WO2023022141A1 - がん治療剤 - Google Patents
がん治療剤 Download PDFInfo
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- WO2023022141A1 WO2023022141A1 PCT/JP2022/030928 JP2022030928W WO2023022141A1 WO 2023022141 A1 WO2023022141 A1 WO 2023022141A1 JP 2022030928 W JP2022030928 W JP 2022030928W WO 2023022141 A1 WO2023022141 A1 WO 2023022141A1
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- cancer
- therapeutic agent
- cells
- pullulan
- positive cells
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Images
Classifications
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- 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
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- 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
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- the present invention relates to cancer therapeutic agents and the like.
- TAM tumor-associated macrophages
- CD209 also known as DC-SIGN
- DC-SIGN a type of immune polysaccharide-binding receptor protein (lectin)
- lectin a type of immune polysaccharide-binding receptor protein
- Non-Patent Document 1 Hydrophobized polysaccharides such as cholesteryl pullulan can self-assemble to form nanogels, have high biocompatibility, function as protein carriers, and have the ability to decompose and inhibit aggregation of encapsulated proteins, so they can be complexed with proteins. It has been reported to be used as an antigen carrier (Non-Patent Document 1).
- An object of the present invention is to provide a cancer therapeutic agent for cancer tissue containing CD209-positive cells.
- the present inventor found that gel particles containing modified polysaccharides containing hydrophobic groups selectively bind to and are taken up by CD209-positive cells. Based on this finding, the inventors have further studied and completed the present invention. That is, the present invention includes the following aspects.
- Item 1 A cancer therapeutic agent for cancer tissues containing CD209-positive cells, containing gel particles containing modified polysaccharides containing hydrophobic groups.
- Item 5 Items 1 to 4, wherein the hydrophobic group contains a hydrophobic group having a sterol skeleton.
- Item 6 Items 1 to 5, wherein the modified polysaccharide has a weight average molecular weight of 5000 to 2,000,000.
- Item 7 Items 1 to 6, wherein the gel particles have a weight average particle size of 20 to 200 nm.
- Item 8 Items 1 to 7, wherein the gel particles contain a drug.
- Item 9. The cancer therapeutic agent according to Item 8, wherein the agent contains at least one selected from the group consisting of adjuvants, cancer antigens, anticancer agents, and nucleic acid drugs.
- Item 10 Items 1 to 9, wherein the CD209-positive cells are macrophages.
- Item 11 The cancer therapeutic agent according to any one of Items 1 to 10, which is used for administration to a patient with cancer tissue containing CD209-positive cells selected from patients with cancer tissue.
- Item 12 The cancer therapeutic agent according to any one of Items 1 to 11, which is used in combination with a drug.
- Item 13 A carrier for delivery to CD209-positive cells, containing gel particles containing modified polysaccharides containing hydrophobic groups.
- Item 14 Item 13, wherein CD209-positive cells are present in cancer tissue, the carrier for delivery according to item 13.
- Item 15 A detection agent for tissue containing CD209-positive cells, containing the delivery carrier and contrast agent according to Item 13 or 14.
- Item 15 A companion diagnostic agent for the cancer therapeutic agent according to any one of Items 1 to 12, which contains a CD209-binding molecule.
- Section 1A A method of treating cancer, comprising administering gel particles containing a modified polysaccharide containing a hydrophobic group to a patient with cancer tissue containing CD209-positive cells.
- Section 1B Selecting patients with cancer tissues containing CD209-positive cells from patients with cancer tissues, and administering gel particles containing a modified polysaccharide containing a hydrophobic group to the selected patients
- the method of paragraph 1A comprising:
- Item 1C A gel particle containing a modified polysaccharide containing a hydrophobic group or a preparation containing the gel particle for use as a cancer therapeutic agent for cancer tissue containing CD209-positive cells.
- Item 1D Use of gel particles containing modified polysaccharides containing hydrophobic groups or preparations containing the gel particles for the production of cancer therapeutic agents for cancer tissues containing CD209-positive cells.
- Item 1E Use of gel particles containing modified polysaccharides containing hydrophobic groups or preparations containing the gel particles as a cancer therapeutic agent for cancer tissues containing CD209-positive cells.
- Item 2A A method of delivering a drug or contrast agent to CD209-positive cells, characterized by loading the drug or contrast agent onto gel particles containing a modified polysaccharide containing a hydrophobic group and administering the agent.
- Item 2B The delivery method according to item 2A, wherein CD209-positive cells are present in cancer tissue.
- Item 2C A gel particle containing a modified polysaccharide containing a hydrophobic group or a formulation containing the gel particle for use as a carrier for delivery to CD209-positive cells.
- Section 2D Use of gel particles containing modified polysaccharides containing hydrophobic groups or formulations containing said gel particles for the production of carriers for delivery to CD209-positive cells.
- Item 2E Use of a gel particle containing a modified polysaccharide containing a hydrophobic group or a formulation containing the gel particle as a carrier for delivery to CD209-positive cells.
- Item 3A A method for detecting a tissue containing CD209-positive cells, comprising administering the delivery carrier and imaging agent of Item 13 or 14, or a preparation containing them, to a subject having a tissue containing CD209-positive cells.
- Section 3B. 15. The delivery carrier and imaging agent according to Item 13 or 14, or a preparation containing these, for use as a detection agent for tissue containing CD209-positive cells.
- Item 3C Use of the delivery carrier and imaging agent according to item 13 or 14, or a preparation containing these, for the production of an agent for detecting tissues containing CD209-positive cells.
- Section 3D Use of the delivery carrier and imaging agent according to item 13 or 14, or a preparation containing these, as an agent for detecting tissue containing CD209-positive cells.
- a cancer therapeutic agent for cancer tissue containing CD209-positive cells can be provided.
- FIG. 1 shows the results of measuring the uptake rate of rhodamine-labeled pullulan nanogel into each cell by flow cytometry in Test Example 1.
- FIG. 2 shows the results of measuring the uptake rate of rhodamine-labeled pullulan nanogel into each cell by flow cytometry in Test Example 2.
- FIG. 2 shows the results of observing the uptake (red) of rhodamine-labeled pullulan nanogel into each cell with a fluorescence microscope in Test Example 3.
- FIG. 4 shows the results of measuring the uptake intensity (fluorescence intensity) of rhodamine-labeled pullulan nanogel into each cell by flow cytometry in Test Example 4.
- FIG. 1 shows the results of measuring the uptake rate of rhodamine-labeled pullulan nanogel into each cell by flow cytometry in Test Example 1.
- FIG. 2 shows the results of measuring the uptake rate of rhodamine-labeled pullulan nanogel into each cell by flow
- FIG. 4 shows the results of measuring the uptake intensity (fluorescence intensity) of rhodamine-labeled pullulan nanogel into each cell by flow cytometry in Test Example 5.
- FIG. 6 shows the results of evaluating the uptake of rhodamine-labeled pullulan nanogel into each cell by fluorescence microscopy and flow cytometry in Test Example 6.
- FIG. 10 shows the results of evaluating the uptake of rhodamine-labeled pullulan nanogels into the indicated cell populations by flow cytometry in Test Example 7.
- FIG. In Test Example 8 the results of evaluating the uptake of rhodamine-labeled pullulan nanogels by observation with a fluorescence microscope are shown.
- FIG. 10 shows the results of evaluating the uptake of rhodamine-labeled pullulan nanogels into the indicated cell populations by flow cytometry in Test Example 9.
- FIG. 2 shows the results of evaluating cell activity with Cell Counting Kit-8 in Test Example 10.
- FIG. The vertical axis indicates the relative percentage of the number of viable cells, and the horizontal axis indicates the administration concentration of the pullulan nanogel-PE complex or PE.
- 5a indicates the case using CMS5a cells
- 209b indicates the case using CMS5a cells expressing mouse SIGNR1/CD209b.
- 2 shows the results of measuring tumor size over time in Test Example 11.
- FIG. The vertical axis indicates tumor size (unit: mm 3 ), and the horizontal axis indicates the number of days elapsed since administration.
- a cancer therapeutic agent for cancer tissue containing CD209-positive cells which contains gel particles containing a modified polysaccharide containing a hydrophobic group (herein, “ (also referred to as “cancer therapeutic agent”). This will be explained below.
- a modified polysaccharide is a compound obtained by modifying a polysaccharide, and is not particularly limited as long as it contains a hydrophobic group as a modification group.
- the polysaccharide that constitutes the modified polysaccharide is not particularly limited as long as it is a polymer in which sugar residues are glycoside-bonded.
- sugar residues constituting polysaccharides for example, residues derived from monosaccharides such as glucose, mannose, galactose and fucose, or sugars such as disaccharides or oligosaccharides can be employed.
- the sugar residues may be 1,2-, 1,3-, 1,4- or 1,6-glycosidically linked, and the linkage may be of either ⁇ - or ⁇ -type linkage.
- the polysaccharide may be linear or branched.
- the sugar residue is preferably a glucose residue
- the polysaccharides include, for example, natural or synthetically derived pullulan, mannan, dextran, amylose, amylopectin, etc., preferably pullulan, mannan, dextran, etc., more preferably pullulan, mannan, etc. Pullulan and the like are particularly preferably used.
- the weight average molecular weight of the polysaccharide is not particularly limited as long as the modified polysaccharide can form gel particles, but is, for example, 5,000 to 2,000,000.
- the weight average molecular weight is preferably 10,000 to 1,000,000, more preferably 20,000 to 500,000, still more preferably 40,000 to 250,000, and even more preferably 80,000 to 125,000.
- polysaccharides commercially available products can be used, or those obtained according to known production methods can be used.
- the hydrophobic group is a group having hydrophobicity, and is not particularly limited as long as the modified polysaccharide can form gel particles.
- the hydrophobic group preferably includes a hydrophobic group having a sterol skeleton, a hydrocarbon group and the like, and particularly preferably a hydrophobic group having a sterol skeleton.
- the sterol skeleton is an alcohol in which a hydroxy group is bonded to the cyclopentahydrophenanthrene ring shown in formula (I).
- the symbols A to D in formula (I) represent each ring constituting the cyclopentahydrophenanthrene ring.
- the sterol skeleton may have a double bond in the cyclopentahydrophenanthrene ring, and the bonding position of the hydroxyl group is not particularly limited.
- sterols having a hydroxy group at the C-3 position and a double bond at the B ring, or stanols having a saturated ring with a hydroxy group at the C-3 position is.
- a hydrophobic group having a sterol skeleton is a modified sterol skeleton, for example, substituted with a hydrocarbon group (for example, a linear or branched alkyl group having 1 to 20 carbon atoms) at the ring-constituting carbon. and groups derived from the following compounds.
- the term “derived group” refers to a group obtained by removing a hydrogen atom or a functional group such as a hydroxyl group from a certain compound.
- Hydrophobic groups having a sterol skeleton include, for example, cholesterol-derived groups, cholestanol-derived groups, lanosterol-derived groups, ergosterol-derived groups, ⁇ -sitosterol-derived groups, campesterol-derived groups, and stigmasterol-derived groups. groups, groups derived from brassicasterol, and the like. Among these, sterol-derived groups such as cholesterol-derived groups, cholestanol-derived groups, lanosterol-derived groups, and ergosterol-derived groups are preferred, and cholesterol-derived groups are more preferred.
- the hydrocarbon group as the hydrophobic group is not particularly limited, and is, for example, a chain (preferably linear) hydrocarbon group having 8 to 50 (preferably 10 to 30, more preferably 12 to 20) carbon atoms. (preferably an alkyl group).
- the weight average molecular weight of the modified polysaccharide is not particularly limited as long as the modified polysaccharide can form gel particles, but is, for example, 5,000 to 2,000,000.
- the weight average molecular weight is preferably 10,000 to 1,000,000, more preferably 20,000 to 500,000, still more preferably 40,000 to 250,000, and even more preferably 80,000 to 125,000.
- the number of hydrophobic groups contained in the modified polysaccharide is not particularly limited as long as the modified polysaccharide can form gel particles. ⁇ 5.
- the hydrophobic group can be linked directly or indirectly (eg, via a linker) to the polysaccharide.
- modified polysaccharide for example, primary hydroxyl groups of 1 to 10 (preferably 1 to 5) sugar units per 100 sugar residues constituting the polysaccharide are represented by the formula (II): -O- ( CH 2 ) m CONH(CH 2 ) n NH-CO-O-R (II) (wherein R represents a hydrophobic group or hydrocarbon group having a sterol skeleton; m represents 0 or 1; n represents Any positive integer) is preferred. n is preferably 1-8.
- Modified polysaccharides can be synthesized according to or according to known methods (eg, International Publication No. WO00/12564).
- An example is the following method. First, a hydroxyl group-containing hydrocarbon or sterol having 12 to 50 carbon atoms and a diisocyanate compound represented by OCN-R 1 NCO (wherein R 1 is a hydrocarbon group having 1 to 50 carbon atoms) to produce an isocyanate group-containing hydrophobic compound in which one molecule of a hydroxyl group-containing hydrocarbon having 12 to 50 carbon atoms or a sterol is reacted.
- OCN-R 1 NCO wherein R 1 is a hydrocarbon group having 1 to 50 carbon atoms
- the resulting isocyanate group-containing hydrophobic compound is further reacted with the polysaccharide to produce a hydrophobic group-containing polysaccharide containing a hydrocarbon group having 12 to 50 carbon atoms or a steryl group as a hydrophobic group. .
- a hydrophobic group-containing polysaccharide containing a hydrocarbon group having 12 to 50 carbon atoms or a steryl group as a hydrophobic group.
- Modified polysaccharides can be used singly or in combination of two or more.
- the gel particles contain modified polysaccharides.
- Gel particles refer to polymeric gel particles having a hydrogel structure.
- a hydrogel is a three-dimensional network structure formed by cross-linking hydrophilic polymers that swells with water.
- modified polysaccharides self-organize through physical cross-links formed based on hydrophobic interaction by hydrophobic groups to form a three-dimensional network structure.
- the shape of the gel particles is not particularly limited, but is usually spherical.
- the gel particles are preferably nano-sized (that is, nanogel particles), and have a weight average particle diameter of, for example, 200 nm or less, preferably 10 to 200 nm, more preferably 15 to 200 nm, and even more preferably 20 to 200 nm. be.
- the upper limit of the weight average particle size is preferably 100 nm, more preferably 70 nm, and even more preferably 50 nm.
- the particle size can be measured by a dynamic light scattering method.
- the gel particles can contain substances other than the modified polysaccharide.
- other substances include proteins, peptides, nucleic acids, sugars, low-molecular-weight compounds, high-molecular-weight compounds, inorganic substances, and complexes thereof. More specifically, other substances include, for example, adjuvants, cancer antigens, anticancer agents, agents such as nucleic acid drugs, contrast agents, and the like.
- the adjuvant can be selected from inactivated bacterial cells, bacterial cell extracts, nucleic acid lipopolysaccharides, lipopeptides, synthetic low-molecular-weight compounds, and the like, preferably imidazoquinolines (e.g., R848, imiquimod, etc.), saponins (e.g., QuilA and QS21, etc.), STING agonists (eg, cyclic di-GMP, etc.), monophosphoryl lipids, lipopeptides, and the like are used.
- imidazoquinolines e.g., R848, imiquimod, etc.
- saponins e.g., QuilA and QS21, etc.
- STING agonists eg, cyclic di-GMP, etc.
- monophosphoryl lipids e.g, lipopeptides, and the like are used.
- adjuvants include taxane drugs, anthracycline drugs, JAK/STAT inhibitors, indole deoxygenase (IDO) inhibitors, and tryptophan deoxygenase (TDO) inhibitors. etc. These inhibitors include compounds having an antagonistic effect against the factor, as well as neutralizing antibodies against the factor.
- Cancer antigens include antigen polypeptides, preferably antigen polypeptides.
- Antigen polypeptides are antigens or partial peptides thereof that are abundantly expressed in cancer cells, and in some cases are expressed only by cancer cells.
- An antigenic polypeptide can be expressed within a cancer cell or on the surface of a cancer cell.
- Antigen polypeptides include but are not limited to ERK1, ERK2, MART-1/Melan-A, gp100, adenosine deaminase binding protein (ADAbp), FAP, cyclophilin b, colorectal associated antigen (CRC)-C017-1A/GA733 , carcinoembryonic antigen (CEA), CAP-1, CAP-2, etv6, AML1, prostate-specific antigen (PSA), PSA-1, PSA-2, PSA-3, prostate-specific membrane antigen (PSMA) ), T cell receptor/CD3-zeta chain, CD20, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3),
- Anticancer agents include, for example, alkylating agents, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum agents, molecular target drugs, hormone agents, and biological agents.
- alkylating agents examples include cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, temozolomide, nimustine, busulfan, melphalan, procarbazine, and ranimustine.
- Antimetabolites include, for example, enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nerarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, Cladribine, doxifluridine, hydroxycarbamide, mercaptopurine and the like.
- microtubule inhibitors examples include alkaloid anticancer agents such as vincristine, and taxane anticancer agents such as docetaxel and paclitaxel.
- Antibiotic anticancer agents include, for example, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, actinomycin D, aclarubicin, idarubicin, pirarubicin, peplomycin, mitoxantrone, amrubicin, and dinostatin stimaramer.
- topoisomerase inhibitors examples include CPT-11, irinotecan, and topotecan, which have topoisomerase I inhibitory action, and etoposide and sobuzoxan, which have topoisomerase II inhibitory action.
- platinum agents examples include cisplatin, nedaplatin, oxaliplatin, and carboplatin.
- Hormonal agents include, for example, dexamethasone, finasteride, tamoxifen, astrozole, exemestane, ethinylestradiol, chlormadinone, goserelin, bicalutamide, flutamide, brednisolone, leuprorelin, letrozole, estramustine, toremifene, fosfestrol, mitotane, Methyltestosterone, medroxyprogesterone, mepitiostane and the like.
- biologics include interferon ⁇ , ⁇ and ⁇ , interleukin 2, ubenimex, dried BCG, and extracellular toxins.
- extracellular toxin Pseudomonas Exotoxin (PE), an exotoxin (protein) produced by bacteria.
- PE has the enzymatic activity of NAD+-diphthamide-ADP-ribosyl transferase and inhibits protein synthesis. exhibits strong toxicity. So far, a CD22 antibody conjugated with PE has been approved as an anticancer agent.
- molecular targeted drugs examples include rituximab, alemtuzumab, trastuzumab, cetuximab, panitumumab, imatinib, dasatinib, nilotinib, gefitinib, erlotinib, temsirolimus, bevacizumab, VEGF trap, sunitinib, sorafenib, tocituzumab, bortezomib, gemtuzumab/ozogamicin, izogamycin , ibritumomab tiuxetan, tamibarotene, tretinoin and the like.
- Human epidermal growth factor receptor 2 inhibitors such as vascular endothelial growth factor receptor 2 inhibitors ( ⁇ -VEGFR-2 antibodies); various tyrosine kinase inhibitors, such as MAP kinase inhibitors; cytokine-targeted inhibitors; Molecularly targeted drugs such as proteasome inhibitors, antibody-anticancer drug combinations, and the like can also be included. These inhibitors also include antibodies.
- a nucleic acid drug is a pharmaceutical active ingredient that is a nucleic acid, and is not particularly limited as long as it is.
- the contrast agent is not particularly limited as long as it is a substance that allows visualization of its location.
- contrast agents include X-ray contrast agents such as barium sulfate, bismuth subcarbonate, bismuth oxide, zirconium oxide, ytterbium fluoride, iodoform, barium apatite, barium titanate, lanthanum glass, barium glass, and strontium glass; iodine contrast agents; Contrast agents for computed tomography (CT) such as gadolinium preparations, Super Paramagnetic Iron Oxide (SPIO) and other MRI contrast agents; Single photon emission such as technetium 99m (99mTc) and molybdenum 99 (99Mo) Examples include radioactive isotopes for computed tomography (SPECT), other various radioactive isotopes, and substances containing them.
- CT computed tomography
- SPIO Super Paramagnetic Iron Oxide
- 99Mo molybdenum 99
- the content of other substances is, for example, 0 to 10000 parts by mass, 0 to 1000 parts by mass, 0 to 500 parts by mass, 0 to 100 parts by mass, and 0 to 50 parts by mass with respect to 100 parts by mass of the modified polysaccharide content. parts, or 0 to 10 parts by mass.
- Gel particles can be produced according to known methods. For example, it can be produced by sonicating a modified polysaccharide-containing solution, or by adding a denaturant such as urea, DMSO, or a surfactant to the solution and then removing the denaturant by dialysis. From the viewpoint of convenience, the former method is more preferable. The latter method can be performed according to or according to known methods.
- the modified polysaccharide-containing solution can be prepared by dissolving the modified polysaccharide in a solvent.
- solvents that can be used include water and organic solvents such as DMSO.
- Modified polysaccharide solutions can generally be prepared using water as the solvent. At this time, it is preferable to use a buffer solution such as PBS instead of water.
- the concentration of the modified polysaccharide in the modified polysaccharide-containing solution is not particularly limited, it is, for example, 5 to 100 uM, preferably 5 to 80 uM, more preferably 8 to 50 uM from the viewpoint of gel particle formation efficiency.
- Ultrasonic treatment can be performed, for example, by fixing a plastic tube containing a modified polysaccharide-containing solution on water in a bath-type ultrasonic bath and irradiating it with ultrasonic waves.
- Conditions for ultrasonic treatment are not particularly limited, but for example, 10 to 40° C. (preferably 20 to 35° C.), 10 to 50 kHz (preferably 20 to 40 kHz), 30 to 200 W (preferably 70 to 150 W), 2 to 30 minutes (preferably 5-15 minutes).
- the gel particles are used as cancer therapeutic agents for cancer tissues containing CD209-positive cells.
- the gel particles target CD209 to bind to and be taken up by cells expressing it. Therefore, the components contained in the gel particles can be selectively transported to cancer tissues containing CD209-positive cells.
- drugs contained in gel particles are selectively transported to cancer tissues containing CD209 positive cells, immunostimulatory effects, It is possible to treat cancer by exerting an anticancer action or the like.
- cancer antigens contained in gel particles are incorporated into CD209-positive cells (preferably macrophages and tumor-associated macrophages), antigen-presented by the cells, and lymphocytes such as T cells are activated to Cancer can be treated.
- CD209-positive cells preferably macrophages and tumor-associated macrophages
- lymphocytes such as T cells are activated to Cancer can be treated.
- the gel particles target CD209 bind to cells expressing it on the cell membrane, and are taken up, so that they can be used as a carrier for delivery to CD209-positive cells (the carrier for delivery of the present invention).
- CD209-positive cells are preferably present in cancer tissues.
- a substance that delivers other substances that the above-described gel particles may contain (e.g., adjuvants, cancer antigens, anticancer agents, agents such as nucleic acid medicines, contrast agents, etc.)
- Deliver the other substance to CD209-positive cells preferably cancer tissue containing CD209-positive cells
- the carrier for delivery includes, for example, a drug delivery carrier.
- tissue containing CD209-positive cells preferably (cancer tissue containing CD209-positive cells
- tissue containing CD209-positive cells can be used as a detection agent.
- the present invention contains CD209-positive cells containing the delivery carrier and contrast agent of the present invention.
- the detection agent for the tissue to be detected can be used as a detection agent for use in, for example, MRI, PET, CT, etc., depending on the type of contrast agent.
- the detection agent can detect tissue containing CD209-positive cells can be visualized.
- CD209 is a C-type lectin receptor, also known as DC-SIGN in humans, and is expressed on the cell surface.
- CD209 in other animals can be determined based on sequence identity with human CD209/DC-SIGN.
- the functional homologue of CD209 in mice is CD209b, also designated SIGNR1.
- a specific cell group (preferably macrophages) in the cancer tissue is selected, and the extent to which CD209-positive cells are contained in the cancer tissue is determined.
- the selection and determination can be performed according to known methods. Examples include immunohistochemical staining. In this method, CD209-positive cells in cancer tissue are stained with anti-human CD209 antibody (fluorescence method or chromogenic method), and positive or negative judgment is made based on the amount of dye emitted by the stained cells (e.g., amount of fluorescence or amount of visible light). It is done by Such staining can typically be performed using a CD209 binding molecule.
- the present invention relates to a companion diagnostic agent (diagnostic agent of the present invention) for the cancer therapeutic agent of the present invention, which contains a CD209-binding molecule.
- a method comprising the step of contacting a CD209-binding molecule with cells in a cancer tissue of a subject can predict the efficacy of the cancer therapeutic agent of the present invention.
- the CD209-binding molecule is not particularly limited as long as it is capable of binding (preferably specifically binding) to CD209.
- Examples of CD209 binding molecules include antibodies, more specifically immunoglobulins, Fab, F(ab') 2 , minibodies, scFv-Fc, Fv, scFv, diabodies, triabodies. (triabody), tetrabody (tetrabody), monobody and the like.
- a determination of positive or negative is made according to a known method based on the amount of dye emitted by the stained cells. This determination can be made according to a known technique. For example, the dye amount emitted by negative control cells (specifically, for example, cells stained with an isotype control antibody) is used as the background dye amount, and the dye amount sufficiently high relative to the background is used as a reference, and the amount is higher than the reference. Cells with a lower dye amount than the standard are determined as negative cells, and cells with a higher fluorescence amount than the standard are determined as positive cells.
- reverse transcription quantitative PCR of CD209 is performed on mRNA extracted from cancer tissues, and the amount of CD209 mRNA is determined.
- the therapeutic agent for cancer of the present invention or the carrier for delivery of the present invention can be administered to patients with cancer tissues containing CD209-positive cells, which are selected from patients with cancer tissues. preferable.
- the cancer therapeutic agent of the present invention or the carrier for delivery of the present invention is not particularly limited as long as it contains gel particles, and may further contain other components as necessary.
- Other ingredients are not particularly limited as long as they are pharmaceutically acceptable ingredients.
- Other components include additives as well as components having pharmacological actions. Examples of additives include bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, humectants, colorants, perfumes, A chelating agent and the like are included.
- the cancer therapeutic agent of the present invention or the delivery carrier of the present invention may contain other substances that the gel particles may contain (for example, drugs such as adjuvants, cancer antigens, anticancer agents, nucleic acid drugs, etc.). , contrast agents, etc.).
- the cancer therapeutic agent of the present invention or the delivery carrier of the present invention may contain other substances that may be contained in the above-described gel particles (for example, adjuvants, cancer antigens, anticancer agents, agents such as nucleic acid medicines, contrast agents, etc.). ) can be used in conjunction with
- the application target of the cancer therapeutic agent of the present invention or the delivery carrier of the present invention is not particularly limited.
- mammals include human, monkey, mouse, rat, dog, cat, rabbit, pig, horse, cow, and sheep. , goats, and deer.
- animal cells etc. are mentioned as a cell.
- the types of cells are not particularly limited, such as blood cells, hematopoietic stem cells/progenitor cells, gametes (sperm, ovum), fibroblasts, epithelial cells, vascular endothelial cells, nerve cells, hepatocytes, keratinocytes, muscle cells. , epidermal cells, endocrine cells, ES cells, iPS cells, tissue stem cells, cancer cells and the like.
- Target cancers of the cancer therapeutic agent of the present invention or the delivery carrier of the present invention are not particularly limited, and examples include leukemia (including chronic lymphocytic leukemia and acute lymphocytic leukemia), lymphoma (non-Hodgkin's lymphoma, Hodgkin's lymphoma).
- leukemia including chronic lymphocytic leukemia and acute lymphocytic leukemia
- lymphoma non-Hodgkin's lymphoma, Hodgkin's lymphoma.
- T-cell lymphoma T-cell lymphoma, B-cell lymphoma, Burkitt's lymphoma, malignant lymphoma, diffuse lymphoma, and follicular lymphoma
- myeloma including multiple myeloma
- breast cancer colorectal cancer
- renal cancer Gastric cancer, ovarian cancer, pancreatic cancer, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, head and neck squamous cell cancer, skin cancer, malignant melanoma, urinary tract cancer, prostate cancer Carcinoma, choriocarcinoma, pharyngeal cancer, laryngeal cancer, choroidoma, male germinoma, endometrial hyperplasia, endometriosis, embryonal tumor, fibrosarcoma, Kaposi's sarcoma, hemangioma, cavernous hemangioma , hemangioblastoma,
- the cancer therapeutic agent of the present invention or the delivery carrier of the present invention can be in any dosage form, such as tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, lozenges, jelly drops, etc.), pills. , granules, fine granules, powders, hard capsules, soft capsules, dry syrups, liquids (including drinks, suspensions, syrups), oral dosage forms such as jelly, injection preparations (e.g., Drip injections (e.g.
- intravenous infusion preparations for intravenous infusion, etc.
- intravenous injections preparations for intravenous injections, intramuscular injections, subcutaneous injections, intradermal injections
- external preparations e.g., ointments, poultices, lotions
- suppository inhalants e.g., eye drops, ophthalmic ointments, nose drops, ear drops, liposomes, and other parenteral formulations.
- the administration route of the cancer therapeutic agent of the present invention or the delivery carrier of the present invention is not particularly limited as long as the desired effect is obtained.
- parenteral administration such as administration, intraarterial administration, intramuscular administration, intracardiac administration, subcutaneous administration, intradermal administration, and intraperitoneal administration;
- the content of the active ingredient in the cancer therapeutic agent of the present invention or the delivery carrier of the present invention depends on the mode of use, the subject of application, the condition of the subject of application, etc., and is not limited, but is for example from 0.0001 to 0.0001. It can be 100% by weight, preferably 0.001 to 50% by weight.
- the dosage of the therapeutic agent for cancer of the present invention or the carrier for delivery of the present invention is not particularly limited as long as it is an effective amount that exhibits efficacy. 0.1 to 1000 mg/kg body weight per day, preferably 0.5 to 500 mg/kg body weight per day, and 0.01 to 100 mg/kg body weight per day, preferably 0.05 to 50 mg/day for parenteral administration. kg body weight.
- the above dosage can be adjusted appropriately depending on age, disease state, symptoms and the like.
- Preparation example 1 Preparation of pullulan nanogel Cholesterol-modified pullulan (CHP) was prepared by introducing 1.2 cholesterol per 100 monosaccharides into pullulan having a weight average molecular weight of 100,000 according to a previous report (Macromolecules 1993, 23, 3062-3068).
- CHP was added to PBS to a concentration of 1 mg/mL, dissolved by stirring with a stirrer at 25°C for 15 hours, and then intermittently irradiated with ultrasonic waves for 6 minutes using a probe-type ultrasonic irradiation device. After centrifuging this solution at 25°C and 20000g for 30 minutes, the supernatant was passed through a 0.22um filter for filtration sterilization to obtain pullulan nanogel (nanogel weight average molecular weight 450,000).
- the average particle size of the resulting pullulan nanogel was measured by cumulant method analysis using a dynamic light scattering spectrometer (DLS).
- the pullulan nanogel had an average particle size of 32.2 ⁇ 2.1 nm and a polydispersity index of 0.26 ⁇ 0.01.
- Test example 1 Binding of pullulan nanogel to mouse CD209 HEK293 cells were transiently transfected with an expression vector encoding mouse SIGNR1/CD209b or mouse DC-SIGN/CD209a cDNA by lipofection. The same procedure was performed using an expression vector containing no cDNA as a control (Vector control). After 48 hours, rhodamine-labeled pullulan nanogel was administered to each cell at the concentration indicated in FIG. 1 and incubated at 37° C. for 3 hours. Cells were washed with cold PBS, detached with cold PBS containing EDTA, and suspended into single cells. The uptake rate of rhodamine-labeled pullulan nanogel into each cell was measured by flow cytometry.
- Test example 2 In the same manner as in Test Example 1 for the binding of pullulan nanogel to human CD209 , expression vectors encoding cDNAs for mouse SIGNR1/CD209b, mouse DC-SIGN/CD209a, or human DC-SIGN/CD209 were added to HEK293 cells by lipofection. Hyperintroduced. The same procedure was performed using an expression vector containing no cDNA as a control (Vector control). After 48 hours, rhodamine-labeled pullulan nanogel was administered to each cell at the concentration indicated in FIG. 2 and incubated at 37° C. for 2 hours. Cells were washed with cold PBS, detached with cold PBS containing EDTA, and suspended into single cells. The uptake rate of rhodamine-labeled pullulan nanogel into each cell was measured by flow cytometry.
- Test example 3 Specific binding of pullulan nanogel to CD209 COS7 cells were transiently transfected with expression vectors encoding the indicated C-type lectin cDNAs by lipofection. The same procedure was performed using an expression vector containing no cDNA as a control (Vector control). After 48 hours, rhodamine-labeled pullulan nanogel was administered to each cell at a concentration of 2 ⁇ g/mL and incubated at 37° C. for 2 hours. Cells were washed with cold PBS, detached with TryPLE (Thermo Scientific) and resuspended into single cells. Uptake of rhodamine-labeled pullulan nanogel into each cell (red) was observed under a fluorescence microscope.
- Test example 4 Binding of polysaccharide nanogel and linear polysaccharide to CD209 Rhodamine-labeled pullulan nanogel (CHP in Fig. 4) or rhodamine-labeled Pullulan (linear, unimer) (Pullulan 400K in FIG. 4) was administered at each concentration shown in FIG. 4 and incubated at 37° C. for 3 hours. Cells were detached with a scraper and suspended to form single cells. The uptake intensity (fluorescence intensity) of the rhodamine-labeled pullulan nanogel into each cell was measured by flow cytometry. In addition, similar tests were performed using mannan (linear, unimer) and mannan nanogel.
- Test example 5 An experiment similar to SIGNR1 dependence test example 4 of binding of pullulan nanogel to RAW SR-1 cells was performed. However, cells were treated with SIGNR1-specific antibodies (clone 22D1 (IgG) or clone ERTR9 (IgM)) for 1 hour before adding rhodamine-labeled pullulan nanogels.
- SIGNR1-specific antibodies clone 22D1 (IgG) or clone ERTR9 (IgM)
- Test example 6 Specific binding of pullulan nanogel to CD209
- Mouse fibrosarcoma cell line CMS5a cells were transiently transfected with an expression vector encoding mouse SIGNR1/CD209b cDNA by electroporation.
- each cell was administered rhodamine-labeled pullulan nanogel at a concentration of 2 ⁇ g/mL and an anti-SIGNR1 antibody (22D1) at a concentration shown in FIG. 6, and incubated at 37° C. for 2 hours. Cells were detached with trypsin and suspended to form single cells. Uptake of rhodamine-labeled pullulan nanogel into each cell was evaluated by fluorescence microscopy and flow cytometry.
- Test example 7 Selective uptake of pullulan nanogel into tumor-associated macrophages (TAM)
- TAM tumor-associated macrophages
- Mouse colon cancer cell line CT26 cells were subcutaneously transplanted into normal BALB/c mice (7 weeks old, female), and after 8 days the tumors were collected and gentle. After disrupting with Max (Miltenyi) to obtain a cell suspension, the cells were cultured on a culture plate in RPMI1640 medium containing 10% fetal bovine serum. To this, rhodamine-labeled pullulan nanogel was administered at a concentration of 2 ⁇ g/mL and incubated at 37°C for 2 hours. Cells were then detached with trypsin and suspended to form single cells.
- TAM tumor-associated macrophages
- Test example 8 Selective uptake of pullulan nanogel into tumor-associated macrophages (TAM)
- TAM tumor-associated macrophages
- Mouse colon cancer cell line CT26 cells were subcutaneously transplanted into normal BALB/c mice (7 weeks old, female), and after 8 days the tumors were collected and gentle. After disrupting with Max (Miltenyi) to obtain a cell suspension, the cells were cultured on a culture plate in RPMI1640 medium containing 10% fetal bovine serum. To this, rhodamine-labeled pullulan nanogel was administered at a concentration of 2 ⁇ g/mL and incubated at 37°C for 2 hours. At this time, SIGNR1 antibody (22D1) was simultaneously added at the concentration shown in FIG.
- uptake of the rhodamine-labeled pullulan nanogel was evaluated by observing with a fluorescence microscope.
- the number of cells with strong luminescence in a field of view of ⁇ 400 was defined as the number of uptake cells.
- Test example 9 Selective uptake of pullulan nanogel into tumor-associated macrophages (TAM)
- TAM tumor-associated macrophages
- Mouse colon cancer cell line CT26 cells were subcutaneously implanted in normal BALB/c mice (7 weeks old, female). ) was administered intravenously.
- SIGNR1 antibody 22D1 was co-administered at the indicated concentrations.
- the tumors were harvested, disrupted with Gentlemax (Miltenyi) to form a cell suspension, stained with anti-CD45 antibody, CD11b antibody, Gr1 antibody, CD209b antibody, CD206 antibody, and MHC class II antibody, followed by flow
- Uptake of rhodamine-labeled pullulan nanogels into the indicated cell populations was assessed by cytometry.
- Test example 10 Cytotoxicity by Pseudomonas Exotoxin (PE) conjugate of pullulan nanogel
- PE Pseudomonas Exotoxin
- cytotoxic activity of PE alone was observed in a dose-dependent manner regardless of SIGNR1/CD209b expression, whereas the cytotoxic activity of the pullulan nanogel-PE complex was predominantly observed in SIGNR1/CD209b-expressing cells.
- Test example 11 Cytotoxicity by pullulan nanogel-PE complex
- Mouse colon cancer cell line CMS5a cells were subcutaneously transplanted into normal BALB/c mice (8 weeks old, female), and 8, 10, and 12 days later, pullulan nanogel-PE complex and PE were implanted. (0.1 ⁇ g) was administered intravenously with CpG (50 ug). Tumor size was measured over time.
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Abstract
Description
既報(Macromolecules 1993, 23, 3062-3068)の記載に従って、重量平均分子量100,000のプルランに100単糖あたりコレステロールが1.2個導入されたコレステロール修飾プルラン(CHP)を作製した。
HEK293細胞にマウスSIGNR1/CD209bまたはマウスDC-SIGN/CD209aのcDNAをコードする発現ベクターをリポフェクション法で一過性導入した。コントロールとしてcDNAを含まない発現ベクターを用いて同様に行った(Vector control)。48時間後に、各細胞にローダミン標識プルランナノゲルを図1に表示の濃度で投与し、37℃で3時間インキュベートした。細胞を冷PBSで洗浄し、EDTA含有冷PBSで剥離してシングルセルとなるように懸濁した。フローサイトメトリーで各細胞へのローダミン標識プルランナノゲルの取り込み率を測定した。
試験例1と同様にして、HEK293細胞にマウスSIGNR1/CD209b、マウスDC-SIGN/CD209a、またはヒトDC-SIGN/CD209のcDNAをコードする発現ベクターをリポフェクション法で一過性導入した。コントロールとしてcDNAを含まない発現ベクターを用いて同様に行った(Vector control)。48時間後に、各細胞にローダミン標識プルランナノゲルを図2に表示の濃度で投与し、37℃で2時間インキュベートした。細胞を冷PBSで洗浄し、EDTA含有冷PBSで剥離してシングルセルとなるように懸濁した。フローサイトメトリーで各細胞へのローダミン標識プルランナノゲルの取り込み率を測定した。
COS7細胞に表示のC型レクチンのcDNAをコードする発現ベクターをリポフェクション法で一過性導入した。コントロールとしてcDNAを含まない発現ベクターを用いて同様に行った(Vector control)。48時間後に、各細胞にローダミン標識プルランナノゲルを2 μg/mLの濃度で投与し、37℃で2時間インキュベートした。細胞を冷PBSで洗浄し、TryPLE (Thermo Scientific)で剥離してシングルセルとなるように懸濁した。蛍光顕微鏡で各細胞へのローダミン標識プルランナノゲルの取り込み(赤色)を観察した。
マウスSIGNR1/CD209b遺伝子を安定発現するマウスRAW264.7細胞(図4中RAW SR-1)に、ローダミン標識プルランナノゲル(図4中 CHP)またはローダミン標識プルラン(直鎖状、ユニマー)(図4中 Pullulan 400K)を図4に表示の各濃度で投与し、37℃で3時間インキュベートした。細胞をスクレーパーで剥離してシングルセルとなるように懸濁した。フローサイトメトリーで各細胞へのローダミン標識プルランナノゲルの取り込み強度(蛍光強度)を測定した。また、マンナン(直鎖状、ユニマー)とマンナンナノゲルを用いて、同様に試験した。
マウス繊維肉腫細胞株CMS5a細胞にマウスSIGNR1/CD209bのcDNAをコードする発現ベクターをエレクトロポレーション法で一過性導入した。翌日に、各細胞にローダミン標識プルランナノゲルを2 μg/mLの濃度で、また抗SIGNR1抗体(22D1)を図6に表示の濃度で投与し、37℃で2時間インキュベートした。細胞をトリプシンで剥離してシングルセルとなるように懸濁した。蛍光顕微鏡観察とフローサイトメトリーで各細胞へのローダミン標識プルランナノゲルの取り込みを評価した。
マウス繊維肉腫細胞株CMS5a細胞にマウスSIGNR1/CD209bのcDNAをコードする発現ベクターをエレクトロポレーション法で一過性導入した。翌日に、各細胞にプルランナノゲルPE複合体もしくはPEを0.3, 1, 3, 9, 10, 30, 90μg/mLの濃度で投与し、37℃で1時間インキュベートした。1時間後に10%FCS RPMIにて洗浄した後、10%FCS RPMIで24時間培養、その後、Cell Counting Kit-8にて細胞活性を評価した。
マウス大腸がん細胞株CMS5a細胞を正常BALB/cマウス(8週令、雌)の皮下に移植し、8, 10, 12日後にプルランナノゲルPE複合体およびPEを(0.1 μg)をCpG(50ug)と共に静脈内投与した。腫瘍サイズを経時的に測定した。
Claims (16)
- 疎水性基を含む修飾多糖類を含有するゲル粒子を含有する、CD209陽性細胞を含有するがん組織に対するがん治療剤。
- 前記ゲル粒子がナノゲル粒子である、請求項1に記載のがん治療剤。
- 前記修飾多糖類の構成多糖類がプルラン、マンナン、及びデキストランからなる群より選択される少なくとも1種を含む、請求項1又は2に記載のがん治療剤。
- 前記修飾多糖類の構成多糖類がプルランを含む、請求項1~3のいずれかに記載のがん治療剤。
- 前記疎水性基がステロール骨格を有する疎水性基を含む、請求項1~4のいずれかに記載のがん治療剤。
- 前記修飾多糖類の重量平均分子量が5000~2,000,000である、請求項1~5のいずれかに記載のがん治療剤。
- 前記ゲル粒子の重量平均粒子径が20~200nmである、請求項1~6のいずれかに記載のがん治療剤。
- 前記ゲル粒子が薬剤を含有する、請求項1~7のいずれかに記載のがん治療剤。
- 前記薬剤がアジュバント、がん抗原、抗がん剤、及び核酸医薬からなる群より選択される少なくとも1種を含む、請求項8に記載のがん治療剤。
- 前記CD209陽性細胞がマクロファージである、請求項1~9のいずれかに記載のがん治療剤。
- がん組織を有する患者から選別された、CD209陽性細胞を含有するがん組織を有する患者に投与するように用いるための、請求項1~10のいずれかに記載のがん治療剤。
- 薬剤との併用に用いられる、請求項1~11のいずれかに記載のがん治療剤。
- 疎水性基を含む修飾多糖類を含有するゲル粒子を含有する、CD209陽性細胞への送達用担体。
- CD209陽性細胞ががん組織に存在する、請求項13に記載の送達用担体。
- 請求項13又は14に記載の送達用担体及び造影剤を含有する、CD209陽性細胞を含有する組織の検出剤。
- CD209結合性分子を含有する、請求項1~12のいずれかに記載のがん治療剤に対するコンパニオン診断薬。
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WO2000012564A1 (fr) | 1998-08-31 | 2000-03-09 | Nof Corporation | Polysaccharide a haut degre de purete contenant des groupes hydrophobes et procede de production de ce polysaccharide |
WO2017138557A1 (ja) * | 2016-02-08 | 2017-08-17 | 国立大学法人三重大学 | 免疫チェックポイント阻害剤抵抗性腫瘍に対するt細胞輸注療法の前処置薬 |
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WO2000012564A1 (fr) | 1998-08-31 | 2000-03-09 | Nof Corporation | Polysaccharide a haut degre de purete contenant des groupes hydrophobes et procede de production de ce polysaccharide |
WO2017138557A1 (ja) * | 2016-02-08 | 2017-08-17 | 国立大学法人三重大学 | 免疫チェックポイント阻害剤抵抗性腫瘍に対するt細胞輸注療法の前処置薬 |
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JPWO2023022141A1 (ja) | 2023-02-23 |
AU2022331178A1 (en) | 2024-03-07 |
KR20240041949A (ko) | 2024-04-01 |
IL310830A (en) | 2024-04-01 |
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