WO2016163489A1 - 医薬 - Google Patents
医薬 Download PDFInfo
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- WO2016163489A1 WO2016163489A1 PCT/JP2016/061463 JP2016061463W WO2016163489A1 WO 2016163489 A1 WO2016163489 A1 WO 2016163489A1 JP 2016061463 W JP2016061463 W JP 2016061463W WO 2016163489 A1 WO2016163489 A1 WO 2016163489A1
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Definitions
- the present invention relates to a medicament containing a Toll-like receptor agonist and LAG-3 protein, a mutant thereof, or a derivative thereof.
- cancer vaccine therapy is a method of inducing cancer by inducing a specific immune response against a cancer antigen in the body of the patient by directly administering the cancer antigen to the patient.
- cancer antigens administered to patients cancer antigen proteins themselves, cancer antigen-derived peptides, nucleic acids encoding them, dendritic cells presenting cancer antigens, and cancer cells themselves are used. .
- adjuvants are also administered together with cancer antigens.
- As adjuvants cytokines and Toll-like receptor (TLR) agonists that stimulate various immunocompetent cells are used.
- TLR3 is one of the innate immune system molecules that recognizes virus-derived double-stranded RNA and promotes the production of type I interferons that exhibit strong antiviral activity. It is known that a double-stranded RNA analog Poly I: C (also called polyinosinic: polycytidylic acid) known as a TLR3 agonist is also used as an adjuvant for vaccines (for example, Patent Document 1). .
- TLR9 is one of the innate immune system molecules that recognizes and functions unmethylated CpG DNA derived from bacteria and viruses. It is known that CpG ODN (synthetic nucleic acid CpG oligodeoxynucleotide) which is a ligand of TLR9 also has an adjuvant effect for vaccines.
- LAG-3 is known to be used as an adjuvant for vaccines (for example, Patent Document 2).
- LAG-3 is a translation product of a lymphocyte activation gene (lymphocyte activation gene 3) and is also called CD223.
- LAG-3 binds to MHC class II molecules, negatively regulates the proliferation of activated T cells and maintains homeostasis of T cells, and plays an important role in the function of regulatory T cells (Treg) It is also known to be involved in the regulation of plasma cell dendritic cell homeostasis.
- OncoImmunology 1 5, 699-716; August 2012
- OncoImmunology 2 8, e25238; August 2013
- An object of the present invention is to provide a medicine containing a novel combination of adjuvants.
- the present inventors have found a novel combination as a drug useful for inducing cancer immunity. That is, the present invention is as follows. [1] A Toll-like receptor agonist, LAG-3 protein, a variant thereof, or a derivative thereof, Containing a medicament. [2] A Toll-like receptor agonist, The pharmaceutical agent according to [1], wherein the LAG-3 protein, a mutant thereof, or a derivative thereof is administered in combination. [3] The medicament according to [1] or [2], wherein the Toll-like receptor agonist is Toll-like receptor 3 agonist or Toll-like receptor 9 agonist.
- a medicine containing a novel combination of adjuvants can be provided.
- FIG. 1 shows an outline of a test protocol comparing the effects of various adjuvants in a cancer vaccine using a cancer antigen-derived peptide.
- FIG. 2 shows the change in tumor size of a group using PBS as a control in the test of FIG.
- FIG. 3 shows the change in tumor size of two groups using IFA as an adjuvant in the study of FIG.
- FIG. 4 shows the change in tumor size of 3 groups using PT as an adjuvant in the test of FIG.
- FIG. 5 shows the change in tumor size of 4 groups using Poly I: C as adjuvant in the test of FIG.
- FIG. 6 shows the change in tumor size of 5 groups using the combination of Poly I: C and CpG as adjuvant in the test of FIG.
- FIG. 1 shows an outline of a test protocol comparing the effects of various adjuvants in a cancer vaccine using a cancer antigen-derived peptide.
- FIG. 2 shows the change in tumor size of a group using PBS as a control in the test of FIG
- FIG. 7 shows changes in tumor size of 6 groups using LAG-3 as an adjuvant in the test of FIG.
- FIG. 8 shows the change in tumor size of 7 groups using LAG-3 and Poly I: C as adjuvant in the test of FIG.
- FIG. 9A shows a hematoxylin-eosin stained image of tumor tissue in the same test as in FIG.
- FIG. 9B shows fluorescent staining images of the nucleus and immune cells of the tumor tissue in the same test as in FIG.
- FIG. 10 shows that mice that were able to suppress the increase in tumor size by cancer vaccine (when LAG-3 and PolyPoI: C were used as adjuvants) in the same test as in FIG. 1 were inoculated with tumor cells again at a later date. The result of measuring the increase in tumor size is shown.
- lymph nodes were collected from mice vaccinated with a cancer vaccine in the same test as in FIG. 1, and immune cells separated from the lymph nodes were co-cultured with tumor cells previously inactivated by irradiation with radiation. Then, the result of having measured the proliferation ability of the immune cell is shown.
- FIG. 11B shows the results of measuring the amount of cytokine and the like in the cell supernatant after the same co-culture as in FIG. 11A.
- FIG. 12A shows that lymph nodes were collected from mice vaccinated with a cancer vaccine in the same test as in FIG. 1, and cell surface marker molecules PD-1, BTLA, TIGIT, and LAG ⁇ in CD8 positive immune cells isolated from the lymph nodes.
- FIG. 12B shows that lymph nodes were collected from mice vaccinated with cancer vaccine in the same test as in FIG. 1, and cell surface marker molecules PD-1, BTLA, TIGIT, and LAG ⁇ in CD4 positive immune cells isolated from the lymph nodes were collected.
- FIG. 13A shows the measurement results of immune cell proliferation ability.
- FIG. 13B shows the measurement results of FN-gamma production.
- FIG. 14 shows the change in tumor size for one group using PBS as a control.
- FIG. 15 shows the change in tumor size of the two groups using Poly I: C as an adjuvant.
- FIG. 16 shows the change in tumor size of the three groups using LAG-3 and Poly I: C as adjuvants.
- FIG. 17 shows the change in tumor size of the 4 groups using only LAG-3 and Poly I: C without using the P1A peptide.
- FIG. 18 shows the change in tumor size of 5 groups using RIBOXXOL as an adjuvant.
- FIG. 19 shows changes in tumor size of 6 groups using a combination of LAG-3 and RIBOXXOL as an adjuvant.
- FIG. 20 shows the change in tumor size of 7 groups using a combination of LAG-3 and MPL as adjuvant.
- FIG. 21 shows the change in tumor size of 8 groups using a combination of LAG-3 and Imiquimod as adjuvant.
- FIG. 22 shows the change in tumor size of 9 groups using a combination of LAG-3 and CpG as an adjuvant.
- FIG. 23 shows the change in tumor size for one group using IFA as an adjuvant.
- FIG. 24 shows the change in tumor size of the two groups using Poly I: C as an adjuvant.
- FIG. 25 shows the change in tumor size of the three groups using LAG-3 as an adjuvant.
- FIG. 26 shows the change in tumor size of 4 groups using LAG-3 and Poly I: C as adjuvants.
- the medicament according to the present invention includes a Toll-like receptor agonist (TLR agonist) and LAG-3 protein, a mutant thereof, or a derivative thereof.
- TLR agonist Toll-like receptor agonist
- LAG-3 protein a mutant thereof, or a derivative thereof.
- TLR agonist refers to a molecule that, when bound to any Toll-like receptor (TLR), stimulates the same as when a natural ligand binds to TLR.
- TLR agonists as described in Trends in ImmunologyunVol.30 No.1, 23-32, Immunity 33, October 29, 2010, 492-503, and World Journal of Vaccines, 2011, 1, 33-78 TLR agonists are known, and these known TLR agonists can be used as TLR agonists in the present invention.
- TLR3 agonist, TLR4 agonist, TLR7 agonist, TLR8 agonist, TLR9 agonist or TLR10 agonist Can do.
- the TLR agonist may be a TLR3 agonist or a TLR9 agonist.
- TLR3 agonist means a molecule that, when bound to TLR3, gives a stimulus in the same manner as when a natural ligand is bound to TLR3.
- TLR3 recognizes virus-derived double-stranded RNA and activates the innate immune system.
- Poly I: C which is a synthetic double-stranded polynucleotide similar in structure to double-stranded RNA, is known, but is not limited thereto.
- Poly I: C may be a salt thereof, for example, a sodium salt.
- RIBOXXOL can also be used as a TLR3 agonist.
- TLR4 agonist means a molecule that, when bound to TLR4, gives a stimulus in the same manner as when a natural ligand is bound to TLR4.
- TLR4 recognizes bacterial lipopolysaccharide (LPS) and activates the innate immune system.
- MPL is known as a TLR4 agonist, but is not limited thereto.
- MPL may be a salt thereof, for example, a sodium salt.
- TLR5 agonist means a molecule that, when bound to TLR5, gives stimulation in the same manner as when a natural ligand is bound to TLR5.
- TLR5 recognizes bacterial flagellin and activates the innate immune system.
- flagellin derived from various bacteria or a recombinant protein of flagellin is known, but not limited thereto.
- TLR7 agonist means a molecule that, when bound to TLR7, provides stimulation in the same manner as when a natural ligand is bound to TLR7.
- TLR8 agonist refers to a molecule that, when bound to TLR8, gives stimulation in the same manner as when a natural ligand is bound to TLR8.
- TLR7 and TLR8 recognize virus-derived single-stranded RNA and activate the innate immune system.
- Imiquimod is known as a TLR7 / 8 agonist, but is not limited thereto.
- Imiquimod may be a salt thereof, for example, a sodium salt.
- TLR9 agonist means a molecule that, when bound to TLR9, gives a stimulus in the same manner as when a natural ligand is bound to TLR9.
- TLR9 recognizes CpG DNA from bacteria and viruses and activates the innate immune system.
- CpG ODN is known as a TLR9 agonist, but is not limited thereto.
- CpG ODN may be a salt thereof, for example, a sodium salt.
- LAG-3 protein, variant thereof, or derivative thereof means LAG-3 protein, functional variant thereof, or functional derivative thereof.
- the LAG-3 protein used in the present invention may be derived from any animal.
- the LAG-3 protein can be a protein derived from the same animal as the subject to which the medicament according to the present invention is administered. Accordingly, human LAG-3 can be used as long as the medicament according to the present invention is administered to humans.
- LAG-3 protein is a protein having the amino acid sequence shown in NCBI Accession No. P18627.5 in the case of humans.
- a functional variant of LAG-3 protein is (i) a variant of LAG-3 consisting of an amino acid sequence in which one or several amino acids are added, substituted, or deleted in the amino acid sequence of LAG-3. And having the function of the LAG-3 protein necessary for exerting the effects of the present invention, (ii) LAG-3 amino acid sequence and at least 80% or more, 85% or more, 90% or more, 95 % Or more, 98% or more, 99% or more of LAG-3 variant consisting of amino acid sequence having the function of LAG-3 necessary to exert the effect of the present invention, (iii) a LAG-3 protein, a mutant of the above (i), or a partial polypeptide of the mutant of (ii), which has the function of the LAG-3 protein necessary for exerting the effects of the present invention.
- “one or several” means one, two, three, four, five, six, seven, eight, nine, or ten.
- amino acid is used in its broadest sense and includes artificial amino acid variants and derivatives in addition to natural amino acids.
- amino acids are: natural proteinaceous L-amino acids; D-amino acids; chemically modified amino acids such as amino acid variants and derivatives; natural non-protein amino acids such as norleucine, ⁇ -alanine, ornithine; And chemically synthesized compounds having properties known in the art.
- non-natural amino acids include ⁇ -methyl amino acids (such as ⁇ -methylalanine), D-amino acids, histidine-like amino acids (such as ⁇ -hydroxy-histidine, homohistidine, ⁇ -fluoromethyl-histidine and ⁇ -methyl-histidine) Amino acids having an extra methylene in the side chain (“homo" amino acids) and amino acids in which the carboxylic acid functional amino acids in the side chain are replaced with sulfonic acid groups (such as cysteic acid).
- ⁇ -methyl amino acids such as ⁇ -methylalanine
- D-amino acids such as ⁇ -methylalanine
- histidine-like amino acids such as ⁇ -hydroxy-histidine, homohistidine, ⁇ -fluoromethyl-histidine and ⁇ -methyl-histidine
- Amino acids having an extra methylene in the side chain (“homo" amino acids)
- Examples of functional derivatives of LAG-3 protein include fusion proteins of all or part of LAG-3 protein with other proteins or polypeptides, proteins with sugar chains and lipids added to LAG-3 protein, etc. It is done.
- An example of a functional derivative of LAG-3 protein is a fusion protein of LAG-3 and IgG.
- Examples of functional derivatives of the LAG-3 protein include those described in Journal of Translational Medicine 2014, 12:97.
- the medicament according to the present invention may contain a TLR agonist, a LAG-3 protein, a mutant thereof, or a derivative thereof, and a substance that induces a specific immune response against cancer cells.
- a “substance that induces a specific immune response against cancer cells” is a substance that can induce an immune response that destroys cancer cells in vivo or induces apoptosis of cancer cells. If it is, it will not specifically limit, For example, cancer antigen protein, cancer antigen origin peptide, the nucleic acid which codes them, cancer antigen presentation cell, tumor cell itself is mentioned.
- cancer antigen protein is a protein that is specifically expressed in cancer cells that the immune system recognizes and attacks as a foreign substance. It may be expressed in cancer cells of all cancer types or expressed in cancer cells of a specific cancer type. As the cancer antigen protein, a protein having strong immunogenicity and not expressed at all in normal cells is preferable. Although it does not specifically limit as a cancer antigen protein, What is described in Clin Cancer Res 2009; 15 (17) 5323 is mentioned.
- the “cancer antigen-derived peptide” has a peptide having a partial amino acid sequence of a cancer antigen protein, or a sequence including addition, substitution, or deletion of 1 or 2 amino acids in the amino acid sequence.
- the cancer antigen-derived peptide may be composed of 8 or more and 11 or less amino acid residues. When such a peptide is administered subcutaneously to a patient, it is taken up by antigen-presenting cells such as dendritic cells and macrophages and presented together with HLA molecules on the cell surface.
- Cytotoxic T cell (CTL) progenitor cells that are reactive to the presented peptides are clonally proliferated, and the proliferated and differentiated mature CTL migrates to the cancer tissue via lymph flow. Mature CTL attacks peptide-expressing cancer cells having the same sequence as the administered peptide and induces apoptosis.
- nucleic acid is not particularly limited as long as it is a nucleic acid encoding cancer antigen protein or cancer antigen-derived peptide, and includes RNA, DNA, PNA, LNA, or a chimera of two or more thereof. . These nucleic acids can be inserted into a vector or the like and administered to a patient according to a known method, and express a cancer antigen protein or a cancer antigen-derived peptide in vivo.
- the “cancer antigen-presenting cell” means an antigen-presenting cell that is present on the surface of the HLA molecule bound with a cancer antigen-derived peptide.
- Dendritic cells and macrophages can be used as antigen-presenting cells. Dendritic cells are particularly highly capable of inducing CTL.
- the dendritic cells presenting the antigen are, for example, isolated mononuclear cells from the patient's own peripheral blood and differentiated into immature dendritic cells, and then added cancer antigen protein or cancer antigen-derived peptide to the medium. And further differentiated into mature dendritic cells.
- the medicament according to the present invention may contain two or more “substances that induce a specific immune response against cancer cells”.
- the medicament according to the present invention may contain cancer antigen-derived peptides derived from two or more different cancer antigen proteins.
- the medicament according to the present invention can be used for cancer vaccine therapy.
- the TLR agonist and the LAG-3 protein, a variant thereof, or a derivative thereof function as an adjuvant and enhance the induction of an immune response by “a substance that induces a specific immune response against cancer cells”.
- a substance that induces a specific immune response against cancer cells As shown in the examples described later, when a TLR agonist and LAG-3 protein are used in combination, an extremely high antitumor effect can be obtained even at a low dose that cannot be obtained when used alone. it can.
- adjuvant means a group of molecules that enhances the induction of an immune response when administered together with a substance that induces the immune response.
- Cancer vaccine therapy can be used for cancer prevention or treatment.
- the prevention or treatment of cancer includes reduction in tumor size, delay or stop of increase, inhibition of cancer metastasis (delay or stop), inhibition of cancer cell growth (delay or stop), It means causing at least one of inhibition (delay or cessation) of cancer recurrence and alleviation of one or more symptoms associated with cancer.
- cancer is used herein in its broadest sense and includes astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, schwannoma, nerve Fibrosarcoma, neuroblastoma, pituitary tumor (eg, pituitary adenoma), medulloblastoma, melanoma, brain tumor, prostate cancer, head and neck cancer, esophageal cancer, renal cancer, renal cell cancer, pancreatic cancer, Breast cancer, lung cancer, colon cancer, colon cancer, stomach cancer, skin cancer, ovarian cancer, bladder cancer, fibrosarcoma, squamous cell carcinoma, neuroectodermal, thyroid tumor, lymphoma, leukemia, multiple myeloma, hepatocellular carcinoma, mesothelial Examples include, but are not limited to, epidermoid carcinoma and the like.
- the present invention also includes an adjuvant for cancer vaccine therapy comprising a TLR agonist and a LAG-3 protein, a variant thereof, or a derivative thereof.
- a TLR agonist is an adjuvant for administration in combination with a LAG-3 protein, variant thereof, or a derivative thereof, and a LAG-3 protein, variant, or derivative thereof is an adjuvant for administration in combination with a TLR agonist obtain.
- Such an adjuvant may be administered to a patient together with various “substances that induce a specific immune response against cancer cells”. As used herein, the meaning of “together” does not mean that they are administered at the same time, and the TLR agonist and the LAG-3 protein, a variant thereof, or a derivative thereof are inside or outside the patient.
- a TLR agonist and a LAG-3 protein, a variant thereof, or a derivative thereof are administered to a patient so that they can function as an adjuvant in cancer vaccine therapy.
- a LAG-3 protein, a variant thereof, or a derivative thereof may be a drug containing a TLR agonist, or a LAG-3 protein for administration in combination with a TLR agonist, its It may be a pharmaceutical containing a mutant or a derivative thereof.
- a medicament containing such a TLR agonist is used as a LAG-3 protein, a variant thereof, or a derivative thereof and an adjuvant, and induces a specific immune response against cancer cells, preferably a peptide derived from a cancer antigen. , Can enhance the induction of immune response.
- a substance containing a LAG-3 protein, a variant thereof, or a derivative thereof for administration in combination with a substance that induces a specific immune response against cancer cells and a TLR agonist A medicament containing such LAG-3 protein, a variant thereof, or a derivative thereof is used as a TLR agonist and an adjuvant to induce a specific immune response against cancer cells, preferably against a cancer antigen-derived peptide. Induction of response may be enhanced.
- a pharmaceutical comprising the TLR agonist according to the present invention and a LAG-3 protein, a variant thereof, or a derivative thereof, and a TLR agonist and the LAG-3 protein, a variant thereof, or a derivative thereof are used as an active ingredient of the pharmaceutical. You can also.
- a pharmaceutical comprising a TLR agonist according to the present invention and a LAG-3 protein, a variant thereof, or a derivative thereof as an active ingredient is used as an anticancer agent exhibiting a high antitumor effect, as shown in Examples described later. It can also be done.
- anticancer agent means an agent that can be used for the prevention or treatment of cancer.
- a drug that is an anticancer agent may contain a TLR agonist and a LAG-3 protein, a variant thereof, or a derivative thereof as active ingredients, and a substance that induces a specific immune response against cancer cells. Further, it may be included. Further, in the present invention, the medicament that is an anticancer agent contains, as an active ingredient, a substance that induces a specific immune response against cancer cells, preferably a peptide derived from a cancer antigen, and as an adjuvant, a TLR agonist and , LAG-3 protein, a variant thereof, or a derivative thereof.
- Each component of the pharmaceutical agent according to the present invention can be dissolved in a water-soluble solvent, formulated into a pharmaceutically acceptable salt form, and administered to a patient.
- Such pharmaceutically acceptable salt forms are buffered at physiological pH in the form of physiologically acceptable water-soluble salts such as sodium, potassium, magnesium, and calcium salts. A form is mentioned.
- a water-insoluble solvent can also be used. Examples of such a water-insoluble solvent include alcohols such as ethanol and propylene glycol.
- the medicament according to the present invention can be used as a pharmaceutical composition, and can be administered orally or parenterally in any aspect of the pharmaceutical composition, and its dosage form is not particularly limited.
- the dosage form of the pharmaceutical composition for example, liquid (for example, injection), dispersion, suspension, tablet, pill, powder, suppository, powder, fine granule, granule, capsule, syrup Nasal drops and natural ear drops.
- parenteral administration for example, intraperitoneal administration, subcutaneous administration, intradermal administration, intramuscular administration, intravenous administration, or intranasal administration can be used.
- the pharmaceutical preparation according to the present invention can be prepared according to a known method.
- pharmaceutically acceptable carriers and additives excipients, binders, dispersants, disintegrants, lubricants, solubilizers, solubilizers, colorants, flavoring agents
- Stabilizers emulsifiers, suspending agents, absorption promoters, surfactants, pH adjusting agents, preservatives, antioxidants, and the like.
- carriers and additives include pharmaceutically acceptable organic solvents such as water, saline, phosphate buffer, dextrose, glycerol, ethanol, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, Sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, glutamic acid, aspartic acid, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, xanthan gum, gum arabic, casein, agar, polyethylene glycol, diglycol Glycerin, glycerin, propylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, Serum albumin, mannitol, sorbitol, lactose, glucose, corn starch, microcrystalline cellulose, surfactant, sodium bisulfite, sodium bisulfate, sodium thios
- surfactants such as polyoxyethylene lauryl ethers, sodium lauryl sulfate, and saponins are used as absorption accelerators for improving absorption of poorly absorbable drugs that are difficult to be absorbed through mucosa such as peptides.
- Bile salts such as glycocholic acid, deoxycholic acid and taurocholic acid; chelating agents such as EDTA and salicylic acids; fatty acids such as caproic acid, capric acid, lauric acid, oleic acid, linoleic acid and mixed micelles; enamine derivatives N-acyl collagen peptides, N-acyl amino acids, cyclodextrins, chitosans, nitric oxide donors, and the like can be used.
- the medicament according to the present invention contains a peptide
- it may be encapsulated or adsorbed in polylactic acid / glycolic acid (PLGA) microcapsules or porous hydroxyapatite fine particles to give sustained release, and pulse-release iontophoresis It may be percutaneously absorbed using a patch system.
- PLGA polylactic acid / glycolic acid
- the medicament according to the present invention may contain, as one preparation, a TLR agonist and a LAG-3 protein, a variant thereof, or a derivative thereof, and each of them as a separate preparation, that is, a preparation containing a TLR agonist. And a combination with a preparation containing the LAG-3 protein, a mutant thereof, or a derivative thereof. Further, the medicament according to the present invention includes, as one preparation, a substance that induces a specific immune response against cancer cells, a TLR agonist, and a LAG-3 protein, a mutant thereof, or a derivative thereof.
- each contains a preparation that contains a substance that induces a specific immune response against cancer cells, a preparation that contains a TLR agonist, and a LAG-3 protein, a variant thereof, or a derivative thereof. It may be a combination with a preparation.
- a combination of preparations may be used, and as long as a combination of three kinds of components is obtained, a combination of a preparation containing any two kinds of ingredients and a preparation containing any two kinds of ingredients may be used.
- the medicament according to the present invention may be a kit.
- the kit may contain a TLR agonist and a LAG-3 protein, a variant thereof, or a derivative thereof, and a substance that induces a specific immune response against cancer cells, a TLR agonist And LAG-3 protein, a variant thereof, or a derivative thereof.
- an additional adjuvant may be included.
- additional adjuvants include precipitating adjuvants such as aluminum hydroxide, sodium hydroxide, aluminum phosphate, calcium phosphate, alum, and carboxyvinyl polymer, as well as Freund's complete adjuvant, Freund's incomplete adjuvant, liquid paraffin, Oily adjuvants such as lanolin, Montanide ISA763AV, and Montanide ISA51 can be mentioned.
- the medicament according to the present invention may be used in combination with other anticancer agents, or may be combined with radiation therapy or surgical treatment.
- Other anticancer agents include adriamycin, daunomycin, mitomycin, cisplatin, vincristine, epirubicin, methotrexate, 5-fluorouracil, aclacinomycin, nitrogen mustard, cyclophosphamide, bleomycin, daunorubicin, doxorubicin, vincristine, vinblastine , Low molecular weight compounds such as vindesine, tamoxifen, and dexamethasone, and cytokines that activate immunocompetent cells (eg, human interleukin 2, human granulocyte macrophage colony stimulating factor, human macrophage colony stimulating factor, and human interleukin 12) And the like.
- immunocompetent cells eg, human interleukin 2, human granulocyte macrophage colony stimulating factor, human macrophage colony stimulating factor, and
- the present invention also includes a method for treating cancer by administering a therapeutically effective amount of the medicament according to the present invention.
- the therapeutically effective amount can be appropriately determined by those skilled in the art according to the patient's symptoms, age, sex, weight, sensitivity difference, administration method, administration interval, type of preparation, and the like.
- a patient's disease can be treated or prevented by administering a TLR agonist, a LAG-3 protein, a mutant thereof, or a derivative thereof, and a patient in need thereof.
- the present invention also includes a TLR agonist, a LAG-3 protein, a mutant thereof, or a derivative thereof, and a method for inducing a specific immune response against cancer cells that is administered to a patient in need thereof. provide.
- a substance that induces a specific immune response against cancer cells preferably a peptide derived from a cancer antigen Further administration may be performed.
- a substance that induces a specific immune response against cancer cells preferably a cancer antigen-derived peptide, can be exerted more potently.
- the medicament according to the present invention is preferably administered in combination.
- Administration of the medicament according to the present invention means that a TLR agonist and a LAG-3 protein, a variant thereof, or a derivative thereof may be administered to a patient, and any combination, at the same time, or It may be administered at another time.
- the medicament according to the present invention contains a substance that induces a specific immune response against cancer cells
- a substance that induces a specific immune response against cancer cells, a TLR agonist, and a LAG-3 protein A mutant thereof, or a derivative thereof may be administered in any combination, at the same time, or at another time.
- a TLR agonist and a LAG-3 protein, a variant thereof, or a derivative thereof are mixed to prepare a dosage preparation for simultaneous administration. May be.
- the LAG-3 protein, a variant, or a derivative thereof may be administered after administering the TLR agonist, or after the LAG-3 protein, a variant, or a derivative thereof is administered.
- a TLR agonist may be administered.
- the medicament according to the present invention contains a substance that induces a specific immune response against cancer cells
- it when administered simultaneously, it may be administered simultaneously as one preparation, and at the time of administration, the cancer cells
- a substance that induces a specific immune response against a TLR agonist, a LAG-3 protein, a mutant thereof, or a derivative thereof may be mixed to prepare a dosage formulation and administered simultaneously.
- the TLR agonist and the LAG-3 protein, a variant, or a derivative thereof are simultaneously or separately.
- a TLR agonist and a LAG-3 protein, a variant thereof, or a derivative thereof may be administered simultaneously or separately, followed by administration of a substance that induces a specific immune response against cancer cells.
- a substance that induces a specific immune response against cancer cells is administered,
- the other of LAG-3 protein, a variant thereof, or a derivative thereof may be administered.
- it may be administered based on the administration interval of each component, that is, based on the respective administration regimen, according to the characteristics of each component.
- Cancer Vaccine According to the protocol shown in FIG. 1, the effects of various adjuvants in a cancer vaccine using a cancer antigen-derived peptide were compared.
- P815 cells (mouse mastocytoma derived from DBA / 2 mice) were transplanted into DBA / 2 mice.
- a cancer antigen-derived peptide a peptide (hereinafter referred to as “P1A peptide”) that consists of a partial sequence of the P1A protein, which is a tumor antigen of P815 tumor, and is known to be presented in an MHC H-2Ld-restricted manner.
- the amino acid sequence of the P1A peptide is LPYLGWLVF (SEQ ID NO: 1).
- P1A CTL T cells expressing a T cell receptor recognizing P1A peptide were used.
- the spleen was collected from the P1A-CTL transgenic mice owned by the present inventor, and the positive rate was confirmed by TCR V ⁇ 8.3 (the TCR marker into which the gene was introduced). Was determined and administered.
- the following substances were used as adjuvants.
- Bordetella pertussis (PT) BioFarma, Bandung, Indonesia) Poly I: C (TLR3 agonist) (Invivogen, SanDiego, USA) CpG (TLR9 agonist) (Invivogen, SanDiego, USA) IFA (Incomplete Freund's Adjuvant) (Seppic, Paris, France) LAG-3 (Adipogen, SanDiego, USA)
- mice were inoculated subcutaneously with 5 ⁇ 10 5 cells of P815 tumor cells per mouse, and this day was designated as Day 0.
- 2.5 ⁇ 10 5 cells of P1A CTL per mouse were injected intravenously.
- 50 ⁇ g of P1A peptide per mouse and an adjuvant mixed in PBS were injected subcutaneously.
- the mice were divided into 9 groups of 5 mice, and the following adjuvants were used for each group.
- Group 1 PBS (control)
- Group 2 IFA (50 ⁇ L / mouse) 3 groups: PT (1 ⁇ 10 8 / mouse)
- Group 4 Poly IC (50 ⁇ g / mouse)
- Group 5 Poly IC (50 ⁇ g / mouse) + CPG (10 ⁇ g / mouse)
- Group 6 LAG-3 (1 ⁇ g / mouse)
- Group 7 LAG-3 (1 ⁇ g / mouse) + Poly IC (50 ⁇ g / mouse)
- mice The changes in tumor size (mm 3 ) for all mice after Day 7 are shown in FIGS. In groups 1-6, the tumor size gradually increased, and many mice died along the way. 0 mice in groups 2, 3 and 6 survived until Day 70, 1 in groups 1 and 4 and 3 in group 5, all 5 in group 7 The mice did not increase in tumor size and survived until Day 115.
- mice were inoculated subcutaneously with 5 ⁇ 10 5 P815 tumor cells per mouse to form cancer model mice.
- 2.5 ⁇ 10 5 cells of P1A CTL per mouse were injected intravenously.
- 50 ⁇ g of P1A peptide per mouse and an adjuvant mixed in PBS were injected subcutaneously. The following adjuvants were used for each mouse.
- Group 1 IFA (50 ⁇ L / mouse)
- Group 2 Poly IC (50 ⁇ g / mouse)
- Group 3 LAG-3 (1 ⁇ g / mouse)
- Group 4 LAG-3 (1 ⁇ g / mouse) + Poly IC (50 ⁇ g / mouse)
- tumor tissue was collected on Day 21, and a preparation of a tumor tissue section was prepared.
- a tissue image was observed by staining with hematoxylin and eosin, and fluorescence staining of cell nuclei and immune cells (CD4 cells and CD8 cells) was performed.
- the following reagents were used for fluorescent tissue staining.
- CD4 cell primary antibody Rat Anti-Mouse CD4 Purified IgG2b. Clone: GK1.5 (eBioscience) CD4 cell secondary antibody: Mouse monoclonal (2B 10A8) Anti-Rat IgG2b heavy chain (Alexa FluorR 647), (abcam) CD8 cell primary antibody: Rat Anti-Mouse CD8 ⁇ Purified IgG2a. Clone: 53-6.7 (eBioscience) CD8 cell secondary antibody: Mouse monoclonal (2A 8F4) Anti-Rat IgG2a heavy chain (Alexa FluorR 488) (abcam)
- FIG. 9A shows a hematoxylin / eosin stained image
- FIG. 9B shows fluorescent stained images of cell nuclei and immune cells.
- mice 10 right shows the change in the average tumor size (mm 3 ) of the mice after inoculation with P815 cells.
- ⁇ is a DBA / 2 mouse judged to have rejected the tumor
- ⁇ is a naive DBA / 2 mouse.
- Naive DBA / 2 mice showed an increase in tumor size when inoculated with either P815 cells or L1210 cells.
- mice judged to have rejected tumor growth caused by P815 cells although tumor size increased with inoculation with another tumor cell, L1210 cells, an increase in tumor size with P815 cell inoculation was observed.
- Group 1 IFA (50 ⁇ L / mouse)
- Group 2 Poly IC (50 ⁇ g / mouse)
- Group 3 LAG-3 (1 ⁇ g / mouse)
- Group 4 LAG-3 (1 ⁇ g / mouse) + Poly IC (50 ⁇ g / mouse)
- lymph nodes close to the tumor site were collected from lymph nodes in the axilla or inguinal region, and 1.5 ⁇ 10 5 separated immune cells and 4 ⁇ 10 4 P815 cells irradiated with 100 Gy were co-cultured for 3 days.
- the immune cell proliferation ability was measured by adding 3 H-thymidine; 37 KBq / well to the culture supernatant and measuring the radioactivity of 3 H-thymidine incorporated into the cells after 4 hours.
- FIG. 11A shows the measurement results of immune cell proliferation ability
- FIG. 11B shows the measurement results of cytokines and the like.
- LAG-3 and poly IC were combined as an adjuvant, an increase in immune cell proliferation ability was observed.
- LAG-3 and poly IC are combined as an adjuvant among cytokines, production of IFN-gamma, GM-CSF, IL-4, IL-5, and IL-17A is increased. It was.
- Group 1 IFA (50 ⁇ L / mouse)
- Group 2 Poly IC (50 ⁇ g / mouse)
- Group 3 LAG-3 (1 ⁇ g / mouse)
- Group 4 LAG-3 (1 ⁇ g / mouse) + Poly IC (50 ⁇ g / mouse)
- lymph nodes near the tumor site are collected from lymph nodes in the axilla or inguinal region, and CD8 and V ⁇ 8.3 expression positive cell group (killer T cell) or CD4 and V ⁇ 8.3 expression positive cell group (Helper T cells) were collected.
- the expression levels of PD-1, BTLA, TIGIT, and LAG-3 which are cell surface marker molecules of cells (CD4 cells and CD8 cells), were measured.
- PD-1 Anti-Mouse CD279 (PD-1) PE.
- BTLA Anti-Mouse CD272 (BTLA) PE.
- TIGIT PE anti-mouse TIGIT (Vstm3) Antibody.
- LAG-3 Anti-Mouse CD223 (Lag-3) PE.
- the results for CD8 cells are shown in FIG. 12A, and the results for CD4 cells are shown in FIG. 12B.
- LAG-3 and poly IC were combined as an adjuvant, both CD4 positive cells and CD8 positive cells showed a significant decrease in the expression level of PD-1, TIGIT, and LAG-3, but BTLA expression There was little decrease in quantity.
- Group 1 IFA (50 ⁇ L / mouse)
- Group 2 Poly IC (50 ⁇ g / mouse)
- Group 3 LAG-3 (1 ⁇ g / mouse)
- Group 4 LAG-3 (1 ⁇ g / mouse) + Poly IC (50 ⁇ g / mouse)
- lymph nodes near the tumor site or both lymph nodes
- the cells were cultured in the presence of 2, 5 or 0 ⁇ g / mL gp100 peptide.
- Immune cell growth capacity is determined by adding 3 H-thymidine; 37 KBq / well to the culture supernatant and measuring the radioactivity of 3 H-thymidine incorporated into the cells during the last 10 hours of the 3-day culture period was measured.
- the amount of IFN-gamma produced in the cell supernatant cultured for 3 days in the presence of 10 ⁇ g / mL gp100 peptide was measured using Bio-Plex Pro mouse cytokine 23-Plex Immunoassay kit (BIO-RAD).
- the measurement result of the immune cell proliferation ability is shown in FIG. 13A, and the measurement result of the IFN-gamma production amount is shown in FIG. 13B.
- FIG. 13A The measurement result of the immune cell proliferation ability is shown in FIG. 13A
- the measurement result of the IFN-gamma production amount is shown in FIG. 13B.
- ⁇ represents the results of the 1 group
- ⁇ represents the 2 groups
- ⁇ represents the 3 groups
- ⁇ represents the 4 groups.
- Group 1 P1A peptide only (control)
- Group 2 Poly IC (50 ⁇ g / mouse)
- Group 3 Poly IC (50 ⁇ g / mouse) + LAG-3 (1 ⁇ g / mouse)
- Group 4 No P1A peptide, Poly IC (50 ⁇ g / mouse) + LAG-3 (1 ⁇ g / mouse) only
- Group 5 RIBOXXOL (100 ⁇ g / mouse) 6 groups: RIBOXXOL (100 ⁇ g / mouse) + LAG-3 (1 ⁇ g / mouse) 7 groups: MPL (10 ⁇ g / mouse) + LAG-3 (1 ⁇ g / mouse) 8 groups: Imiquimod (50 ⁇ g / mouse) + LAG-3 (1 ⁇ g / mouse) 9 groups: CpG (10 ⁇ g / mouse) + LAG-3 (1 ⁇ g / mouse) Changes in tumor size (mm 3 ) for all mice after Day 7 are shown in FIGS.
- Group 1 IFA (50 ⁇ L / mouse)
- Group 2 Poly IC (50 ⁇ g / mouse)
- Group 3 LAG-3 (1 ⁇ g / mouse)
- Group 4 LAG-3 (1 ⁇ g / mouse) + Poly IC (50 ⁇ g / mouse) Changes in tumor size (mm 3 ) for all mice after Day 5 are shown in FIGS. 21-24. Five mice in each group died on Day 31 in Group 1, Day 35 in Group 2, Day 37 in Group 3, and Day 37, while all mice died on Day 57 in Group 4. Compared to group 1, there was no significant effect of extending survival in groups 2 and 3, but in group 4, a significant increase in survival was confirmed for all groups 1, 2, and 3. It was.
- SEQ ID NO: 1 shows the amino acid sequence of the P1A peptide.
- SEQ ID NO: 2 shows the amino acid sequence of the gp100 peptide.
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Abstract
Description
すなわち、本発明は、以下のとおりである。
〔1〕
Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、
を含む、医薬。
〔2〕
Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、を併用投与するための、〔1〕に記載の医薬。
〔3〕
前記Toll様受容体アゴニストが、Toll様受容体3アゴニスト又はToll様受容体9アゴニストである、〔1〕又は〔2〕に記載の医薬。
〔4〕
前記Toll様受容体アゴニストが、Poly I:C又はその塩である、〔1〕から〔3〕のいずれかに記載の医薬。
〔5〕
前記LAG-3タンパク質、その変異体、又はその誘導体が、LAG-3タンパク質とIgGの融合タンパク質である、〔1〕から〔4〕のいずれかに記載の医薬。
〔6〕
少なくとも1種のがん細胞に対する特異的な免疫応答を誘導する物質をさらに含む、〔1〕から〔5〕のいずれかに記載の医薬。
〔7〕
Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、
少なくとも1種のがん細胞に対する特異的な免疫応答を誘導する物質と、を併用投与するための、〔6〕に記載の医薬。
〔8〕
前記がん細胞に対する特異的な免疫応答を誘導する物質が、がん抗原由来ペプチドである、〔6〕又は〔7〕に記載の医薬。
〔9〕
2種以上のがん抗原由来ペプチドを含む、〔8〕に記載の医薬。
〔10〕
がんワクチン療法に用いるための、〔1〕から〔9〕のいずれかに記載の医薬。
〔11〕
抗がん剤である、〔1〕から〔10〕のいずれかに記載の医薬。
〔12〕
Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、
を含むがん細胞に対する特異的な免疫応答の誘導に用いられる、あるいは、がんワクチン療法に用いられるアジュバント。
〔13〕
Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、
を含むがん細胞に対する特異的な免疫応答の誘導に用いられる、あるいは、がんワクチン療法に用いられる組合せ。
〔14〕
Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、それを必要とする患者に投与する、患者の疾患を治療又は予防する方法。
〔15〕
Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、それを必要とする患者に投与する、がん細胞に対する特異的な免疫応答を誘導する方法。
また、本明細書において「TLR8アゴニスト」とは、TLR8に結合すると、TLR8に天然のリガンドが結合したときと同じように刺激を与える分子をいう。
TLR7及びTLR8は、ウイルス由来の一本鎖RNAを認識し、自然免疫系を活性化する。TLR7/8アゴニストとしては、Imiquimodが知られているがこれに限定されない。本発明に用いる場合、Imiquimodはその塩であってもよく、例えばナトリウム塩とすることができる。
本明細書において「1又は数個」とは、1個、2個、3個、4個、5個、6個、7個、8個、9個、又は10個を意味する。
本明細書において「アジュバント」は、免疫応答を誘導する物質と一緒に投与されることにより、当該免疫応答の誘導を増強させる分子群を意味する。
本発明においては、LAG-3タンパク質、その変異体、又はその誘導体と併用投与するための、TLRアゴニストを含む医薬であってもよく、TLRアゴニストと併用投与するための、LAG-3タンパク質、その変異体、又はその誘導体を含む医薬であってもよい。
また、本発明においては、がん細胞に対する特異的な免疫応答を誘導する物質と、LAG-3タンパク質、その変異体、又はその誘導体と併用投与するための、TLRアゴニストを含む医薬であってもよく、かかるTLRアゴニストを含む医薬は、LAG-3タンパク質、その変異体、又はその誘導体とアジュバントとして、がん細胞に対する特異的な免疫応答を誘導する物質、好ましくは、がん抗原由来ペプチドに対し、免疫応答の誘導を増強し得る。本発明においては、がん細胞に対する特異的な免疫応答を誘導する物質と、TLRアゴニストと併用投与するための、LAG-3タンパク質、その変異体、又はその誘導体を含む医薬であってもよく、かかるLAG-3タンパク質、その変異体、又はその誘導体を含む医薬は、TLRアゴニストとアジュバントとして、がん細胞に対する特異的な免疫応答を誘導する物質、好ましくは、がん抗原由来ペプチドに対し、免疫応答の誘導を増強し得る。
また、本発明において、抗がん剤である医薬は、有効成分として、がん細胞に対する特異的な免疫応答を誘導する物質、好ましくは、がん抗原由来ペプチドを含み、アジュバントとして、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体とを含んでいてもよい。
本発明に係る医薬ががんワクチンとして用いられる場合も経口投与又は非経口投与することができる。非経口投与としては、例えば、腹腔内投与、皮下投与、皮内投与、筋肉内投与、静脈内投与、又は鼻腔内投与を用いることができる。
本発明に係る医薬がペプチドを含む場合、ポリ乳酸・グリコール酸(PLGA)マイクロカプセルや多孔性ヒドロキシアパタイト微粒子等に封入又は吸着させて徐放性を付与してもよく、パルス放出型イオントフォレシス貼付剤システムを利用して経皮吸収させてもよい。
また、本発明に係る医薬が、一の製剤として、がん細胞に対する特異的な免疫応答を誘導する物質、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体と、を含んでいてもよく、それぞれ別の製剤として、すなわち、がん細胞に対する特異的な免疫応答を誘導する物質を含む製剤と、TLRアゴニストを含む製剤と、LAG-3タンパク質、その変異体、又はその誘導体を含む製剤との組み合わせであってもよい。がん細胞に対する特異的な免疫応答を誘導する物質と、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体とを、2種の成分を含む製剤と、残り1種の成分を含む製剤の組み合せとしてもよく、3種の成分の組み合わせとなるのであれば、任意の2種の成分を含む製剤と、任意の2種の成分を含む製剤の組み合わせとしてもよい。
また、本発明に係る医薬は、キットであってもよい。キットである場合、キットは、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体と、を含いんでいてもよく、がん細胞に対する特異的な免疫応答を誘導する物質、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体と、を含んでいてもよい。
本発明においては、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体と、それを必要とする患者に投与することにより、患者の疾患を治療又は予防することができる。また、本発明においては、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体と、それを必要とする患者に投与する、がん細胞に対する特異的な免疫応答を誘導する方法をも提供する。
患者の疾患を治療又は予防する場合、あるいは、がん細胞に対する特異的な免疫応答を誘導する方法において、がん細胞に対する特異的な免疫応答を誘導する物質、好ましくは、がん抗原由来ペプチドをさらに投与してもよい。
がん細胞に対する特異的な免疫応答を誘導することにより、がん細胞に対する特異的な免疫応答を誘導する物質、好ましくは、がん抗原由来ペプチドの薬効をより強力に発揮させることができる。
本発明に係る医薬が併用投与されるとは、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体とが、患者に投与されていればよく、それぞれ任意の組み合わせで、同時に、また、別時に投与してもよい。また、本発明に係る医薬ががん細胞に対する特異的な免疫応答を誘導する物質を含む場合には、がん細胞に対する特異的な免疫応答を誘導する物質と、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体とを、それぞれ任意の組み合わせで、同時に、また、別時に投与してもよい。
同時に投与する場合には、一の製剤として同時に投与してもよく、投与時にTLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体とを混合して投与製剤として調整して同時に投与してもよい。
別時に投与する場合には、TLRアゴニストを投与した後に、LAG-3タンパク質、その変異体、又はその誘導体を投与してもよく、LAG-3タンパク質、その変異体、又はその誘導体を投与した後に、TLRアゴニストを投与してもよい。
別時に投与する場合には、がん細胞に対する特異的な免疫応答を誘導する物質を投与した後に、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体とを、それぞれ同時に又は別時に投与してもよく、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体とを、それぞれ同時に又は別時に投与した後に、がん細胞に対する特異的な免疫応答を誘導する物質を投与してもよく、また、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体の一方を投与した後に、がん細胞に対する特異的な免疫応答を誘導する物質を投与し、TLRアゴニストと、LAG-3タンパク質、その変異体、又はその誘導体の他方を投与してもよい。別時に投与する場合には、各成分の特性に応じて、各成分の投与間隔に基づき、すなわち、それぞれの投与レジメンに基づいて投与してもよい。
図1に示すプロトコールにしたがって、がん抗原由来ペプチドを用いたがんワクチンにおける各種アジュバントの効果を比較した。
がんモデルマウスとして、DBA/2マウスにP815細胞(DBA/2マウス由来のマウス肥満細胞腫)を移植して用いた。
がん抗原由来ペプチドとして、P815腫瘍の腫瘍抗原であるP1Aタンパク質の部分配列からなり、MHCのH-2Ld拘束性に提示されることが知られているペプチド(以下「P1Aペプチド」という。)を用いた。P1Aペプチドのアミノ酸配列はLPYLGWLVF(配列番号:1)である。
P1A CTLとして、P1Aペプチドを認識するT細胞受容体を発現するT細胞を用いた。実験では、本発明者が所有するP1A-CTLトランスジェニックマウスから脾臓を採取し、TCR Vα8.3(遺伝子導入したTCRのマーカー)にて陽性率を確認し、それに基づいてP1A-CTLの細胞数を決定し、投与した。
アジュバントとしては以下の物質を用いた。
百日咳菌全菌体(PT)(BioFarma, Bandung, Indonesia)
Poly I:C(TLR3アゴニスト)(Invivogen, SanDiego, USA)
CpG(TLR9アゴニスト)(Invivogen, SanDiego, USA)
IFA(不完全フロイントアジュバント)(Seppic, Paris, France)
LAG-3(Adipogen, SanDiego, USA)
DBA/2マウスに1匹当たり5×105細胞のP815腫瘍細胞を皮下接種し、この日をDay 0とした。Day 8に1匹当たり2.5×105細胞のP1A CTLを静脈注射した。Day 9及びDay 16に、1マウス当たり50μgのP1AペプチドとアジュバントをPBS中に混和したものを皮下注射した。マウスを5匹ずつ9群に分け、それぞれに以下のアジュバントを用いた。
1群:PBS(コントロール)
2群:IFA(50μL/mouse)
3群:PT(1×108/mouse)
4群:Poly IC(50μg/mouse)
5群:Poly IC(50μg/mouse)+CPG(10μg/mouse)
6群:LAG-3(1μg/mouse)
7群:LAG-3(1μg/mouse)+Poly IC(50μg/mouse)
Day 7以降のすべてのマウスについての腫瘍サイズ(mm3)の変化を図2~8に示す。
1~6群では、いずれも徐々に腫瘍サイズが増大し、多くのマウスが途中で死亡した。Day 70まで腫瘍サイズが増大することなく生存したマウスは、2、3及び6群では0匹、1及び4群では1匹、5群では3匹であったところ、7群では、5匹すべてのマウスにおいて腫瘍サイズの増大が見られず、Day 115まで生存した。
DBA/2マウスに1匹当たり5×105細胞のP815腫瘍細胞を皮下接種してがんモデルマウスとし、この日をDay 0とした。Day 8に1匹当たり2.5×105細胞のP1A CTLを静脈注射した。Day 9及びDay 14に、1マウス当たり50μgのP1AペプチドとアジュバントをPBS中に混和したものを皮下注射した。各マウスに以下のアジュバントを用いた。
1群:IFA(50μL/mouse)
2群:Poly IC(50μg/mouse)
3群:LAG-3(1μg/mouse)
4群:LAG-3(1μg/mouse)+Poly IC(50μg/mouse)
その後Day21に腫瘍組織を採取し、腫瘍組織切片のプレパラートを作製した後、ヘマトキシリン・エオジン染色により組織像を観察するとともに、細胞核及び免疫細胞(CD4細胞及びCD8細胞)の蛍光染色を行った。
蛍光組織染色は、以下の試薬を用いた。
細胞核:ProLongR Gold Antifade Reagent with DAPI (Invitrogen)
CD4細胞1次抗体:Rat Anti-Mouse CD4 Purified IgG2b. Clone: GK1.5 (eBioscience)
CD4細胞2次抗体:Mouse monoclonal (2B 10A8) Anti-Rat IgG2b heavy chain (Alexa FluorR 647), (abcam)
CD8細胞1次抗体:Rat Anti-Mouse CD8α Purified IgG2a. Clone: 53-6.7 (eBioscience)
CD8細胞2次抗体:Mouse monoclonal (2A 8F4) Anti-Rat IgG2a heavy chain (Alexa FluorR 488) (abcam)
DBA/2マウスに1匹当たり5×105細胞のP815腫瘍細胞を皮下接種してがんモデルマウスとし、この日をDay 0とした。Day 8に1匹当たり2.5×105細胞のP1A CTLを静脈注射した。Day 9及びDay 14に、1マウス当たり50μgのP1AペプチドとアジュバントをPBS中に混和したものを皮下注射した。アジュバントとしては、LAG-3 (1μg/mouse) + Poly IC(50μg/mouse)を用いた。
続いて、P815腫瘍細胞を接種しても腫瘍サイズの増大が見られず、腫瘍を拒絶したと判断されたDBA/2マウス、及び何の処置もしていないナイーブなDBA/2マウスを用いて、再度、1匹当たり1x106細胞のP815腫瘍細胞、又は1匹当たり1x106細胞のL1210腫瘍細胞を皮下接種した。腫瘍を拒絶したと判断されたDBA/2マウスについては、最初のP815細胞接種から115日後(Day115)に、再度腫瘍細胞を接種した。
図10左にL1210細胞接種後のマウスの平均腫瘍サイズ(mm3)の変化を示し、図10右にP815細胞接種後のマウスの平均腫瘍サイズ(mm3)の変化を示す。いずれも○が腫瘍を拒絶したと判断されたDBA/2マウス、●がナイーブなDBA/2マウスである。
ナイーブなDBA/2マウスでは、P815細胞及びL1210細胞のいずれを接種しても腫瘍サイズの増大が見られた。一方、P815細胞による腫瘍増大を拒絶したと判断されたマウスでは、別の腫瘍細胞であるL1210細胞接種に伴う腫瘍サイズの増大が見られたものの、P815細胞接種に伴う腫瘍サイズの増大は観察されず、マウス側に同一腫瘍に対する拒絶能が維持されていることが確認された。
DBA/2マウスに1匹当たり5×105細胞のP815腫瘍細胞を皮下接種しがんモデルマウスとし、この日をDay 0とした。Day 8に1匹当たり2.5×105細胞のP1A CTLを静脈注射した。Day 9及びDay 14に、1マウス当たり50μgのP1AペプチドとアジュバントをPBS中に混和したものを皮下注射した。各マウスに以下のアジュバントを用いた。
1群:IFA(50μL/mouse)
2群:Poly IC(50μg/mouse)
3群:LAG-3(1μg/mouse)
4群:LAG-3(1μg/mouse)+Poly IC(50μg/mouse)
その後Day21に、腋窩又は鼠径部のリンパ節のうち腫瘍部位に近いリンパ節を採取し、分離した免疫細胞1.5x105個と、100Gy放射線照射したP815細胞4x104個を、3日間共培養した。
免疫細胞増殖能は、3H-thymidine;37KBq/wellを培養上清中に添加し、4時間後に細胞取り込まれた3H-thymidineの放射活性を測定することにより測定した。
細胞上清中のサイトカイン量は、Bio-Plex Pro mouse cytokine 23-Plex Immunoassay kit (BIO-RAD)を用いて測定した。
免疫細胞増殖能の測定結果を図11Aに、サイトカイン等の測定結果を図11Bに示す。
アジュバントとしてLAG-3とpoly ICを組み合わせた場合に、免疫細胞増殖能の増大が観察された。また、サイトカイン等のうち、アジュバントとしてLAG-3とpoly ICを組み合わせた場合に、IFN-gamma、GM-CSF、IL-4、IL-5、IL-17Aの産生が増加していることが分かった。
DBA/2マウスに1匹当たり5×105細胞のP815腫瘍細胞を皮下接種してがんモデルマウスとし、この日をDay 0とした。Day 8に1匹当たり2.5×105細胞のP1A CTLを静脈注射した。Day 9及びDay 14に、1マウス当たり50μgのP1AペプチドとアジュバントをPBS中に混和したものを皮下注射した。各マウスに以下のアジュバントを用いた。
1群:IFA(50μL/mouse)
2群:Poly IC(50μg/mouse)
3群:LAG-3(1μg/mouse)
4群:LAG-3(1μg/mouse)+Poly IC(50μg/mouse)
その後Day21に、腋窩又は鼠径部のリンパ節のうち腫瘍部位に近いリンパ節を採取し、CD8及びVα8.3発現陽性の細胞群(キラーT細胞)、又はCD4及びVα8.3発現陽性の細胞群(ヘルパーT細胞)を回収した。
細胞(CD4細胞及びCD8細胞)の細胞表面マーカー分子であるPD-1、BTLA、TIGIT、及びLAG-3の発現量を測定した。細胞表面マーカー分子に対する抗体として、以下のものを用いた。
PD-1:Anti-Mouse CD279 (PD-1) PE. Clone: J43 (eBioscience)
BTLA:Anti-Mouse CD272 (BTLA) PE. Clone: 8F4 (eBioscience)
TIGIT:PE anti-mouse TIGIT (Vstm3) Antibody. Clone: 1G9 (BioLegend)
LAG-3:Anti-Mouse CD223 (Lag-3) PE. Clone: eBioC9B7W (C9B7W) (eBioscience)
CD8細胞の結果を図12Aに示し、CD4細胞の結果を図12Bに示す。
アジュバントとしてLAG-3とpoly ICを組み合わせた場合に、CD4陽性細胞及びCD8陽性細胞のともに、PD-1、TIGIT、LAG-3については顕著な発現量の減少が見られたが、BTLAの発現量の減少は少なかった。
C57BL/6マウスに1匹当たり1×105個のB16-F10メラノーマ細胞を皮下接種してがんモデルマウスとし、この日をDay 0とした。Day 8に1マウス当たり50μgのgp100ペプチドとアジュバントをPBS中に混和したものを皮下注射した。各マウスに以下のアジュバントを用いた。gp100ペプチドのアミノ酸配列はKVPRNQDWL(配列番号:2)である。
1群:IFA(50μL/mouse)
2群:Poly IC(50μg/mouse)
3群:LAG-3(1μg/mouse)
4群:LAG-3(1μg/mouse)+Poly IC(50μg/mouse)
その後Day 14に、腋窩又は鼠径部のリンパ節のうち腫瘍部位に近いリンパ節(あるいはその両方のリンパ節)を採取し、分離した免疫細胞を1ウェルあたり3x105個にて、10、5、2,5、又は0μg/mLのgp100ペプチド存在下で培養した。
免疫細胞増殖能は、3H-thymidine;37KBq/wellを培養上清中に添加し、3日間の培養期間中の最後の10時間の間に細胞取り込まれた3H-thymidineの放射活性を測定することにより測定した。
10μg/mLのgp100ペプチド存在下で3日間培養した細胞上清中のIFN-gamma産生量は、Bio-Plex Pro mouse cytokine 23-Plex Immunoassay kit (BIO-RAD)を用いて測定した。
免疫細胞増殖能の測定結果を図13Aに、IFN-gamma産生量の測定結果を図13Bに示す。図13Aにおいて、●が1群、□が2群、■が3群、○が4群の結果を示す。
B16-F10メラノーマ接種モデルマウス系を用いた場合でも、アジュバントとしてLAG-3とpoly ICを組み合わせた場合に、gp100腫瘍抗原特異的な免疫細胞増殖能の増大及びIFN-gamma産生量の増加が観察された。
腫瘍モデル系及び免疫抗原となるペプチドの種類によらず、アジュバントとしてLAG-3とpoly ICを組み合わせた場合に、顕著な免疫系の活性効果を発揮することが確認された。
アジュバントとしては以下の物質を用いた。
Poly I:C(TLR3アゴニスト)(Invivogen, SanDiego, USA)
RIBOXXOL (TLR3アゴニスト) (Riboxx, Radebeul, Germany)
MPL (TLR4アゴニスト) (Invivogen, SanDiego, USA)
Imiquimod (TLR7/8アゴニスト) (Invivogen, SanDiego, USA)
CpG(TLR9アゴニスト)(Invivogen, SanDiego, USA)
LAG-3(Adipogen, SanDiego, USA)
DBA/2マウスに1匹当たり5×105細胞のP815腫瘍細胞を皮下接種してがんモデルマウスとし、この日をDay 0とした。Day 7に1匹当たり2.5×105細胞のP1A CTLを静脈注射した。Day 8及びDay 15に、1マウス当たり50μgのP1AペプチドとアジュバントをPBS中に混和したものを皮下注射した。マウスを4匹又は5匹ずつ9群に分け、それぞれに以下のアジュバントを用いた。
1群:P1Aペプチドのみ(コントロール)
2群:Poly IC(50μg/mouse)
3群:Poly IC(50μg/mouse)+ LAG-3(1μg/mouse)
4群:P1Aペプチドなし、Poly IC(50μg/mouse)+ LAG-3(1μg/mouse)のみ
5群:RIBOXXOL(100μg/mouse)
6群:RIBOXXOL(100μg/mouse)+ LAG-3(1μg/mouse)
7群:MPL(10μg/mouse)+ LAG-3(1μg/mouse)
8群:Imiquimod(50μg/mouse)+ LAG-3(1μg/mouse)
9群:CpG(10μg/mouse)+ LAG-3(1μg/mouse)
Day 7以降のすべてのマウスについての腫瘍サイズ(mm3)の変化を図14~20に示す。
1群ではDay40までに5匹中5匹が全て死亡したが、2群では5匹中4匹が、3群では5匹中5匹が、4群では5匹中2匹が、5~7群では5匹中1匹が生存し、さらに、3群では5匹中3匹がDay66まで生存した。2群~4群、5群と6群とを比較することにより、アジュバントの併用効果が示された。また、P1Aペプチドを投与しない4群では全てのマウスがDay43までに死亡し、アジュバントとP1Aペプチドの両方を投与することが好適であることが示された。
C57BL/6マウスに1匹当たり1×105個のB16-F10メラノーマ細胞を皮下接種してがんモデルマウスとし、この日をDay0とした。Day5及びDay12の計2回、1マウス当たり50μgのgp100ペプチドとアジュバントをPBS中に混和したものを皮下注射した。各マウスに以下のアジュバントを用いた。
1群:IFA(50μL/mouse)
2群:Poly IC(50μg/mouse)
3群:LAG-3(1μg/mouse)
4群:LAG-3(1μg/mouse)+Poly IC(50μg/mouse)
Day 5以降のすべてのマウスについての腫瘍サイズ(mm3)の変化を図21~24に示す。 各群5匹のマウスは、1群ではDay31、2群ではDay35、3群ではDay37で5匹全てが死亡した一方、4群ではDay57で死亡した。1群に比較して、2及び3群では有意な生存期間の延長効果は認められなかったが、4群では1、2及び3群の全てに対して、有意な生存期間の延長が確認された。
配列番号:2は、gp100ペプチドのアミノ酸配列を示す。
Claims (13)
- Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、
を含む医薬。 - Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、を併用投与するための、請求項1に記載の医薬。 - 前記Toll様受容体アゴニストが、Toll様受容体3アゴニスト又はToll様受容体9アゴニストである、請求項1又は2に記載の医薬。
- 前記Toll様受容体アゴニストが、Poly I:C又はその塩である、請求項1から3のいずれか1項に記載の医薬。
- 前記LAG-3タンパク質、その変異体、又はその誘導体が、LAG-3タンパク質とIgGの融合タンパク質である、請求項1から4のいずれか1項に記載の医薬。
- 少なくとも1種のがん細胞に対する特異的な免疫応答を誘導する物質をさらに含む、請求項1から5のいずれか1項に記載の医薬。
- Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、
少なくとも1種のがん細胞に対する特異的な免疫応答を誘導する物質と、を併用投与するための、請求項6に記載の医薬。 - 前記がん細胞に対する特異的な免疫応答を誘導する物質が、がん抗原由来ペプチドである、請求項6又は7に記載の医薬。
- 2種以上のがん抗原由来ペプチドを含む、請求項8に記載の医薬。
- がんワクチン療法に用いられる、請求項1から9のいずれか1項に記載の医薬。
- 抗がん剤である、請求項1から10のいずれか1項に記載の医薬。
- Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、
を含むがん細胞に対する特異的な免疫応答の誘導に用いられるアジュバント。 - Toll様受容体アゴニストと、
LAG-3タンパク質、その変異体、又はその誘導体と、
を含むがん細胞に対する特異的な免疫応答の誘導に用いられる組合せ。
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Also Published As
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JP6311094B2 (ja) | 2018-04-18 |
TW201642907A (zh) | 2016-12-16 |
TWI738646B (zh) | 2021-09-11 |
BR112017020404A2 (ja) | 2018-07-10 |
DK3281641T3 (da) | 2021-01-18 |
US10842848B2 (en) | 2020-11-24 |
RU2709015C2 (ru) | 2019-12-13 |
US20210000916A1 (en) | 2021-01-07 |
JPWO2016163489A1 (ja) | 2017-12-07 |
AU2016244570B2 (en) | 2020-08-27 |
CN107530432B (zh) | 2021-04-27 |
EP3281641A4 (en) | 2018-12-19 |
EP3797794A1 (en) | 2021-03-31 |
CN107530432A (zh) | 2018-01-02 |
EP3281641B1 (en) | 2020-12-16 |
US20180071362A1 (en) | 2018-03-15 |
US11491204B2 (en) | 2022-11-08 |
ES2844049T3 (es) | 2021-07-21 |
EP3281641A1 (en) | 2018-02-14 |
RU2017134693A3 (ja) | 2019-09-20 |
CA2981468A1 (en) | 2016-10-13 |
RU2017134693A (ru) | 2019-04-04 |
AU2016244570A1 (en) | 2017-10-05 |
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