WO2023145749A1 - Adjuvant - Google Patents
Adjuvant Download PDFInfo
- Publication number
- WO2023145749A1 WO2023145749A1 PCT/JP2023/002171 JP2023002171W WO2023145749A1 WO 2023145749 A1 WO2023145749 A1 WO 2023145749A1 JP 2023002171 W JP2023002171 W JP 2023002171W WO 2023145749 A1 WO2023145749 A1 WO 2023145749A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lipid
- lipid particles
- antigen
- immunostimulant
- administration
- Prior art date
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- CGSJXLIKVBJVRY-XTGBIJOFSA-N zymosterol Chemical compound C([C@@]12C)C[C@H](O)C[C@@H]1CCC1=C2CC[C@]2(C)[C@@H]([C@@H](CCC=C(C)C)C)CC[C@H]21 CGSJXLIKVBJVRY-XTGBIJOFSA-N 0.000 description 1
Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
-
- 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
-
- 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
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to immunostimulators and the like.
- an immunostimulant such as aluminum hydroxide.
- aluminum hydroxide has many problems, such as being inflammatory and being unable to induce a Th1-type immune response at all.
- an adjuvant capable of inducing a Th1-type immune response
- strong infection is observed. Show defense. In this way, the induction of Th1-type immune responses is becoming essential in the development of vaccines against viral infections.
- Patent Document 1 describes an immunostimulant using 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-containing lipid particles.
- DOTAP 1,2-dioleoyl-3-trimethylammonium-propane
- An object of the present invention is to provide an immunostimulant containing lipid particles with higher immune response-inducing ability (preferably Th1-type immune response-inducing ability).
- the present inventor found that the above problems could be solved by an immunostimulator containing lipid particles containing cationic lipids represented by general formula (1). Based on this finding, the inventors have further studied and completed the present invention. That is, the present invention includes the following aspects.
- R 1 and R 2 are the same or different and represent an unsaturated chain hydrocarbon group.
- R 3 , R 4 and R 5 are the same or different and represent an alkyl group.
- p is an integer from 1 to 3;
- q is an integer from 0 to 3.
- r represents an integer from 1 to 3;
- Section 2 wherein the unsaturated chain hydrocarbon group has only one double bond and has 10 to 30 carbon atoms.
- Section 3. The immunostimulant according to item 1 or 2, wherein the p is 1, the q is 0, and the r is 1.
- Section 4 Items 1 to 3, wherein the cationic lipid is 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA).
- DOTMA 1,2-di-O-octadecenyl-3-trimethylammonium propane
- Item 5 Items 1 to 4, wherein the content of the cationic lipid is 10 to 75 mol% relative to 100 mol% of the lipid constituting the lipid particles.
- Item 6 Items 1 to 5, wherein the lipid particles contain at least one selected from the group consisting of phospholipids, sterols, and water-soluble polymer-modified lipids.
- Item 7 Items 1 to 6, wherein the lipid particles contain a phospholipid, a sterol, and a water-soluble polymer-modified lipid.
- Item 8 Items 1 to 7, which do not contain CpG oligodeoxynucleotides and aluminum compounds.
- Item A Items 1 to 8, wherein the lipid particles are lipid nanoparticles.
- Item 9 A pharmaceutical containing the immunostimulant according to any one of Items 1 to 8 and A.
- Item 10 Item 10. Item 9, which is a vaccine composition.
- Item 11 Item 9 or 10, further comprising an antigen.
- Item B Item 12, wherein the antigen comprises at least one selected from the group consisting of influenza vaccine antigens and SARS-CoV-2 vaccine antigens.
- an immunostimulant containing lipid particles with a higher ability to induce immune responses.
- FIG. 1 shows the evaluation results of the ability to induce antibody production in Test Example 1.
- FIG. The vertical axis indicates the ELISA measurement value of the antibody shown above each graph. In the horizontal axis, Cont. indicates the case without drug administration, SV indicates the case of antigen alone administration, and others indicate the case of administration of lipid particles together with antigen. 1 shows the evaluation results of T cell response-inducing ability of Test Example 1.
- FIG. The vertical axis indicates the concentration value measured by ELISA of the molecule shown above each graph. In the horizontal axis, Cont. indicates the case without drug administration, SV indicates the case of antigen alone administration, and others indicate the case of administration of lipid particles together with antigen. 1 shows the evaluation results of the ability to induce antibody production in Test Example 1.
- the vertical axis indicates the ELISA measurement value of the antibody shown above each graph.
- Cont. indicates the case without drug administration
- SV indicates the case of antigen alone administration
- others indicate the case of administration of lipid particles together with antigen.
- 1 shows the evaluation results of T cell response-inducing ability of Test Example 1.
- FIG. The vertical axis indicates the concentration value measured by ELISA of the molecule shown above each graph.
- Cont. indicates the case without drug administration
- SV indicates the case of antigen alone administration
- others indicate the case of administration of lipid particles together with antigen.
- 2 shows the evaluation results of the ability to induce antibody production in Test Example 2.
- FIG. The vertical axis indicates the ELISA measurement value of the antibody shown above each graph.
- Cont. indicates the case of no drug administration
- SV indicates the case of antigen alone administration
- others indicate the case of administration of lipid particles or an existing adjuvant together with the antigen.
- 2 shows the evaluation results of the ability to induce T cell responses in Test Example 2.
- FIG. The vertical axis indicates the concentration value measured by ELISA of the molecule shown above each graph.
- Cont. indicates the case of no drug administration
- SV indicates the case of antigen alone administration
- others indicate the case of administration of lipid particles or an existing adjuvant together with the antigen.
- FIG. 10 shows changes in body weight (upper graph) and measurement results of survival rate (lower graph) in Test Example 2.
- FIG. 2 shows changes in body weight (upper graph) and measurement results of survival rate (lower graph) when DOTMA-containing LNP was administered in Test Example 2.
- FIG. The legend indicates the antibody administered.
- 3 shows the evaluation results of the ability to induce antibody production in Test Example 3.
- FIG. The vertical axis indicates the ELISA measurement value of the antibody shown above each graph. In the horizontal axis, Cont. indicates the case of no drug administration, S indicates the case of antigen alone administration, and others indicate the case of administration of lipid particles or an existing adjuvant together with the antigen. 3 shows the evaluation results of the ability to induce T cell responses in Test Example 3.
- FIG. The vertical axis indicates the concentration value measured by ELISA of the molecule shown above each graph.
- Cont. indicates the case of no drug administration
- S indicates the case of antigen alone administration
- others indicate the case of administration of lipid particles or an existing adjuvant together with the antigen.
- 4 shows the measurement results of spleen weight and body weight ratio of spleen weight in Test Example 4.
- SV indicates the case of administration of antigen alone, and others indicate the case of administration of lipid particles or an existing adjuvant together with antigen.
- 4 shows the measurement results of inflammatory cytokines in Test Example 4.
- SV indicates administration of antigen alone, and others indicate administration of lipid particles or an existing adjuvant together with antigen.
- the horizontal axis indicates the elapsed time after drug administration. 4 shows the evaluation results of the ability to induce antibody production in Test Example 5.
- FIG. The vertical axis indicates the ELISA measurement value of the antibody shown above each graph. In the horizontal axis, Cont. indicates the case without drug administration, SV indicates the case of antigen alone administration, and others indicate the case of administration of lipid particles together with antigen. 5 shows the evaluation results of the ability to induce T cell responses in Test Example 5.
- FIG. The vertical axis indicates the concentration value measured by ELISA of the molecule shown above each graph. In the horizontal axis, Cont.
- FIG. The vertical axis indicates the ELISA measurement value of the antibody shown above each graph.
- Cont. indicates the case of no drug administration
- PspA indicates the case of antigen alone administration
- others indicate the case of administration of lipid particles or an existing adjuvant together with the antigen.
- 1 shows the evaluation results of the ability to induce T cell responses in Test Example 6.
- FIG. The vertical axis indicates the concentration value measured by ELISA of the molecule shown above each graph.
- Cont. indicates the case of no drug administration
- PspA indicates the case of antigen alone administration
- others indicate the case of administration of lipid particles or an existing adjuvant together with the antigen.
- lipid particle of the present invention a lipid particle containing a cationic lipid represented by general formula (1) (herein also referred to as “the lipid particle of the present invention”) is provided.
- Contained immunostimulant in this specification, it may be indicated as “immunostimulator of the present invention”. This will be explained below.
- R 1 and R 2 are the same or different and represent an unsaturated chain hydrocarbon group;
- R 3 , R 4 and R 5 are the same or different and represent an alkyl group.
- p is an integer from 1 to 3;
- q is an integer from 0 to 3.
- r represents an integer from 1 to 3;
- the unsaturated chain hydrocarbon group is a monovalent chain hydrocarbon group containing a double bond, and is not particularly limited as long as it is.
- the unsaturated chain hydrocarbon group includes both straight-chain and branched-chain, and particularly preferably straight-chain.
- the number of carbon atoms in the unsaturated chain hydrocarbon group is not particularly limited as long as it is capable of forming lipid particles. 22, more preferably 16-20, particularly preferably 17-19, particularly preferably 18.
- the number of double bonds contained in the unsaturated chain hydrocarbon group is not particularly limited as long as it is the number capable of forming lipid particles, for example 1 to 6, preferably 1 to 4, more preferably 1 to 3, and further Preferably 1 to 2, particularly preferably 1.
- the unsaturated hydrocarbon group preferably includes a group represented by general formula (2).
- s is an integer greater than or equal to 0.
- s is preferably 2 to 26, more preferably 3 to 20, even more preferably 4 to 14, even more preferably 5 to 10, especially preferably 6 to 8, particularly preferably 7.
- t is an integer greater than or equal to 1.
- t is preferably 3 to 27, more preferably 4 to 21, even more preferably 5 to 15, even more preferably 6 to 11, especially preferably 7 to 9, particularly preferably 8.
- the sum of s and t is, for example, 5 to 27, preferably 7 to 27, more preferably 9 to 23, still more preferably 11 to 19, even more preferably 13 to 17, particularly preferably 14 to 16, particularly preferably is 15.
- p is preferably 1 to 2, particularly preferably 1.
- q is particularly preferably 0.
- r is preferably 1 to 2, particularly preferably 1. In a preferred embodiment of the invention, p is 1, q is 0 and r is 1.
- a preferred embodiment of general formula (1) is general formula (1A).
- a particularly preferred embodiment of general formula (1) is general formula (1AA).
- two s may be the same or different, and two t may be the same or different.
- the cationic lipid represented by general formula (1) is particularly preferably 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA).
- DOTMA 1,2-di-O-octadecenyl-3-trimethylammonium propane
- the cationic lipid represented by general formula (1) can also be in the form of a salt.
- Cationic lipids represented by the general formula (1) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; acetate, propionate, tartrate, fumaric acid It can be a salt, an organic acid salt such as maleate, malate, citrate, methanesulfonate, paratoluenesulfonate.
- the cationic lipid represented by general formula (1) may be used alone or in combination of two or more.
- the lipid particles of the present invention are not particularly limited as long as they contain the cationic lipid represented by general formula (1).
- the particle size of the lipid particles of the present invention is not particularly limited.
- the particle size is preferably nano-sized, specifically for example 10-700 nm, 10-400 nm, 10-200 nm, 10-150 nm or less than 100 nm.
- the lipid particles of the present invention are preferably lipid nanoparticles (LNP: Lipid NanoParticles) having a nano-sized particle size.
- the lipid particles of the present invention may contain lipids other than the cationic lipid represented by general formula (1) as lipids constituting the particles, or may contain no other lipids. can be.
- the content of the cationic lipid represented by general formula (1) is not particularly limited as long as lipid particles can be formed. From the viewpoint of the immune response-inducing action of the lipid particles, the content is, for example, 10 to 100 mol%, preferably 10 to 85 mol%, more preferably 100 mol% of the lipid constituting the lipid particles of the present invention. 10 to 75 mol %, more preferably 20 to 70 mol %, even more preferably 30 to 65 mol %, particularly preferably 40 to 60 mol %, particularly preferably 45 to 55 mol %.
- the content is, for example, 10 mol% or more, preferably 20 mol% or more, more preferably 100 mol% of the lipid constituting the lipid particles of the present invention. It is 30 mol % or more, more preferably 40 mol % or more, and particularly preferably 45 mol % or more. In one aspect of the present invention, the content is preferably 80 mol% or less, more preferably 70 mol% or less, even more preferably 65 mol% or less, still more preferably 60 mol%, from the viewpoint of lipid particle formation. Below, particularly preferably 55 mol % or less, particularly preferably 50 mol % or less.
- lipids include, but are not particularly limited to, phospholipids, sterols, water-soluble polymer-modified lipids, cationic lipids other than the cationic lipids represented by general formula (1), glycolipids, and the like.
- the lipid particles of the present invention preferably contain at least one selected from the group consisting of phospholipids, sterols, and water-soluble polymer-modified lipids, all of which (phospholipids, sterols, , and water-soluble polymer-modified lipids).
- phospholipids include phosphatidylcholines such as dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, dilinoleoylphosphatidylcholine, myristoylpalmitoylphosphatidylcholine, myristoylstearoylphosphatidylcholine, palmitoylstearoylphosphatidylcholine; Phosphatidyl such as lauroyl phosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol, dilinoleoylphosphatidylg
- Phospholipids may be used alone or in combination of two or more.
- the content is not particularly limited as long as the lipid particles can be formed. %, preferably 10 to 30 mol %, more preferably 15 to 25 mol %, still more preferably 17 to 23 mol %.
- sterols include cholesterol, cholesteryl hemisuccinate, lanosterol, dihydrolanosterol, desmosterol, dihydrocholesterol, phytosterol, phytosterol, stigmasterol, zymosterol, ergosterol, sitosterol, campesterol, and brassicasterol.
- the sterol has the effect of stabilizing the lipid particle membrane and adjusting the fluidity of the lipid particle membrane, so it is desirable that the sterol is contained as a constituent lipid of the lipid particle membrane.
- the sterols may be of one type alone or in combination of two or more types.
- the content is not particularly limited as long as the lipid particles can be formed. , preferably 20 to 40 mol %, more preferably 25 to 35 mol %, still more preferably 27 to 33 mol %.
- a water-soluble polymer-modified lipid is a lipid to which a water-soluble polymer has been added, and is not particularly limited as long as it is.
- water-soluble polymers include, but are not limited to, polyethylene glycol (PEG) chains.
- the molecular weight of the water-soluble polymer is not particularly limited, but is, for example, 200-10000, preferably 500-7000, more preferably 500-4000, still more preferably 1000-3000, still more preferably 1500-2500.
- Lipids modified with water-soluble polymers preferably include amphipathic lipids, more preferably phospholipids.
- the water-soluble polymer-modified lipid may be used singly or in combination of two or more.
- the content is not particularly limited as long as the lipid particles can be formed. 0 to 10 mol%, preferably 0 to 5 mol%, more preferably 0 to 2 mol%, still more preferably 0 to 1 mol%, even more preferably 0.2 to 1 mol%, particularly preferably 0.3 to 0.7 mol% is.
- the lipid particles of the present invention may contain other components (other than the solvent) in addition to the lipid.
- other components include various components known to be incorporated into lipid particles, specifically, for example, membrane stabilizers, charged substances, antioxidants, membrane proteins, polyethylene glycol (PEG), antibodies, peptides. , sugar chains, and the like.
- Antioxidants can be contained to prevent oxidation of the film, and are used as necessary as a component of the film.
- Antioxidants used as membrane constituents include, for example, butylated hydroxytoluene, propyl gallate, tocopherols, tocopherol acetate, concentrated mixed tocopherols, vitamin E, ascorbic acid, L-ascorbic stearate, palmitic acid. Examples include ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, citric acid and the like.
- Membrane proteins can be contained for the purpose of adding functions to membranes or stabilizing membrane structures, and are used as necessary as membrane constituents.
- Membrane proteins include, for example, surface membrane proteins, integral membrane proteins, albumin, recombinant albumin and the like.
- the content of other components is, for example, 10% by mass or less, preferably 5% by mass or less, more preferably 2% by mass or less, and still more preferably 1% by mass or less, relative to 100% by mass of the lipid particles of the present invention. .
- the other ingredients may be used singly or in combination of two or more.
- the lipid particles of the present invention can exhibit a high ability to induce Th1-type immune responses without relying on other adjuvants. Therefore, from the viewpoint of reducing side effects caused by other adjuvants, the lipid particles of the present invention preferably do not contain other adjuvants or their content is less.
- Other adjuvants include CpG oligodeoxynucleotide (CpG nucleic acid: CpG ODN: e.g. A type, B type, C type, P type etc.), aluminum compounds (e.g. aluminum hydroxide, aluminum phosphate etc.), oil emulsions and the like. mentioned.
- the content of other adjuvants is, for example, 10% by mass or less, preferably 5% by mass or less, more preferably 2% by mass or less, more preferably 1% by mass or less, with respect to 100% by mass of the lipid particles of the present invention. Preferably it is 0% by mass.
- the lipid particles may be of one type alone or in combination of two or more types.
- the lipid particles of the present invention are usually formed in an aqueous solution.
- aqueous solutions include various buffers (eg, acetate buffer, phosphate buffer, formate buffer, histidine buffer, etc.).
- the lipid particles of the present invention can be produced according to or according to known methods for lipid particles.
- the lipid particles of the present invention can be preferably produced by a method including a step of mixing a lipid-containing alcohol solution and an aqueous solution (Step 1).
- the alcohol that is the solvent for the alcohol solution is not particularly limited as long as it can dissolve lipids.
- Ethanol is preferably mentioned as the alcohol.
- the lipid concentration in the alcohol solution is, for example, 0.1-20% by mass, preferably 0.1-10% by mass, more preferably 0.5-3.0% by mass.
- the mixing ratio of the aqueous solution and the alcohol solution is, for example, 20/1 to 1/1, preferably 4/1 to 2/1.
- the mode of mixing is not particularly limited as long as it is a mode in which lipid particles can be formed, but it is usually a mode of vigorously stirring with a vortex or the like. Alternatively, when it is performed in a reaction system using a microchannel, mixing occurs within the reaction system.
- Step 1 is usually performed at room temperature or under heating.
- the immunostimulant of the present invention may contain other substances besides the lipid particles of the present invention.
- Other substances include, but are not particularly limited to, adjuvants other than the lipid particles of the present invention.
- the content of other substances is, for example, 10% by mass or less, preferably 5% by mass or less, more preferably 2% by mass or less, and still more preferably 1% by mass or less with respect to 100% by mass of the immunostimulant of the present invention. be.
- the other substance may be of one type alone or may be a combination of two or more types.
- the lipid particles of the present invention can exhibit a high ability to induce Th1-type immune responses without relying on other adjuvants. Therefore, from the viewpoint of reducing side effects caused by other adjuvants, the immunostimulant of the present invention preferably does not contain other adjuvants or contains them in a smaller amount. Other adjuvants are the same as above.
- the content of other adjuvants is, for example, 10% by mass or less, preferably 5% by mass or less, more preferably 2% by mass or less, more preferably 1% by mass or less, relative to 100% by mass of the immunostimulant of the present invention, Particularly preferably, it is 0% by mass.
- the immunostimulant of the present invention can be obtained from the lipid particles of the present invention as they are or by adding the above-described components/substances to the particles.
- the immunostimulant of the present invention can exhibit a higher ability to induce immune responses.
- the immunostimulant of the present invention is capable of exhibiting higher cell-mediated immunity induction (in particular, Th1-type immune response induction) (for example, IFN- ⁇ induction) and higher antibody induction. can also be demonstrated.
- the immunostimulant of the present invention can exert the above-mentioned various inducing abilities while suppressing side reactions such as inflammation as compared with other existing adjuvants. Therefore, the immunostimulant of the present invention can be used in various applications utilizing its immunostimulatory action, such as medicines, reagents, etc. Specifically, it can be used for vaccine compositions, antiviral agents, antibacterial agents, and the like.
- the drug of the present invention is not particularly limited as long as it contains the immunostimulant of the present invention, and may further contain other ingredients 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 action. Examples of additives include various components known to be blended with immunostimulants, and specific examples include bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, and binders. , disintegrants, lubricants, thickeners, humectants, coloring agents, fragrances, chelating agents and the like.
- the lipid particles of the present invention can exhibit a higher ability to induce immune responses without relying on other adjuvants. Therefore, from the viewpoint of reducing side effects caused by other adjuvants, the drug of the present invention preferably does not contain other adjuvants or contains less adjuvants. Other adjuvants are the same as above.
- the content of other adjuvants is, for example, 10% by mass or less, preferably 5% by mass or less, more preferably 2% by mass or less, still more preferably 1% by mass or less, particularly preferably 1% by mass or less, relative to 100% by mass of the drug of the present invention. is 0% by mass.
- the agent of the present invention preferably contains an antigen.
- An antigen is any agent (e.g., protein , peptides, polysaccharides, glycoproteins, glycolipids, nucleic acids or combinations thereof).
- an antigen-induced immune response may be humoral, cellular, or both.
- An agent is said to be "antigenic” when it is capable of specifically interacting with an antigen-recognition molecule of the immune system, such as an immunoglobulin (antibody) or T-cell antigen receptor (TCR).
- one or more antigens are protein-based antigens. In other embodiments, one or more antigens are peptide-based antigens. In various embodiments, the one or more antigens are selected from the group consisting of cancer antigens, viral antigens, bacterial antigens (bacterial antigens, fungal antigens), and pathogen antigens.
- a "microbial antigen,” as used herein, is an antigen of a microorganism and includes, but is not limited to, infectious viruses, infectious bacteria, infectious parasites, and infectious fungi.
- Microbial antigens are intact microorganisms as well as natural isolates, fragments or derivatives thereof, as well as the same or similar to naturally occurring microbial antigens, preferably specific to the corresponding microorganism (from which the naturally occurring microbial antigen is derived). It may also be a synthetic compound that induces a potent immune response.
- the antigen is a cancer antigen.
- the antigen is a viral antigen.
- the antigen is a fungal antigen.
- the antigen is a pathogen antigen.
- pathogen antigens are synthetic or recombinant antigens.
- Antigens preferably include viral antigens.
- Viruses from which antigens are derived are not particularly limited, but examples include influenza viruses (e.g., type A, type B, etc.), rubella virus, Ebola virus, coronavirus, measles virus, varicella-zoster virus, herpes simplex virus, mumps virus, Enveloped viruses such as arbovirus, respiratory syncytial virus, SARS virus, hepatitis virus (e.g., hepatitis B virus, hepatitis C virus, etc.), yellow fever virus, AIDS virus, rabies virus, hantavirus, dengue virus, Nipah virus, lyssa virus viruses); non-enveloped viruses (viruses without envelopes) such as adenovirus, norovirus, rotavirus, human papillomavirus, poliovirus, enterovirus, coxsackievirus, human parvovirus, encephalomyocarditis
- SARS-CoV-2 SARS coronavirus 2
- SARS-CoV-2 is not particularly limited, and includes not only known strains such as Wuhan strain, alpha strain, delta strain, lambda strain, and Omicron strain, and their substrains, but also various unknown strains that will be discovered in the future. mentioned.
- Antigens preferably include bacterial antigens.
- Bacteria from which antigens are derived are not particularly limited. acnes, faecalis, difficile, pneumococcus, haemophilus influenzae, moraxella, pneumoniae, coynebacterium, hemolytic streptococcus, pseudomonas aeruginosa, staphylococcus, mycoplasma, candida, and aspergillus.
- the mode of use of the drug of the present invention is not particularly limited, and an appropriate mode of use can be adopted according to its type.
- the agent of the present invention can be used, for example, in vitro (e.g., added to the culture medium of cultured cells) or in vivo (e.g., administered to an animal), depending on its use. can also
- the application target of the agent of the present invention is not particularly limited, but examples of mammals include humans, monkeys, mice, rats, dogs, cats, rabbits, pigs, horses, cows, sheep, goats, and deer. Moreover, 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.
- the agent 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, Oral dosage forms such as hard capsules, soft capsules, dry syrups, liquids (including drinks, suspensions, and syrups), jelly, and injection preparations (e.g., drip injections (e.g., intravenous drip preparations, etc.), intravenous injections, intramuscular injections, subcutaneous injections, intradermal injections), external preparations (e.g., ointments, poultices, lotions), suppository inhalers, eye drops, ophthalmic ointments, drops Parenteral formulations such as nose drops, ear drops, and liposomes can be used.
- tablets including orally disintegrating tablets, chewable tablets, effervescent tablets, lozenges, jelly drops, etc.
- pills granule
- the administration route of the agent of the present invention is not particularly limited as long as the desired effect is obtained, and oral administration; enteral administration such as tube feeding and enema administration; intravenous administration, transarterial administration, intramuscular administration, Examples include parenteral administration such as intracardiac administration, subcutaneous administration, intradermal administration, intraperitoneal administration, and nasal administration.
- the content of the immunostimulant of the present invention in the drug of the present invention depends on the mode of use, the subject of application, the state of the subject of application, etc., and is not limited, but is, for example, 0.0001 to 100% by weight, preferably It can be from 0.001 to 50% by weight.
- the dosage is not particularly limited as long as it is an effective amount that exhibits efficacy.
- the above dosage can be adjusted appropriately depending on age, disease state, symptoms and the like.
- DOTAP 1,2-dioleoyl-3-trimethylammonium-propane
- DPPC 1,2-dipalmitoyl-sn-glycero-3-phosphocholine
- NG-DOPE N-glutaryl-L- ⁇ -dioleoylphosphatidylethanolamine
- DODAP 1,2-dioleoyloxy-3-dimethylaminopropane
- DOTMA 1,2-di-O-octadecenyl-3-trimethylammonium propane
- DSPE-PEG-Ome N-(methylpolyoxyethyleneoxycarbonyl)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG chain molecular weight: 2000)
- Production example 1 Production of lipid particles 1 An ethanol solution (lipid concentration: 1.0% by mass) containing lipids with the composition and molar ratio shown in Table 1 and 25 mM Sodium Acetate (pH 4.0) were prepared using NanoAssemblr (manufactured by Precision NanoSystems) at a ratio of 1:3 (ethanol solution : 25 mM sodium acetate aqueous solution (pH 4.0, mixing ratio), mixed at 15 mL / min to form lipid nanoparticles, dialyzed (5% glucose aqueous solution), and each lipid particle with the name shown in Table 1 (hereinafter referred to as It is sometimes indicated as “LNP”.) was obtained.
- the lipid particles of this production example were used in Test Examples 1 to 4 below.
- Test example 1 Assessment of immunostimulatory capacity1 ⁇ Experimental animals, reagents> - Mice: 6-week-old male C57BL6 mice - Antigen: A split vaccine (SV) derived from H1N1 influenza A virus (strain: A/California/7/2009 (Cal7)) was administered at 0.5 ⁇ g/mouse. - Lipid nanoparticles (LNP): Each LNP listed in Table 1 was administered at 100 ⁇ g/mouse.
- SV split vaccine
- H1N1 influenza A virus strain: A/California/7/2009 (Cal7)
- LNP Lipid nanoparticles
- mice were immunized subcutaneously on days 0 and 21 after SV alone or SV mixed with various LNPs. On day 28, blood was collected and plasma SV-specific total IgG, IgG1, IgG2b, and IgG2c were evaluated by ELISA.
- ⁇ Method Evaluation of ability to induce T cell responses: Figures 2 and 4> Immune cells were harvested from the spleens on day 31 and cultured with SV (10 ⁇ g/mL). After 1 or 3 days, the culture supernatant was collected and IL-2, IFN- ⁇ and IL-13 levels were measured by ELISA.
- Figures 1 and 2 used LNPs created by varying the content of DOTAP, which is used as a cationic lipid.
- DOTAP LNP using the anionic lipid NG-DOPE was used.
- the surface charge of the LNP used becomes close to neutral by decreasing the amount of DOTAP, and the negative charge increases by increasing the amount of NG-DOPE.
- IFN- ⁇ production an indicator of Th1 immunity
- NG-DOPE an indicator of Th2 immunity
- DOTAP was used as the cationic lipid
- LNPs with varying contents of polyethylene glycol (PEG)-modified lipids were used.
- PEG polyethylene glycol
- LNPs using DODAP or DOTMA which are cationic lipids, were used.
- a downward trend was observed for antibody production and T-cell responses with increasing PEG-modified lipid content.
- DODAP-containing LNPs also tended to induce lower immune responses than DOTAP-containing LNPs.
- increased antibody production was observed for DOTMA-containing LNPs compared to DOTAP-containing LNPs.
- Th1 and Th2 immunity were found to be strongly induced by DOTMA-containing LNP.
- Test example 2 Comparison with existing adjuvants ⁇ laboratory animals, reagents> - Mice: 6-week-old male C57BL6 mice - Antigen: A split vaccine (SV) derived from H1N1 influenza A virus (strain: A/California/7/2009 (Cal7)) was administered at 0.5 ⁇ g/mouse.
- Adjuvant Aluminum hydroxide (alum) was administered at 50 ⁇ g/mouse, or B-type CpG nucleic acid (CpG K3) was administered at 50 ⁇ g/mouse.
- mice were immunized subcutaneously on days 0 and 21 after SV alone or mixed with alum, CpG K3, DOTAP-containing LNPs or DOTMA-containing LNPs. On day 28, blood was collected and plasma SV-specific total IgG, IgG1, IgG2b, and IgG2c were evaluated by ELISA.
- ⁇ Method (Evaluation of ability to induce T cell response: Fig. 6)> Immune cells were harvested from the spleens on day 31 and cultured with SV (10 ⁇ g/mL). After 1 or 3 days, the culture supernatant was collected and IL-2, IFN- ⁇ and IL-13 levels were measured by ELISA.
- mice were nasally infected with H1N1 influenza A virus (strain: A/Puerto Rico/8/1934 (PR8)) different from the vaccine strain, and body weight changes and survival rates were measured over the course of the day.
- H1N1 influenza A virus strain: A/Puerto Rico/8/1934 (PR8)
- ⁇ Method body weight change, survival rate: Fig. 8>
- Anti-IFN- ⁇ antibody or isotype control antibody was administered intraperitoneally on day 30 (one day before infection). After that, on the 31st day, they were infected nasally with H1N1 influenza A virus (strain: A/Puerto Rico/8/34 (PR8)) different from the vaccine strain, and body weight changes and survival rate were measured over time. .
- Test example 3 Evaluation of immunostimulatory ability when using SARS-CoV-2 antigen ⁇ laboratory animal, reagent> ⁇ Mice: 6-week-old male BALB/c mice ⁇ Antigen: Recombinant S protein derived from SARS-CoV-2 was produced in mammalian cells. S protein was administered at 1 ⁇ g/mouse.
- Adjuvant Aluminum hydroxide (alum) was administered at 50 ⁇ g/mouse, or B-type CpG nucleic acid (CpG K3) was administered at 50 ⁇ g/mouse.
- mice were immunized subcutaneously on days 0 and 21 after S protein alone or mixed with alum, CpG K3, DOTAP-containing LNPs or DOTMA-containing LNPs. Blood was collected on day 28, and SV-specific total IgG, IgG1, IgG2a, and IgG2b in plasma were evaluated by ELISA.
- ⁇ Method Evaluation of ability to induce T cell response: Fig. 10.
- Immune cells were harvested from the spleen on day 31 and cultured with S protein (10 ⁇ g/mL). One day later, the culture supernatant was collected and the IFN- ⁇ level was measured by ELISA.
- Test example 4 Evaluation of side reactions ⁇ laboratory animals, reagents> - Mice: 6-week-old male C57BL6 mice - Antigen: A split vaccine (SV) derived from H1N1 influenza A virus (strain: A/California/7/2009 (Cal7)) was administered at 0.5 ⁇ g/mouse. • Adjuvant: B-type CpG nucleic acid (CpG K3) was administered at 50 ⁇ g/mouse. - Lipid nanoparticles (LNP): DOTMA-containing LNP was administered at 100 ⁇ g/mouse.
- SV split vaccine
- CpG K3 B-type CpG nucleic acid
- LNP Lipid nanoparticles
- mice After mixing SV with CpG K3 or DOTMA-containing LNPs, mice were immunized subcutaneously twice every two days. Spleen weights were assessed 6 days after the first dose.
- ⁇ Method (measurement of inflammatory cytokine: FIG. 12)> Mice were immunized subcutaneously with SV alone or after SV was mixed with CpG K3 or DOTMA-containing LNPs. Blood inflammatory cytokine level (IL-12 p40 level) was measured daily by ELISA.
- Production example 2 Production of lipid particles 2 An ethanol solution (lipid concentration 1.0% by mass) containing lipids in the composition and molar ratio shown in Table 2 and 25 mM Sodium Acetate (pH 4.0) were prepared using NanoAssemblr (manufactured by Precision NanoSystems) at a ratio of 1:3 (ethanol solution: 25 mM sodium acetate aqueous solution (pH 4.0, mixing ratio), mixed at 15 mL/min to form lipid nanoparticles, and dialyzed (5% glucose aqueous solution) to obtain each lipid particle with the name shown in Table 2.
- DOTMA50 in Table 2 has the same composition as DOTMA in Table 1.
- the lipid particles of this production example were used in Test Examples 5 and 6 below.
- Test example 5 Evaluation of immunostimulatory capacity 2 ⁇ Experimental animals, reagents> - Mice: 6-week-old male C57BL6 mice - Antigen: A split vaccine (SV) derived from H1N1 influenza A virus (strain: A/California/7/2009 (Cal7)) was administered at 0.5 ⁇ g/mouse. - Lipid nanoparticles (LNP): DOTMA-containing LNP was administered at 100 ⁇ g/mouse.
- SV split vaccine
- H1N1 influenza A virus strain: A/California/7/2009 (Cal7)
- LNP Lipid nanoparticles
- mice were immunized subcutaneously on days 0 and 21 after SV alone or SV mixed with DOTMA-containing LNPs. On day 28, blood was collected and plasma SV-specific total IgG, IgG1, IgG2b, and IgG2c were evaluated by ELISA.
- ⁇ Method Evaluation of ability to induce T cell response: Fig. 14> Immune cells were harvested from the spleens on day 31 and cultured with SV (10 ⁇ g/mL). After 1 or 3 days, the culture supernatant was collected and IL-2, IFN- ⁇ and IL-13 levels were measured by ELISA.
- DOTMA50 had the highest antibody titers.
- IgG2b and IgG2c were remarkable.
- Test example 6 Evaluation of immunostimulatory ability when using pneumococcal antigen ⁇ laboratory animal, reagent> ⁇ Mouse: 6-week-old male C57BL6 mouse ⁇ Antigen: Recombinant PspA protein derived from Streptococcus pneumoniae was produced in Escherichia coli. PspA protein was administered at 1 ⁇ g/mouse. ⁇ Adjuvant: Aluminum hydroxide (alum) was administered at 50 ⁇ g/mouse, and B-type CpG nucleic acid (CpG K3) was administered at 50 ⁇ g/mouse. - Lipid nanoparticles (LNP): DOTMA-containing LNP was administered at 100 ⁇ g/mouse.
- alum Aluminum hydroxide
- CpG K3 B-type CpG nucleic acid
- LNP Lipid nanoparticles
- mice were immunized subcutaneously on days 0 and 21 after PspA protein alone or mixed with LNP containing alum, CpG K3 and DOTMA. Blood was collected on the 28th day, and PspA-specific total IgG in plasma was evaluated by ELISA.
- Fig. 16 ⁇ Method (Evaluation of ability to induce T cell response: Fig. 16)> Immune cells were harvested from the spleens on day 31 and cultured with PspA protein (10 ⁇ g/mL). One day later, the culture supernatant was collected and the IFN- ⁇ level was measured by ELISA.
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Abstract
L'invention a pour but de fournir un adjuvant contenant des particules lipidiques ayant une capacité d'induction de réponse immunitaire plus élevée (de préférence, une capacité d'induction de réponse immunitaire de type Th1). Le présent adjuvant contient des particules lipidiques contenant un lipide cationique représenté par la formule générale (1).
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