of a KRAS Q61X mutation is KRAS Q61K
  • an example of a KRAS A146X mutation is A146T mutation.
  • KRAS inhibitor refers to a drug capable of inhibiting the function of KRAS protein and/or suppressing the expression of KRAS protein.
  • the KRAS inhibitor may be a small molecule compound, a peptide, or a nucleic acid drug.
  • the peptide may be an antibody or an antibody fragment.
  • KRAS inhibitors can be classified into KRAS G12C inhibitors, KRAS G12D inhibitors, KRAS G12V inhibitors, KRAS G13C inhibitors, KRAS Q61K inhibitors, and KRAS A146T inhibitors, which have high inhibitory activity against KRAS proteins having specific mutations, as well as pan-KRAS inhibitors, whose inhibitory activity does not depend on the type of mutation, and the like, and the KRAS inhibitor may be any of them.
  • KRAS inhibitors are those that have inhibitory activity against mutant KRAS in KRAS mutant cancers targeted by the therapeutic agent or pharmaceutical composition of the present invention, and for example, in the case of KRAS G12C mutation, KRAS G12C inhibitors or pan-KRAS inhibitors are preferred, and in the case of KRAS G12D mutation, KRAS G12D inhibitors or pan-KRAS inhibitors are preferred.
  • KRAS G12C inhibitors include sotorasib, adagrasib, JDQ443, LY3537982, RG6330, and RMC-6291.
  • KRAS G12D inhibitors include MRTX1133, RMC-9805, and ASP3082.
  • KRAS G13C inhibitors include RMC-8839.
  • pan-KRAS inhibitors include BI1701963, RMC-6236, LUNA18, BI-2865, and BI-2493.
  • CD47 Cluster of Differentiation 47
  • IAP integrated protein
  • CD47 is a five-transmembrane protein that functions as a ligand for SIRP ⁇ , which will be described later.
  • CD47 is presented on the surface of various cells, including cancer cells and blood cells, and inhibits the phagocytic action of SIRP ⁇ by binding as a ligand to SIRP ⁇ on macrophages and dendritic cells, so its function is sometimes called the "Don't eat me” signal. It is known that CD47 expression is increased by the activation of MYC (Casey, S. C., et al., Science, 2016, 352(6282):227-231.).
  • SIRP ⁇ signal regulatory protein ⁇
  • phagocytes such as macrophages and dendritic cells.
  • SIRP ⁇ is also known as CD172a.
  • CD47 inhibitor refers to a drug capable of inhibiting the function of CD47 and/or suppressing the expression of CD47.
  • the CD47 inhibitor may be a low molecular weight compound, a peptide, or a nucleic acid drug.
  • the peptide may be an antibody or an antibody fragment.
  • the nucleic acid drug may be, for example, an aptamer.
  • the CD47 inhibitor is an anti-CD47 antibody or a fragment thereof.
  • anti-CD47 antibodies include magrolimab, AO-176, IBI188, IMC-002, AK117, ZL-1201, TQB2928, lemzoparimab (TJC4), SRF231, CC-90002, HX009, IBI322, and PF-07257876.
  • the CD47 inhibitor is an Fc fusion protein containing the extracellular domain of SIRP ⁇ .
  • Fc fusion protein containing the extracellular domain of SIRP ⁇ refers to a fusion polypeptide containing the extracellular domain of SIRP ⁇ and the Fc domain of an immunoglobulin.
  • Fc fusion proteins containing the extracellular domain of SIRP ⁇ include TTI-621, TTI-622, evolupercept (ALX148), and SL-172154.
  • Evolupercept is a fusion protein of the N-terminal fragment of SIRP ⁇ and an IgG1 fragment, and SL-172154 is known as a SIRPa-Fc-CD40L fusion protein.
  • the CD47 inhibitor is a nucleic acid drug that controls the expression of the CD47 gene.
  • nucleic acid drugs that control the expression of the CD47 gene include antisense nucleic acids, siRNA, shRNA, and miRNA.
  • siRNA is a short double-stranded RNA molecule
  • shRNA is a hairpin RNA that can be processed by Dicer in vivo to generate siRNA.
  • siRNA and shRNA can be introduced into cells in vitro or in vivo, for example, together with a transfection reagent such as lipofectamine.
  • siRNA and shRNA can be incorporated into a vector and introduced into cells.
  • SIRP ⁇ inhibitor refers to a drug capable of inhibiting the function of SIRP ⁇ and/or suppressing the expression of SIRP ⁇ .
  • the SIRP ⁇ inhibitor may be a low molecular weight compound, a peptide, or a nucleic acid drug.
  • the peptide may be an antibody or an antibody fragment.
  • the nucleic acid drug may be, for example, an aptamer.
  • the SIRP ⁇ inhibitor is an anti-SIRP ⁇ antibody or a fragment thereof.
  • anti-SIRP ⁇ antibodies include BI-765063/OSE172, GS-189, CC-95251, and ADU-1805.
  • the SIRP ⁇ inhibitor is a nucleic acid drug that controls the expression of the SIRP ⁇ gene.
  • nucleic acid drugs that control the expression of the SIRP ⁇ gene include antisense nucleic acids, siRNA, shRNA, and miRNA.
  • CD47 inhibitors and SIRP ⁇ inhibitors see literature such as Maute, R. et al., Immuno-oncology and Technology, 2022, 13(C):1-13.
  • the KRAS inhibitor and the CD47 inhibitor and/or the SIRP ⁇ inhibitor are further administered in combination with an immune checkpoint inhibitor.
  • the KRAS mutant cancer therapeutic agent of the present invention contains a CD47 inhibitor and/or a SIRP ⁇ inhibitor as an active ingredient, and the CD47 inhibitor and/or the SIRP ⁇ inhibitor are administered in combination with a KRAS inhibitor and an immune checkpoint inhibitor.
  • the KRAS mutant cancer therapeutic agent of the present invention contains a KRAS inhibitor as an active ingredient, and the KRAS inhibitor is administered in combination with a CD47 inhibitor and/or a SIRP ⁇ inhibitor and an immune checkpoint inhibitor.
  • immune checkpoint inhibitor refers to a molecule that can inhibit cancer cells from evading the host immune response.
  • immune checkpoint inhibitors include, for example, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, Lag-3 inhibitors, Tim-3 inhibitors, TIGIT inhibitors, and BTLA inhibitors.
  • the immune checkpoint inhibitor may be an anti-PD-1 antibody or a fragment thereof, an anti-PD-L1 antibody or a fragment thereof, an anti-CTLA-4 antibody or a fragment thereof, or an anti-Lag-3 antibody or a fragment thereof, and specific examples include antibodies and fragments thereof such as pembrolizumab, nivolumab, atezolizumab, durvalumumab, avelumab, tislelizumab, cemiplimab, dostallimab, tremelimumab, and ipilimumab.
  • administered in combination or “used in combination” means, in principle, that two or more drugs are administered to the same individual by any method, and the administration method and timing of each drug administered in combination may be the same or different.
  • drugs that target two or more molecules can also be administered as single agents such as multispecific antibodies or complexes, and in this specification, this case is also included in “administered in combination.”
  • the method of administration of KRAS mutant cancer therapeutic agents shall conform to the explanation of the pharmaceutical composition for treating KRAS mutant cancer described below, and will not be explained here.
  • the above-mentioned CD47 inhibitor or SIRP ⁇ inhibitor can be administered in combination with an immune checkpoint inhibitor as a bispecific antibody
  • bispecific antibodies include anti-CD47/PD-1 bispecific antibodies, anti-CD47/PD-L1 bispecific antibodies, anti-CD47/CTLA-4 bispecific antibodies, anti-SIRP ⁇ /PD-1 bispecific antibodies, anti-SIRP ⁇ /PD-L1 bispecific antibodies, and anti-SIRP ⁇ /CTLA-4 bispecific antibodies.
  • Specific examples of anti-CD47/PD-1 bispecific antibodies or anti-CD47/PD-L1 bispecific antibodies include HX009, IBI322, and PF-07257876.
  • composition for treating KRAS mutant cancer in one embodiment of the present invention, a pharmaceutical composition for treating KRAS mutant cancer is provided.
  • the pharmaceutical composition for treating KRAS mutant cancer of the present invention comprises any one of the above-mentioned KRAS mutant cancer therapeutic agents and can treat KRAS mutant cancer.
  • the pharmaceutical composition for treating KRAS mutant cancer of the present invention includes an active ingredient as an essential component, and a pharma- ceutical acceptable carrier or other drug as an optional component.
  • the pharmaceutical composition for treating KRAS mutant cancer of the present invention may be composed of only the active ingredient. However, in order to facilitate the formation of a dosage form and to maintain the pharmacological effect and/or dosage form of the active ingredient, it is preferable that the pharmaceutical composition is composed of a pharmaceutical composition that includes a pharma- ceutical acceptable carrier, which will be described later.
  • the active ingredient in the pharmaceutical composition for treating KRAS mutant cancer of the present invention is a KRAS mutant cancer therapeutic agent.
  • the composition has already been described in detail above, so a detailed description thereof will be omitted here.
  • the number of KRAS mutant cancer therapeutic agents contained in the pharmaceutical composition for treating KRAS mutant cancer of the present invention is not limited, and may be one or more.
  • “Pharmaceutically acceptable carrier” refers to a solvent and/or additive that can be commonly used in the field of pharmaceutical formulation technology and that is little or not harmful to living organisms.
  • Examples of pharma- ceutically acceptable solvents include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. These are preferably sterilized and, if necessary, adjusted to be isotonic with blood.
  • pharma- ceutically acceptable additives include, for example, excipients, binders, disintegrants, fillers, emulsifiers, flow regulators, lubricants, etc.
  • Excipients include, for example, sugars such as monosaccharides, disaccharides, cyclodextrins, and polysaccharides (more specifically, including, but not limited to, glucose, sucrose, lactose, raffinose, mannitol, sorbitol, inositol, dextrin, maltodextrin, starch, and cellulose), metal salts (e.g., sodium chloride, sodium or calcium phosphate, calcium sulfate, magnesium sulfate, calcium carbonate), citric acid, tartaric acid, glycine, low, medium, or high molecular weight polyethylene glycols (PEGs), pluronics, kaolin, silicic acid, or combinations thereof.
  • sugars such as monosaccharides, disaccharides, cyclodextrins, and polysaccharides (more specifically, including, but not limited to, glucose, sucrose, lactose, raffinose
  • Binders include, for example, starch paste made from corn, wheat, rice, or potato starch, simple syrup, glucose solution, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, shellac, and/or polyvinylpyrrolidone.
  • Disintegrants include, for example, the above-mentioned starches, lactose, carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, sodium hydrogen carbonate, calcium carbonate, alginic acid or sodium alginate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, or salts thereof.
  • fillers include the above-mentioned sugars and/or calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate).
  • emulsifiers examples include sorbitan fatty acid esters, glycerin fatty acid esters, sucrose fatty acid esters, and propylene glycol fatty acid esters.
  • flow regulators and lubricants examples include silicates, talc, stearates, or polyethylene glycol.
  • the formulation may contain, as necessary, dissolution aids (solubilizers), suspending agents, diluents, surfactants, stabilizers, absorption promoters (e.g., quaternary ammonium salts, sodium lauryl sulfate), bulking agents, moisturizers (e.g., glycerin, starch), adsorbents (e.g., starch, lactose, kaolin, bentonite, colloidal silicic acid), coating agents, preservatives, antioxidants, buffers, etc.
  • dissolution aids solubilizers
  • suspending agents e.g., diluents, surfactants, stabilizers, absorption promoters (e.g., quaternary ammonium salts, sodium lauryl sulfate), bulking agents, moisturizers (e.g., glycerin, starch), adsorbents (e.g., starch, lactose, kaolin
  • the pharmaceutical composition for treating KRAS mutant cancer of the present invention may contain other drugs to the extent that the pharmacological effect of the active ingredient is not lost.
  • other drugs include drugs that have a therapeutic effect against KRAS mutant cancer, similar to the KRAS mutant cancer treatment agent.
  • the dosage form of the pharmaceutical composition for treating KRAS mutant cancer of the present invention is not particularly limited as long as it does not or hardly inactivates the active ingredient, the KRAS mutant cancer therapeutic agent of the present invention, and is capable of fully exerting its pharmacological effect in vivo after administration.
  • Dosage forms can be classified into liquid dosage forms or solid dosage forms (including semi-solid dosage forms such as gels) depending on their form, but the pharmaceutical composition for treating KRAS mutant cancer of the present invention may be either of them.
  • Dosage forms can also be broadly classified into oral dosage forms and parenteral dosage forms depending on the method of administration, but either of these may be used.
  • Specific dosage forms include, for oral dosage forms, liquid dosage forms such as suspensions, emulsions, and syrups, and solid dosage forms such as powders (including powders, powders, and candy powders), granules, tablets, capsules, sublingual tablets, and lozenges.
  • liquid dosage forms such as injections, suspensions, and emulsions are examples.
  • the pharmaceutical composition for treating KRAS mutant cancer of the present invention can be administered by any method known in the art, so long as it is a method that can administer an effective amount of the KRAS mutant cancer therapeutic agent of the present invention, which is an active ingredient, to a living body for the treatment of KRAS mutant cancer.
  • effective amount refers to the amount of an active ingredient required to exert its function, i.e., in this invention, the amount of a therapeutic agent required to treat KRAS mutant cancer, and which causes little or no harmful side effects to the living body to which it is applied. This effective amount may vary depending on conditions such as information about the subject, the route of administration, and the number of doses.
  • subject refers to an individual animal to which the KRAS mutant cancer therapeutic agent or pharmaceutical composition for treating KRAS mutant cancer of the present invention is applied. Specifically, it refers to a mammal, including, for example, primates, pet animals, livestock, and sports animals, and humans are particularly preferred.
  • Subject information refers to various individual information about the subject, including, for example, the subject's age, weight, sex, general health condition, drug sensitivity, and whether or not the subject is taking any medication. The effective amount and the dosage calculated based thereon are determined by the judgment of a physician or veterinarian depending on the information about each individual subject. When it is necessary to administer a large amount of the pharmaceutical composition for treating KRAS mutant cancer of the present invention to obtain a sufficient effect in treating KRAS mutant cancer, it can be administered in several divided doses to reduce the burden on the subject.
  • the pharmaceutical composition for treating KRAS mutant cancer of the present invention may be administered either systemically or locally.
  • systemic administration include intravascular injection such as intravenous injection and oral administration.
  • local administration include intratumoral administration, rectal administration, and intraperitoneal administration.
  • Preferred administration methods are intravenous administration, subcutaneous administration, intratumoral administration, and oral administration.
  • DDS drug delivery system
  • the dosage or intake is appropriately selected depending on the age, body weight, symptoms, health condition, type of composition, etc. of the subject. For example, based on the weight of the KRAS mutant cancer therapeutic agent, it may be 0.001 mg/kg/day to 1000 mg/kg/day, 0.01 mg/kg/day to 500 mg/kg/day, 0.1 mg/kg/day to 200 mg/kg/day, 1 mg/kg/day to 100 mg/kg/day, 5 mg/kg/day to 50 mg/kg/day, or 10 mg/kg/day.
  • the pharmaceutical composition for treating KRAS mutant cancer of the present invention includes a CD47 inhibitor and/or a SIRP ⁇ inhibitor, and the CD47 inhibitor and/or the SIRP ⁇ inhibitor are administered in combination with a KRAS inhibitor.
  • the KRAS inhibitor and the CD47 inhibitor and/or the SIRP ⁇ inhibitor can also be administered in combination with an immune checkpoint inhibitor.
  • the pharmaceutical composition for treating KRAS mutant cancer of the present invention includes a KRAS inhibitor, and the KRAS inhibitor is administered in combination with a CD47 inhibitor and/or a SIRP ⁇ inhibitor.
  • the KRAS inhibitor and the CD47 inhibitor and/or the SIRP ⁇ inhibitor can also be administered in combination with an immune checkpoint inhibitor.
  • the pharmaceutical composition for treating KRAS mutant cancer of the present invention contains a CD47 inhibitor and/or a SIRP ⁇ inhibitor and an immune checkpoint inhibitor, and the CD47 inhibitor and/or the SIRP ⁇ inhibitor and the immune checkpoint inhibitor are administered in combination with a KRAS inhibitor.
  • the KRAS inhibitor may be administered orally, and/or the CD47 inhibitor and/or the SIRP ⁇ inhibitor may be administered intravenously. Additionally, the immune checkpoint inhibitor may be administered intravenously.
  • the CD47 inhibitor and/or SIRP ⁇ inhibitor and the immune checkpoint inhibitor can be co-administered.
  • the co-administration may be intravenous.
  • KRAS mutant cancer includes any cancer expressing mutated KRAS protein, for example, solid cancer.
  • KRAS mutant solid cancer is not particularly limited, but may be, for example, KRAS mutant lung cancer (e.g., non-small cell lung cancer), colon cancer (e.g., colorectal cancer), pancreatic cancer, bile duct cancer, gallbladder cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, or thyroid cancer.
  • a method for treating KRAS mutant cancer includes a step of administering a KRAS inhibitor to a subject and a step of administering a CD47 inhibitor and/or a SIRP ⁇ inhibitor to a subject as essential steps, and includes a step of administering an immune checkpoint inhibitor to a subject as an optional step.
  • the subject may be a human or a non-human animal.
  • the step of administering a CD47 inhibitor and/or a SIRP ⁇ inhibitor to a subject may be a step of co-administering a CD47 inhibitor and/or a SIRP ⁇ inhibitor and an immune checkpoint inhibitor.
  • a KRAS inhibitor typically 0.01 g to 10 g, 0.1 g to 5 g, or 0.5 g to 2 g of the KRAS inhibitor can be administered once to several times a day, every other day, every third day, once a week, or once every two weeks.
  • the KRAS inhibitor can be administered, for example, orally.
  • a CD47 inhibitor and/or a SIRP ⁇ inhibitor typically 0.1 mg to 10 g, 1 mg to 5 g, 10 mg to 2 g, 100 mg to 1 g, or 200 mg to 500 mg of a CD47 inhibitor and/or a SIRP ⁇ inhibitor can be administered once to several times a week, every two weeks, every three weeks, every four weeks, once a month, once every two months, every six months, or once a year.
  • the CD47 inhibitor and/or the SIRP ⁇ inhibitor can be administered, for example, intravenously.
  • an immune checkpoint inhibitor typically 0.1 mg to 10 g, 1 mg to 5 g, 10 mg to 2 g, 100 mg to 1 g, or 200 mg to 500 mg of the immune checkpoint inhibitor can be administered once to several times a week, every two weeks, every three weeks, every four weeks, once a month, once every two months, every six months, or once a year.
  • the immune checkpoint inhibitor can be administered, for example, intravenously.
  • an agent for enhancing the therapeutic effect of a KRAS inhibitor against KRAS mutant cancer which consists of or contains a CD47 inhibitor and/or a SIRP ⁇ inhibitor.
  • an agent for enhancing the combined therapeutic effect of a KRAS inhibitor and an immune checkpoint inhibitor against KRAS mutant cancer which consists of or contains a CD47 inhibitor and/or a SIRP ⁇ inhibitor.
  • KRAS mutant cancer therapeutic agents in the treatment of KRAS mutant cancer.
  • a CD47 inhibitor and/or a SIRP ⁇ inhibitor for use in enhancing the therapeutic effect of a KRAS inhibitor.
  • a KRAS inhibitor in the manufacture of a medicament for treating a KRAS mutant cancer, wherein the KRAS inhibitor is administered in combination with a CD47 inhibitor and/or a SIRP ⁇ inhibitor.
  • the KRAS inhibitor and the CD47 inhibitor and/or the SIRP ⁇ inhibitor may further be administered in combination with an immune checkpoint inhibitor.
  • a CD47 inhibitor and/or a SIRP ⁇ inhibitor in the manufacture of a medicament for treating a KRAS mutant cancer, wherein the CD47 inhibitor and/or the SIRP ⁇ inhibitor are administered in combination with a KRAS inhibitor.
  • the CD47 inhibitor and/or the SIRP ⁇ inhibitor and the KRAS inhibitor may further be administered in combination with an immune checkpoint inhibitor.
  • Example 1 Verification of the macrophage accumulation promoting effect of KRAS inhibitors (the purpose) An inhibitor for the KRAS G12C mutation was approved in 2021. However, the response rate of the single agent against KRAS mutant tumors is only about 40%, and combination therapy with an immune checkpoint inhibitor is seen as a promising way to further improve the response rate. In this example, we examine the dynamics of macrophages in tumor tissue to examine the effect of the KRAS G12C inhibitor on the tumor immune environment.
  • LLC cell line As a cancer cell line with KRAS G12C mutation, a cell line (hereinafter simply referred to as "LLC cell line”) was prepared by knocking out the NRAS gene in the LCC mouse lung cancer cell line (JCRB, JCRB1348) with KRAS G12C mutation and NRAS mutation. After culturing this LLC cell line in RPMI medium, 5 ⁇ 105 cells were transplanted into the thoracic cavity of mice (C57BL/6JJcl, male, 4-6 weeks old) to prepare a thoracic dissemination model. From day 7 to day 10 after cell transplantation, 100 ⁇ L of 50 mg/kg of the KRAS G12C inhibitor Sotorasib (MCE, HY-114277) was orally administered every day.
  • MCE KRAS G12C inhibitor Sotorasib
  • Tumor tissue was isolated from the mice on day 3 of KRAS G12C inhibitor treatment, sections were prepared from the tumor tissue, and stained with the macrophage-specific marker F4/80 (APC anti-mouse F4/80, BioLegend, 123116).
  • Example 2 Verification of the CD47 expression induction effect by KRAS inhibitors (the purpose) We will investigate immune checkpoint-related molecules induced by KRAS inhibitors.
  • the colon cancer cell line SNU-407 which has a KRAS G12D mutation, was exposed to 1 ⁇ M of a KRAS G12D inhibitor (MRTX1133), and proteins were extracted 72 hours later.
  • MRTX1133 a KRAS G12D inhibitor
  • the results of detecting CD47 by Western blotting are shown in Figure 3. It was revealed that exposure to the KRAS G12D inhibitor significantly increased the expression level of CD47 protein.
  • CD47 is known as a "Don't eat me signal" that inhibits phagocytosis by macrophages. It is generally known that CD47 is controlled by myc downstream of KRAS, and it is believed that KRAS inhibitors suppress CD47 expression. However, the results of Examples 1 and 2 revealed that KRAS G12C inhibitors induce macrophage infiltration into tumor tissue while enhancing CD47 expression in tumor cells. This suggests the possibility that KRAS G12C inhibitors enhance the "Don't eat me signal" by enhancing CD47 expression, thereby contributing to immune checkpoint inhibitor resistance.
  • Example 3 Verification of anti-tumor effect of anti-CD47 antibody in resistance to KRAS inhibitor/anti-PD-L1 antibody combination therapy (the purpose)
  • KRAS inhibitors increase CD47 expression in cancer cells.
  • Increased CD47 expression leads to enhanced "Don't eat me signaling" and may contribute to resistance to immune checkpoint inhibitors. Therefore, in this Example, we examine whether immune checkpoint inhibitor resistance can be overcome by combining a CD47 inhibitor with a KRAS G12C inhibitor.
  • a pleural dissemination model was prepared in the same manner as in Example 1, and then the KRAS G12C inhibitor monotherapy group was treated with the above-mentioned method.
  • the KRAS G12C inhibitor/anti-PD-L1 antibody group in addition to the KRAS G12C inhibitor, 2.5 mg/mL of the anti-PD-L1 antibody Tecentriq (Chugai Pharmaceutical, 21K010Y) was intraperitoneally administered to the mice twice a week at 100 ⁇ L.
  • the above-mentioned anti-PD-L1 antibody and 0.5 mg/mL of the anti-CD47 antibody were intraperitoneally administered to the mice three times a week at 100 ⁇ L.
  • Example 4 Analysis of survival time (the purpose) We will verify that the combination of KRAS G12C inhibitor with CD47 inhibitor increases survival time in a pleural dissemination model.
  • the survival rate of mice was analyzed over a one-year period based on the start date of treatment for the LLC thoracic dissemination model.
  • Example 5 Verification of the CD47 expression induction effect of pan-KRAS inhibitor (the purpose) The effect of pan-KRAS inhibitors on enhancing CD47 expression in tumor cells will be examined.
  • KRAS G12C mutant lung cancer cell lines NCI-H358 and LU65, were exposed to 1 ⁇ M of a pan-RAS inhibitor (BI-2865), and after 72 hours, the cells were fixed with paraformaldehyde and expression was detected by FACS using CD47 antibody and fluorescent secondary antibody.
  • a pan-RAS inhibitor BI-2865

Landscapes

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

Abstract

Le but de la présente invention est de permettre d'obtenir une nouvelle polythérapie pour améliorer l'effet thérapeutique d'un inhibiteur de KRAS contre un cancer à mutation de KRAS.　L'invention concerne également un agent thérapeutique dirigé contre le cancer à mutation de KRAS, contenant un inhibiteur de CD47 et/ou un inhibiteur de SIRPα en tant que principes actifs, l'inhibiteur de CD47 et/ou l'inhibiteur de SIRPα étant administrés en combinaison avec un inhibiteur de KRAS.
PCT/JP2023/041919 2022-11-24 2023-11-22 Agent thérapeutique pour un cancer à mutation de kras WO2024111609A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2022187560 2022-11-24
JP2022-187560 2022-11-24

Publications (1)

Publication Number Publication Date
WO2024111609A1 true WO2024111609A1 (fr) 2024-05-30

Family

ID=91196180

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2023/041919 WO2024111609A1 (fr) 2022-11-24 2023-11-22 Agent thérapeutique pour un cancer à mutation de kras

Country Status (1)

Country Link
WO (1) WO2024111609A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020106647A2 (fr) * 2018-11-19 2020-05-28 Amgen Inc. Polythérapie comprenant un inhibiteur de krasg12c et un ou plusieurs principes pharmaceutiquement actifs supplémentaires pour le traitement de cancers
JP2022548791A (ja) * 2019-09-24 2022-11-21 ミラティ セラピューティクス， インコーポレイテッド 組み合わせ療法
WO2023165615A1 (fr) * 2022-03-04 2023-09-07 I-Mab Biopharma Co., Ltd. Polythérapies comprenant un inhibiteur de kras pour le traitement du cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020106647A2 (fr) * 2018-11-19 2020-05-28 Amgen Inc. Polythérapie comprenant un inhibiteur de krasg12c et un ou plusieurs principes pharmaceutiquement actifs supplémentaires pour le traitement de cancers
JP2022548791A (ja) * 2019-09-24 2022-11-21 ミラティ セラピューティクス， インコーポレイテッド 組み合わせ療法
WO2023165615A1 (fr) * 2022-03-04 2023-09-07 I-Mab Biopharma Co., Ltd. Polythérapies comprenant un inhibiteur de kras pour le traitement du cancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HU HUANHUAN, CHENG RONGJIE, WANG YANBO, WANG XIAOJUN, WU JIANZHUANG, KONG YAN, ZHAN SHOUBIN, ZHOU ZHEN, ZHU HONGYU, YU RANRAN, LIA: "Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47", JOURNAL OF CLINICAL INVESTIGATION, vol. 133, no. 2, 17 January 2023 (2023-01-17), pages 1 - 18, XP093088510, DOI: 10.1172/JCI153470 *
JUDE CANON, KAREN REX, ANNE Y. SAIKI, CHRISTOPHER MOHR, KEEGAN COOKE, DHANASHRI BAGAL, KEVIN GAIDA, TYLER HOLT, CHARLES G. KNUTSON: "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity", NATURE, vol. 575, no. 7781, 7 November 2019 (2019-11-07), pages 217 - 223, XP055770919, DOI: 10.1038/s41586-019-1694-1 *

Similar Documents

Publication Publication Date Title
JP6894952B2 (ja) 癌治療のためのｐｄ−１拮抗薬およびｖｅｇｆｒ阻害剤の組み合わせ
JP6774421B2 (ja) がんの治療のための方法、組成物、及びキット
RU2702332C2 (ru) Антитела к в7-н1 и к ctla-4 для лечения немелкоклеточного рака легкого
US10253111B2 (en) Methods and compositions relating to anti-Chi3l1 antibody reagents
US20210069147A1 (en) Pharmaceutical combination and uses thereof
US9642918B2 (en) Combination of inotuzumab ozogamicin and torisel for the treatment of cancer
US20210246208A1 (en) Combined inhibition of pd-1/pd-l1, tgfb and dna-pk for the treatment of cancer
TW201639597A (zh) 用於治療癌症之ｐｄ－１／ｐｄ－ｌ１抑制劑
Panchal et al. Role of targeted immunotherapy for pancreatic ductal adenocarcinoma (PDAC) treatment: An overview
JP2021534094A (ja) 未分化リンパ腫キナーゼ阻害剤と組み合わせてｅｇｆ／ｅｇｆｒ経路を抑制するための方法および組成物
JPWO2020027100A1 (ja) 抗体−薬物コンジュゲート投与による転移性脳腫瘍の治療
US20220195059A1 (en) Rank Pathway Inhibitors in Combination with CDK Inhibitors
Do et al. First-in-human, first-in-class, phase I trial of the fucosylation inhibitor SGN-2FF in patients with advanced solid tumors
CN104853756A (zh) 利用netrin-1干扰药物和化疗药物的联合治疗
JP2022064906A (ja) ｕＰＡＲＡＰを標的にする抗体薬物複合体
Olaoba et al. Is the new angel better than the old devil? Challenges and opportunities in CD47-SIRPα-based cancer therapy
WO2024111609A1 (fr) Agent thérapeutique pour un cancer à mutation de kras
JP2023512276A (ja) 癌及び癌転移の治療のための併用療法
Liu et al. Development and evaluation of a novel anti-colorectal cancer monoclonal antibody, WL5
JP2022504468A (ja) 転移性膵臓腺癌の処置
US20220064304A1 (en) Methods of treating cancer pain by administering a pd-1 inhibitor
WO2024101382A1 (fr) Composition à utiliser dans la régulation du point de contrôle immunitaire
US20230136997A1 (en) Targeting abcb5 in glioblastoma multiforme
US20210214442A1 (en) Neoadjuvant cancer treatment with immunotoxin and checkpoint inhibitor combination
WO2024054848A1 (fr) Amélioration de la phagocytose