JP2019031481A - Therapeutic or prophylactic agents for autoimmune disease - Google Patents

Abstract

To provide novel techniques to treat or prevent autoimmune diseases.SOLUTION: Disclosed herein is a therapeutic or prophylactic agent for autoimmune disease caused by an autoantigen, which comprises a drug delivery agent comprising a drug that is cytotoxic to an immune cell that responds to the autoantigen, a drug carrier in which the drug is enclosed, a linker molecule bound to the surface of the drug carrier and the autoantigen held on the surface of the drug carrier via the linker molecule.SELECTED DRAWING: Figure 1

Description

  The present invention relates to an agent for treating or preventing an autoimmune disease.

  Autoimmune diseases are diseases in which immune cells respond to components (self-antigens) constituting themselves, and immune cells damage their organs and tissues. Immunosuppressants and steroids are known as drugs that are effective against this autoimmune disease. However, these drugs are known to cause side effects because they act on normal cells as well as immune cells that respond to self-antigens and cells that have been mutated due to damage.

  Drug Delivery System (DDS) is a general term for technology for selectively delivering a drug to a target site. In this drug delivery system, in order to selectively deliver a drug to a target site, a drug delivery body obtained by encapsulating a drug in a drug carrier such as a liposome or a polymer micelle is used. The site is targeted (for example, Patent Document 1). Targeting of the target site is performed by forming a functional molecule such as a sugar chain that specifically binds to the target site on the surface of the drug carrier. The targeted drug delivery body can selectively deliver the drug to the target site by specific binding between the functional molecule and the target site, and can suppress side effects caused by the drug.

  Patent Document 2 discloses immunosuppression that targets cells expressing any of E-selectin, L-selectin, and P-selectin, and uses a predetermined sugar chain that binds to E-selectin and the like. A therapeutic agent for an autoimmune disease comprising a liposome encapsulating an agent and a steroid is disclosed.

JP 2005-170807 A International Publication No. 2005/011633

 When a targeted conventional drug delivery body is administered in vivo, it is carried to the whole body using blood or lymph. When the drug delivery body is carried near the target site, the functional molecule on the surface of the drug delivery body specifically binds to the target site and the drug is released. Thus, targeting in conventional drug delivery bodies is a technique that provides active delivery that directs the drug delivery body to a target site.

  However, active delivery that directs the drug delivery body to the target site depends on blood flow and lymph flow until the drug delivery body is brought near the target site. For this reason, it is considered that the drug delivery body does not reach the vicinity of the target site depending on the blood flow or lymph flow. In addition, drug delivery bodies that flow through blood or lymph fluid may accumulate in organs or tissues into which blood or lymph fluid flows, causing side effects due to the drug.

  An object of this invention is to provide the novel technique which can treat or prevent an autoimmune disease.

The gist of the present invention is as follows.
(1) A therapeutic or preventive agent for an autoimmune disease caused by an autoantigen, a drug that damages immune cells that respond to the autoantigen, a drug carrier in which the drug is encapsulated, and the drug carrier An agent for treating or preventing autoimmune disease, comprising: a drug molecule having a linker molecule bound to the surface of the drug and the self-antigen retained on the surface of the drug carrier via the linker molecule.
(2) The therapeutic or prophylactic agent for autoimmune disease according to (1), wherein the drug carrier is a liposome.
(3) The therapeutic or prophylactic agent for autoimmune diseases according to (1) or (2), wherein the immune cells are T cells.
(4) The therapeutic or preventive agent for an autoimmune disease according to any one of (1) to (3), wherein the autoimmune disease is an organ-specific autoimmune disease.
(5) The organ-specific autoimmune disease is multiple sclerosis, and the autoantigen is the same amino acid sequence as at least part of the amino acid sequence of myelin oligodendrocyte glycoprotein represented by SEQ ID NO: 2 in the sequence listing The therapeutic or prophylactic agent for autoimmune diseases according to (4), wherein
(6) The autoimmune disease therapeutic or prophylactic agent according to (5), wherein the autoantigen is MOG35-55 having the amino acid sequence represented by SEQ ID NO: 4 in the Sequence Listing.
(7) The organ-specific autoimmune disease is multiple sclerosis or experimental autoimmune encephalomyelitis, and the autoantigen is a myelin oligodendrocyte glycoprotein represented by SEQ ID NO: 1 in the sequence listing. The therapeutic or prophylactic agent for autoimmune disease according to claim (4), which is a peptide having the same amino acid sequence as at least a part of the amino acid sequence.
(8) The agent for treating or preventing autoimmune disease according to (7), wherein the self-antigen is MOG35-55 having an amino acid sequence represented by SEQ ID NO: 3 in the sequence listing.

  ADVANTAGE OF THE INVENTION According to this invention, the novel technique which can treat or prevent an autoimmune disease can be provided.

FIG. 1 is a schematic view of a drug delivery body. FIG. 2 is a diagram for explaining the mechanism by which multiple sclerosis develops. FIG. 3 is a diagram illustrating a mechanism for treating multiple sclerosis. FIG. 4 is a flowchart illustrating an example of a method for producing a therapeutic agent. FIG. 5 is a diagram showing the results of a binding test for anti-MOG antibodies. FIG. 6 is a diagram showing the results of multiple sclerosis treatment test 1 (neurological symptoms from day 0 to day 19). FIG. 7 is a diagram showing the results of multiple sclerosis treatment test 2 (neurological symptoms from day 0 to day 36). FIG. 8 is a diagram showing the results of treatment test 2 for multiple sclerosis (neurologic symptoms after 101 days). FIG. 9 is a diagram showing the results of multiple sclerosis treatment test 2 (survival rate from day 0 to day 101). FIG. 10 is a diagram showing the results of Multiple sclerosis treatment test 2 (average body weight from day 0 to day 57). FIG. 11 shows the amino acid sequences of SEQ ID NOs: 1 to 4.

  Hereinafter, embodiments of the present invention will be described in detail.

  The therapeutic agent of this embodiment is a therapeutic agent for autoimmune diseases. Autoimmune disease is a general term for diseases in which one's own immune cells respond to components (self-antigens) that constitute one's own, and their own organs, tissues, cells, etc. are damaged by immune cells.

  First, the components contained in the therapeutic agent of this embodiment will be described. The therapeutic agent of this embodiment contains a drug delivery body at least. The drug delivery body includes a drug that damages immune cells that respond to self-antigens, a drug carrier in which the drug is encapsulated, a linker molecule that is bound to the surface of the drug carrier, and a linker molecule that binds to the linker molecule. And a self-antigen held on the surface of the drug carrier via the molecule.

  The drug carrier is a carrier in which a drug is encapsulated. For example, lipid nanoparticles such as liposomes and polymer micelles can be used.

  Lipid nanoparticles are particles having a particle size (diameter) of 1 nm or more and less than 1000 nm constituted by a lipid membrane, and a lumen capable of encapsulating a drug is formed inside the membrane. The number of lipid nanoparticle membranes may be one, or two or more. Examples of lipids constituting the membrane include triglycerides, diglycerides, monoglycerides, long chain fatty alcohols, fatty alcohol esters of long chain fatty acids, sterols, cholesterol esters, phospholipids, aliphatic amines, waxes, ceramides, vegetable oils , Hydrogenated (hardened) vegetable oils, fish oils, algal oils, petroleum-derived oils, short chain fatty alcohols, fatty acid esters with medium chain fatty alcohols or short chain alcohols, medium chain fatty acid triglycerides, fatty alcohol ethers, etc. It is done.

  Liposomes are particles composed of two membranes (hereinafter also referred to as “lipid bilayer membrane”) of lipid nanoparticles, an inner membrane containing phospholipids and an outer membrane. The liposome has a first lumen formed inside the inner membrane and a second lumen formed between the inner membrane and the outer membrane, and one of these two lumens or Both can be filled with drug. The particle diameter of the liposome can be, for example, 30 nm or more and less than 1000 nm.

  Specific examples of phospholipids contained in the lipid bilayer include phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidylethanolamine, sphingomyelin, phosphatidic acid, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC). ), Dimyristolphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), 1-palmitoyl 2-oleoylphosphatidylcholine (POPC), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylserine (DSPS), distearoylphosphatidylglycerol (DSPG), dipalmitoyl phosphatidylinositol (DPPI), distearoyl phosphatid Inositol (DSPI), mention may be made of dipalmitoyl phosphatidic acid (DPPA), distearoyl lysophosphatidic acid (DSPA). These phospholipids can be used in combination of two or more.

  The lipid bilayer membrane constituting the liposome may contain amphiphilic lipids such as glycolipids, sterols, and cationic lipids in addition to phospholipids. The amphipathic lipid is a lipid having both a hydrophilic group and a hydrophobic group in the molecule.

  Examples of the glycolipid include glycerolipids such as digalactosyl diglyceride and galactosyl diglyceride sulfate, galactosylceramide, galactosylceramide sulfate, lactosylceramide, sphingoglycolipids such as ganglioside G7, ganglioside G6, and ganglioside G4. it can. These glycolipids can be used in combination of two or more.

  Examples of sterols include cholesterol, dihydrocholesterol, cholesterol ester, phytosterol, sitosterol, stigmasterol, campesterol, cholestanol, and lanosterol. In addition, these sterols can also be used in combination of 2 or more types.

  Cationic lipids are 1,2-dioleoyloxy-3- (trimethylammonium) propane (DOTAP), N, N-dioctadecylamidoglycylspermine (DOGS), dimethyldioctadecylammonium bromide (DDAB), N- [1- (2,3-dioleyloxy) propyl] -N, N, N-trimethylammonium chloride (DOTMA), 2,3-dioleyloxy-N- [2 (spermine-carboxamido) ethyl] -N, N-dimethyl-1-propanaminium trifluoroacetate (DOSPA) and N- [1- (2,3-dimyristyloxy) propyl] -N, N-dimethyl-N- (2-hydroxyethyl) ammonium bromide ( DMRIE), esters of phosphatidic acid with amino alcohols such as dipalmitoyl phosphatidic acid (DPPA) Or the like distearoyl lysophosphatidic acid (DSPA) and esters of hydroxy ethylene diamine and the like. These cationic lipids can be used in combination of two or more.

  In the lipid bilayer constituting the liposome, the above-described lipids such as phospholipids are arranged such that either one of the hydrophilic group and the hydrophobic group is arranged inside the membrane, and one of the hydrophilic group and the hydrophobic group is arranged outside the membrane. Arranged to be arranged. In addition, the arrangement of the hydrophilic group and the hydrophobic group is reversed in the inner membrane and the outer membrane. That is, when the hydrophilic group of the lipid forming the inner membrane is arranged inside the inner membrane (the hydrophobic group is arranged outside the inner membrane), the hydrophilic group of the lipid forming the outer membrane is Arranged outside (hydrophobic groups are located inside the outer membrane). Moreover, when the hydrophilic group of the lipid forming the inner membrane is arranged outside the inner membrane (the hydrophobic group is arranged inside the inner membrane), the hydrophilic group of the lipid forming the outer membrane is inside the outer membrane. (Hydrophobic groups are located outside the outer membrane). The arrangement of the hydrophilic group and the hydrophobic group can be adjusted by changing the properties (hydrophilicity and hydrophobicity) of the solvent used in the liposome production and the drug filled in the lumen.

  The polymer micelle is a single membrane particle formed of a block copolymer of a hydrophilic polymer and a hydrophobic polymer, and a lumen capable of encapsulating a drug is formed inside the membrane. The particle size of the polymer micelle can be, for example, 10 to 100 nm.

  Examples of the block copolymer that forms a polymer micelle film include, for example, polyethylene glycol-polyaspartic acid block copolymer, polyethylene oxide-polyglutamic acid block copolymer, polyethylene glycol-polyarginine block copolymer, polyethylene glycol. -Polyhistidine block copolymer, polyethylene glycol-polymethacrylic acid block copolymer, polyethylene glycol-polyethyleneimine block copolymer, polyethylene glycol-polyvinylamine block copolymer, polyethylene glycol-polyallylamine block copolymer, poly Ethylene oxide-polyaspartic acid block copolymer, polyethylene oxide-polyglutamic acid block copolymer, polyethylene oxide-polyrigid Block copolymer, polyethylene oxide-polyacrylic acid block copolymer, polyethylene oxide-polyvinylimidazole block copolymer, polyacrylamide-polyaspartic acid block copolymer, polyacrylamide-polyhistidine block copolymer, polymethacrylamide -Polyacrylic acid, polymethacrylamide-polyvinylamine block copolymer, polyvinylpyrrolidone-polymethacrylic acid block copolymer, polyvinyl alcohol-polyaspartic acid block copolymer, polyvinyl alcohol-polyarginine block copolymer, polyacrylic Acid ester-polyglutamic acid block copolymer, polyacrylic acid ester-polyhistidine block copolymer, polymethacrylic acid ester-polyvinylamine bromide Click copolymers, polymethacrylic acid - may be used polyvinyl imidazole block copolymer. In addition, these block copolymers can be used in combination of 2 or more types.

  The block copolymer that forms the polymer micelle membrane has either a hydrophilic polymer or hydrophobic polymer placed inside the membrane, and either the hydrophilic polymer or hydrophobic polymer placed outside the membrane. Are arranged to be. The arrangement of the hydrophilic polymer and the hydrophobic polymer can be adjusted by changing the properties (hydrophilicity and hydrophobicity) of the solvent used in the production of polymer micelles and the drug filled in the lumen of the membrane. it can.

  The ratio of the drug carrier is not particularly limited and can be appropriately determined by those skilled in the art. However, the drug carrier may be 80% by mass to 98% by mass with respect to 100% by mass of the drug delivery body in which the drug or the like is encapsulated. It is preferable from the viewpoint that it can be stably held inside the carrier.

  A linker molecule for holding the self-antigen on the surface of the drug delivery body is bound to the surface of the drug carrier. The linker molecule may be any substance that can hold the self-antigen on the surface of the drug delivery body, and can be appropriately set by those skilled in the art depending on the components constituting the drug carrier, and is not particularly limited. For example, amino acids, carbon chains, and PEG lipid derivatives (polyethylene glycol lipid derivatives) can be used as linker molecules. As more specific linker molecules, for example, DSPE-PEG-NHS (Distiary phosphosphatidylamine-polyethylenyl-N-hydroxysuccinimide) and DSPE-PEG-maleimide can be mentioned. In addition, when using a polyethyleneglycol derivative as a linker molecule, the molecular weight of polyethyleneglycol can be 500-6,000, for example. The polyethylene glycol derivative can be used in combination of two or more kinds of polyethylene glycols having different molecular weights. When two or more types of polyethylene glycol having different molecular weights are used in combination, the molecular weight of one polyethylene glycol can be set to, for example, 500 to 2,000. These PEG lipid derivatives can be used in combination of two or more.

  The ratio of the linker molecule is not particularly limited and can be appropriately determined by those skilled in the art. However, the drug may be contained in a drug carrier by 1% by mass or more and 15% by mass or less with respect to 100% by mass of the drug delivery body in which the drug is encapsulated It is preferable from the viewpoint that it can be stably held inside and the ability to impart damaging properties to immune cells to the drug delivery body (drug carrier).

The self antigen is held on the surface of the drug carrier via a linker molecule. For example, the autoantigen is bound to the linker molecule at the end opposite to the end that is bound to the drug carrier in the linker molecule.
The autoantigen retained on the surface of the drug carrier may be any autoantigen that causes the autoimmune disease that is the target of the therapeutic agent of the present embodiment, and is an autoantigen collected from an individual to which the therapeutic agent is administered. Alternatively, it may be an autoantigen collected from another individual different from the individual to which the therapeutic agent is administered. It may also be a chemically synthesized self antigen. Examples of substances that act as self-antigens include proteins, peptides, sugar chains, and nucleic acids, and can be appropriately selected depending on the target disease. In the present specification, a protein is a polypeptide composed of 50 or more amino acids, and a peptide is a polypeptide composed of 2 or more and less than 50 amino acids.

  The number of self-antigens retained on the surface of the drug carrier is not particularly limited, but is preferably 1 or more and 20,000 or less, and more preferably 2 or more and 10,000 or less. When the number of self-antigens is 2 or more, the effect of multivalent effect that makes immune cells more responsive to the self-antigen retained on the surface of the drug carrier compared to the case where the number of antigens is one Is demonstrated. The number of self antigens retained on the surface of the drug carrier can be measured by high performance liquid chromatography (HPLC).

  The ratio of the self-antigen can be appropriately set by those skilled in the art, and is not particularly limited. However, the immune cell may be 0.006% by mass to 30% by mass with respect to 100% by mass of the drug delivery body in which the drug or the like is encapsulated. From the viewpoint of being easily recognized.

  A drug encapsulated in the lumen of a drug carrier is a drug that damages immune cells that respond to self-antigens. Specific drugs include, for example, anticancer drugs such as doxorubicin, daunorubicin, and vincristine, drugs that act as both anticancer and antirheumatic drugs such as methotrexate, and immunosuppression such as tacrolimus, cyclosporine, and fingolimod. And photosensitizers such as verteporfin.

  Here, an immune cell that responds to a self antigen is a concept that includes not only an immune cell that recognizes the self antigen but also an immune cell that eliminates the self antigen. Specific examples of immune cells that respond to self antigens include B cells, T cells, NK cells, NKT cells, macrophages, dendritic cells, neutrophils, eosinophils, and basophils. Further, “damaging immune cells” is a concept including not only killing (disappearing) immune cells, but also making immune cells unable to function or suppressing immune cell functions.

  The ratio of the drug can be appropriately set by a person skilled in the art and is not particularly limited. However, the drug may be contained in the drug carrier in an amount of 1% by mass to 15% by mass with respect to 100% by mass of the drug delivery body in which the drug is encapsulated. It is preferable from the viewpoint that it can be stably maintained and that a disorder to immune cells can be imparted to a drug delivery body (drug carrier).

  The average particle size of the drug delivery body is not particularly limited, but can be 1 nm or more and less than 1,000 nm, and preferably 30 nm or more and 200 nm or less. When the average particle size is 30 nm or more and 200 nm or less, there is an effect that drug delivery bodies are easily accumulated in immune cells due to the EPR effect (Enhanced Permeability and Retention effect). In addition, an average particle diameter shows a volume average particle diameter, and means the value measured by the dynamic light scattering method. The average particle size can be measured using, for example, Zetasizer Nano (Spectris Co., Malvern Instruments).

  The therapeutic agent of this embodiment includes a pharmaceutically acceptable excipient, binder, disintegrant, lubricant, fluidizing agent, wetting agent, solvent, diluent (solvent) in addition to the above-described drug delivery body. And other components may be included.

  The form (dosage form) of the therapeutic agent of this embodiment is not particularly limited. For example, preparations for oral administration such as powders, tablets, capsules, syrups, liquids, injections, ointments, eye drops, It can be in the form of a suppository, a patch, or a lotion. A preferred therapeutic agent form is an injection. When the therapeutic agent of this embodiment is an injection, the drug delivery body is easily introduced into the blood without being decomposed.

  Autoimmune diseases can be classified into two types: systemic autoimmune diseases in which the whole body is impaired and organ-specific autoimmune diseases in which only specific organs are impaired. The therapeutic agent of the present embodiment can be used as a therapeutic agent for any autoimmune disease classified as long as it is an autoimmune disease caused by an autoantigen.

  Examples of autoimmune diseases that can be treated with the therapeutic agent of the present embodiment include rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid antibody syndrome, polymyositis, dermatomyositis, scleroderma, Sjogren's syndrome, IgG4-related diseases, vasculitis Systemic autoimmune diseases such as syndrome, mixed connective tissue disease, Hashimoto's disease, Graves' disease, Addison's disease, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, ulcerative colitis, primary biliary cirrhosis And organ-specific autoimmune diseases such as myelopathy, myelopathy, myasthenia gravis, multiple sclerosis, rheumatic fever, pemphigus vulgaris, and lens-induced uveitis.

  In autoimmune diseases, immune cells recognize self-antigens and try to eliminate self-antigens, so that their organs and tissues are damaged. In the therapeutic agent of the present embodiment, an autoantigen that is recognized and eliminated by immune cells is held on the surface of the drug carrier (drug delivery body), and the immunity is contained inside the drug carrier (drug delivery body). Drugs that damage cells are encapsulated. For this reason, when the therapeutic agent of the present embodiment is introduced into the body, immune cells recognize and eliminate the self-antigen retained on the surface of the drug delivery body. At this time, the drug encapsulated in the drug carrier (drug delivery body) is released by the stimulation of immune cells to the drug delivery body, and the immune cells are damaged. For this reason, immune cells that respond to self-antigens are impaired and autoimmune diseases can be treated.

  As described above, the therapeutic agent of the present embodiment is not a technique for performing active delivery that directs the drug delivery body toward immune cells, but a drug delivery body (specifically, a self-antigen retained on the surface). Is a technique for performing passive delivery in which immune cells are recognized and immune cells are directed to a drug delivery body. For this reason, even if the drug delivery body becomes difficult to move due to the flow of blood flow or lymph, the immune cells can go to the drug delivery body and reach the drug delivery body. Further, even if the drug delivery body accumulates in an organ or tissue, immune cells can go to the drug delivery body and reach the drug delivery body. Therefore, side effects caused by accumulation of drug delivery bodies can be suppressed. Thus, the therapeutic agent of this embodiment can provide a new technique different from the conventional technique.

  Next, an embodiment in which the therapeutic agent of the present invention is applied to a therapeutic agent for multiple sclerosis will be described with reference to FIG. FIG. 1 is a schematic view of a drug delivery body contained in a therapeutic agent for multiple sclerosis.

  As shown in FIG. 1, a drug delivery body 1 included in a therapeutic agent for multiple sclerosis includes a drug carrier 2 in which a drug 3 is encapsulated, a linker molecule 4 that binds to the surface of the drug carrier 2, and a linker molecule 4 The self-antigen 5 is held on the surface of the drug carrier 2 via

  The drug carrier 2 is a liposome composed of an inner membrane 2a and an outer membrane 2b made of sterols and phospholipids. Specific examples of the combination of sterols and phospholipids include cholesterol and dipalmitoylphosphatidylcholine (hereinafter also referred to as “DPPC”). When the inner membrane 2a and the outer membrane 2b are composed of cholesterol and DPPC, the molar ratio of cholesterol and DPPC (cholesterol: DPPC) is not particularly limited, but from the viewpoint that the inner membrane 2a and the outer membrane 2b can be stably maintained. The ratio is preferably 1: 5 to 1: 1.

  In the inner membrane 2a, the hydrophilic groups of phospholipids and sterols are arranged inside the inner membrane 2a, and the hydrophobic groups of phospholipids and sterols are arranged outside the inner membrane 2a. In the outer membrane 2b, the hydrophilic groups of phospholipids and sterols are arranged outside the outer membrane 2b, and the hydrophobic groups of phospholipids and sterols are arranged inside the outer membrane 2b. A first lumen 2c is formed in the inner membrane 2a, and a second lumen 2d is formed between the inner membrane 2a and the outer membrane 2b.

  The drug 3 is enclosed in the first lumen 2c. Since the lumen 2c is a space surrounded by the phospholipid and sterol hydrophilic groups constituting the inner membrane 2a, a hydrophilic drug such as daunorubicin or doxorubicin is used as the drug 2. Here, in the drug delivery body 1, no drug is sealed in the second lumen 2d. However, when a hydrophobic drug such as methotrexate, tacrolimus, cyclosporine, etc. is sealed in the drug carrier 2, the membranes 2a and 2b are formed. These hydrophobic drugs can be encapsulated in the second lumen 2d surrounded by the hydrophobic groups of phospholipids and sterols.

  A plurality of linker molecules 4 are bonded to the surface of the drug delivery body 1. As the linker molecule 4, an activated PEG lipid derivative such as DSPE-PEG-NHS or DSPE-PEG-maleimide that can bind to the phospholipid constituting the drug carrier 2 and can bind to an antigen (for example, a peptide) described later is used. be able to.

  A plurality of self-antigens 5 are held on the surface of the drug delivery body 1 via linker molecules 4. The self-antigen 5 can be a peptide that causes multiple sclerosis. Examples of peptides that cause multiple sclerosis include SEQ ID NO: 1 (mouse amino acid sequence) in the sequence listing (or FIG. 11) and SEQ ID NO: 2 (human amino acid sequence) in the sequence listing (or FIG. 11). A peptide having the same amino acid sequence as at least a part of the amino acid sequence of the myelin oligodendrocyte glycoprotein shown can be used, and can be composed of, for example, 21 or more and less than 50 amino acids. More specific examples of the autoantigen 5 include those shown in SEQ ID NO: 3 (mouse amino acid sequence) in the sequence listing (or FIG. 11) and SEQ ID NO: 4 (human amino acid sequence) in the sequence listing (or FIG. 11). In addition, a peptide composed of 21 consecutive amino acids contained in SEQ ID NOs: 1 and 2 (hereinafter also referred to as “MOG35-55”) can be used.

  Next, the treatment mechanism of multiple sclerosis by the therapeutic agent containing the drug delivery body 1 will be described with reference to FIGS.

  FIG. 2 is a diagram for explaining the mechanism by which multiple sclerosis develops. Multiple sclerosis is an organ-specific autoimmune disease in which immune cells damage neurons. As shown in FIG. 2, the nerve cell 100 has a cell body 101, an axon 102 extending from the cell body 101, and a plurality of myelin sheaths (myelin sheaths) 103 wound around the axon 102, and generates an action potential. It is a cell that transmits information to other cells. In multiple sclerosis, T cells 50 damage myelin 103 using myelin oligodendrocyte glycoprotein contained in myelin sheath 103 or its peptide fragment as self-antigen 5 among these components constituting nerve cell 100. It is thought that it develops as one of the causes.

  FIG. 3 is a diagram illustrating a mechanism for treating multiple sclerosis with the therapeutic agent of this embodiment including the drug delivery body 1. When the therapeutic agent of the present embodiment including the drug delivery body 1 is administered to a patient with multiple sclerosis, the T cells 50 respond to the autoantigen 5 contained in the myelin sheath 103 as shown in FIG. In addition, it responds to the self-antigen 5 held on the surface of the drug delivery body 1. At this time, the drug 2 encapsulated in the drug delivery body 1 is released by the stimulation of the T cell 50 with respect to the drug delivery body 1 and damages the T cell 50. As a result, damage to the myelin sheath 103 by the T cell 50 is suppressed, and multiple sclerosis is treated.

  The drug delivery body 1 can be used not only for treatment of autoimmune diseases but also for prevention of autoimmune diseases. If an autoimmune disease preventive agent including the drug delivery body 1 is administered before the autoimmune disease develops, the immune cells respond to the self antigen when the immune cells respond to the self antigen. It can instantly damage immune cells and prevent damage to organs and tissues. The preventive agent for autoimmune diseases including the drug delivery body 1 may contain not only the drug delivery body 1 but also other pharmaceutically acceptable components described above. Moreover, it does not specifically limit about a form (dosage form), For example, it can be set as the form mentioned above.

  Next, the manufacturing method of the therapeutic agent of this embodiment is demonstrated. FIG. 4 is a flowchart for explaining the method for producing the therapeutic agent of the present embodiment.

  In step S101, a drug carrier enclosing a drug is obtained. A method for obtaining a drug carrier encapsulating a drug can be appropriately set according to the type of the drug carrier.

  When the drug carrier is a lipid nanoparticle such as a liposome, conventionally known techniques such as the Bangham method, ultrasonic treatment method, organic solvent extraction method, freeze-thaw method, remote loading method (also called pH gradient method) are used. Thus, lipid nanoparticles encapsulating the drug can be obtained. In the Bangham method, lipids (phospholipids and the like) are dissolved in an organic solvent in a container, and then the organic solvent is evaporated to form a thin film on the inner surface of the container. , Also referred to as “PBS”) to swell the thin film, add the drug, and shake the container to obtain lipid nanoparticles encapsulating the drug. The ultrasonic treatment method is a method in which after obtaining lipid nanoparticles by the Bangham method, the lipid nanoparticles are further subjected to ultrasonic treatment to obtain lipid nanoparticles encapsulating a drug. The organic solvent extraction method is a method of obtaining lipid nanoparticles by injecting lipid (phospholipid or the like) dissolved in an organic solvent into an aqueous solution containing a drug. The freeze-thaw method is a method of freeze-drying an organic solvent mixed with a drug and lipid (phospholipid, etc.), adding water or PBS, then freezing it with liquid nitrogen, and thawing it to obtain a lipid containing the drug. This is a method for obtaining nanoparticles. In the remote loading method, an organic solvent mixed with lipid (phospholipid, etc.) is evaporated to form a thin film on the inner surface of the container, and then ammonium sulfate or a citrate buffer (adjusted to pH 3-6) is added to the thin film. After hydration of the thin film to obtain lipid nanoparticles, the external solution of lipid nanoparticles is neutralized (for example, pure water or Hepes buffer (about pH 6-8)) by dialysis or ultracentrifugation. This is a method for obtaining lipid nanoparticles encapsulating a drug by substituting the drug and shaking the container.

  When the drug carrier is a polymer micelle, a polymer micelle encapsulating the drug can be obtained using a conventionally known technique such as an encapsulation method, a solvent evaporation method, or a dialysis method. The encapsulation method is a method of obtaining polymer micelles encapsulating a drug by mixing and stirring the drug in an aqueous solution in which a block copolymer is dispersed. The solvent volatilization method is a method of obtaining a polymer micelle encapsulating a drug by mixing an organic solvent containing a drug and an aqueous solution in which a block copolymer is dispersed, and volatilizing the organic solvent while stirring. The dialysis method is a method in which a drug and a block copolymer are dissolved in an organic solvent, and then the resulting solution is dialyzed against PBS and / or water using a dialysis membrane to obtain a polymer micelle encapsulating the drug. is there.

  In the above-described method, examples of the organic solvent include hydrocarbons such as pentane, hexane, heptane, and cyclohexane, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene and toluene, Lower alcohols such as methanol and ethanol, esters such as methyl acetate and ethyl acetate, ketones such as acetone and the like can be used alone or in combination of two or more.

  In step S102, the linker molecule and the self antigen are combined. The linker molecule and the self-antigen can be bound using a conventionally known method according to the kind of the linker molecule and the self-antigen.

  When the self-antigen is a peptide, the linker molecule and the self-antigen can be bound by mixing a linker molecule having a reactive group capable of binding to the peptide together with the peptide in a solvent. As the reactive group capable of binding to the peptide, for example, N-succinimide and maleimide can be used. As a linker molecule having N-succinimide, for example, DSPE-PEG-NHS ([1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n- [poly (ethyleneglycol)]-hydroxysuccinamide (PEGMW, for example, 2000]) As a solvent for mixing the linker molecule and the peptide, for example, pure water or an aqueous boric acid solution can be used.

  In step S103, the linker molecule obtained in S102 (linker molecule bound with a self-antigen) is bound to the surface of the drug carrier obtained in S101 (the drug carrier in which the drug is encapsulated) to obtain a drug delivery body. A conventionally known technique can be used as a method for binding the linker molecule to the surface of the drug carrier, and it can be appropriately set depending on the substance constituting the drug carrier and the type of the linker molecule.

  For example, when the linker molecule bound to the peptide exemplified in S102 is bound to the surface of the liposome (drug carrier), the liposome is mixed in a solvent containing the linker molecule (linker molecule bound to the self antigen) generated in S102. Thus, a linker molecule can be bound to the surface of the drug carrier.

  A drug delivery body can be generated by the steps S101 to S103. In the step S103, after the drug delivery body is generated, if necessary, a separation process for separating the linker molecule that is not bound to the surface of the drug carrier and the drug delivery body can be performed. . For the separation treatment, for example, gel filtration chromatography or ultracentrifuge can be used.

  In step S104, the drug delivery body obtained in S103 and other components contained as necessary are mixed and processed into a predetermined dosage form (form).

  The therapeutic agent of this embodiment can be obtained by the processing of steps S101 to S104 described above.

  In the above-described production method, after obtaining a drug carrier encapsulating a drug (step S101), the linker molecule and the self antigen are bound (step S102), but after the linker molecule and the self antigen are bound, A drug carrier encapsulating a drug may be obtained. In the manufacturing method described above, the linker molecule and the self-antigen are bonded (step S102), and then the linker molecule bonded with the self-antigen is bonded to the surface of the drug carrier (step S103). It may be done. When step S102 and step S103 are performed simultaneously, for example, a linker molecule having a reactive group capable of binding to a peptide, the peptide, and a liposome encapsulating a drug may be mixed in pure water. In the manufacturing method described above, the linker molecule and the self-antigen are bonded (step S102), and then the linker molecule bonded with the self-antigen is bonded to the surface of the drug carrier (step S103). The self-antigen may be bound to the drug carrier after binding to.

  Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to only these examples.

<Example 1: Production of autoimmune disease treatment agent>
In a container, DPPC (manufactured by Nippon Seika Co., Ltd.) and cholesterol (manufactured by Nippon Seika Co., Ltd.) are mixed in a chloroform solution so that the molar ratio (DPPC: cholesterol) is 2: 1, and then an evaporator (Tokyo Rika). Chloroform was distilled off with an instrument) and vacuum dried for 1 hour. A 0.25 mol / l ammonium sulfate solution (pH 5.5) was added to the lipid thin film formed on the wall surface of the container for hydration. The obtained aqueous solution was frozen in liquid nitrogen, and the frozen product was thawed using a thermostatic water bath set at 55 ° C. Freezing and thawing operations were repeated three times to produce liposomes. The produced liposomes are treated with an ultrasonic treatment machine (Branson) for 5 minutes, and the produced liposomes are passed through an extruder (Transfer Nanoscience) equipped with a 100 nm pore size filter 7 times to adjust the size. It was. Furthermore, the produced liposomes were dialyzed in pure water to replace the liposome external solution, and further separated using an ultracentrifuge, and hydrated to 0.3 mol / l Hepes buffer (pH 7.4). did. A doxorubicin solution (manufactured by Kyowa Hakko Kirin Co., Ltd.) was added to the solution at a molar ratio ((DPPC: cholesterol: doxorubicin = 2: 1: 0.24)) and mixed with shaking at 60 ° C. for 1 hour, and doxorubicin was enclosed. The generated liposomes were separated using an ultracentrifuge (manufactured by Hitachi, Ltd.) set at 453,000 g and 4 ° C., and the resulting liposomes were added to 0.3 mol / l hepes buffer (pH 7.4). Hydrated.

  To a 0.3 mol / l Hepes buffer (pH 7.4) mixed with mouse MOG35-55 (manufactured by Medical Biological Research Institute, the sequence is shown in SEQ ID NO: 3), DSPE-PEG-NHS ( The total molecular weight of PEG manufactured by NOF Corporation, 2,000) was added and reacted at 4 ° C. for 2 hours at pH 7.4, and then the reaction was stopped by adding ethanolamine. Bound DSPE-PEG (hereinafter also referred to as “DSPE-PEG-MOG35-55”) was obtained. The produced DSPE-PEG-MOG35-55 solution and the liposome encapsulating doxorubicin were mixed and reacted at 55 ° C. for 1 hour to bind DSPE-PEG-MOG35-55 to the surface of the liposome. Liposomes bound with DSPE-PEG-MOG35-55 were separated using an ultracentrifuge (manufactured by Hitachi) set at 453,000 g, 4 ° C., and 0.3 mol / l hepes buffer (pH 7.4). ) To obtain a liposome solution.

The content of the constituent components in the liposome to which DSPE-PEG-MOG35-55 was bound (hereinafter also simply referred to as “reverse targeting liposome”) was measured using a spectrophotometer and HPLC. The measurement conditions were as follows: 880 μl of phosphate buffered saline (hereinafter also referred to as PBS) to 100 μl of 10% sodium dodecyl sulfate solution was added to 20 μl of the liposome solution, mixed for 15 minutes at 55 ° C. The amount of doxorubicin was calculated by measuring the absorbance. Further, 50 μl of tetrahydrofuran was added to 50 μl of the liposome solution and mixed, and the amount of DSPE-PEG-MOG35-55 was calculated by measuring the absorbance at 280 nm using HPLC. The HPLC conditions were as follows. The results are shown in Table 1 described later.
<HPLC measurement conditions>
Column: TSK-gel ODS-100Z 4.6 mm × 150 mm, 3 μm
Measurement wavelength: 280 nm
Mobile phase: methanol / ultra pure water (40 → 100%) + 0.05% trifluoroacetic acid Flow rate: 1 mL / min Column temperature: 45 ° C.

[Table 1]

  The average particle diameter of the liposome bound with DSPE-PEG-MOG35-55 was measured using Zetasizer Nano (manufactured by Spectris Malvern Instruments). The results are shown in Table 2 described later.

  The number of MOG35-55 per one liposome bound with DSPE-PEG-MOG35-55 was calculated from the amount of DSPE-PEG-MOG35-55 bound to the liposome (content ratio). The results are shown in Table 2 described later.

[Table 2]

<Test Example 1: Binding test for anti-MOG antibody>
Using BIACORE (registered trademark) 200 (manufactured by GE Healthcare) under the conditions shown below for the binding property of the liposome (reverse targeting liposome) conjugated with DSPE-PEG-MOG35-55 to the anti-MOG35-55 antibody Measured. For the measurement, an aqueous solution containing liposomes bound with DSPE-PEG-MOG35-55 of Example 1 (hereinafter referred to as “Example 2”) and DSPE-PEG-MOG35- in the step of producing the liposomes of Example 1 were used. An aqueous solution (hereinafter referred to as “Comparative Example 1”) containing liposomes not bound to DSPE-PEG-MOG35-55 (liposomes in which doxorubicin is encapsulated) produced without being subjected to a treatment for binding 55 is used. did. The aqueous solution of Example 2 and the aqueous solution of Comparative Example 1 were both aqueous solutions in which DPPC contained in the liposome was adjusted to 0.01 mol / l. Specifically, the liposome solution of Example 1 or DSPE-PEG-MOG35 To 10 μl of a liposome solution obtained without subjecting -55 to binding to liposomes, 0.01 mol / l Hepes buffer (pH 7.4), 0.15 mol / l sodium chloride, 0.003 mol / l ethylenediaminetetraacetic acid, It was obtained by adding 990 μl of a buffer solution (HBS-EP buffer solution) containing 0.005% (v / v) surfactant P20 and mixing. A sensor chip in which a mouse control antibody and a mouse anti-MOG35-55 antibody (manufactured by MyBioSource) were attached to BIACORE (registered trademark), and the obtained aqueous solutions of Example 2 and Comparative Example 1 were attached to the sensor chip. The binding dissociation curve was measured by flowing through BIRECORE (registered trademark) at 20 μl / min. The results are shown in FIG.
<BIACORE measurement conditions>
Sensor chip: CM5
Mobile phase: HBS-EP buffer Sample flow rate: 20 μl / min
Sample injection time: 2 minutes Standby time after sample injection: 2.5 minutes Washing solution: 10 mM glycine buffer (pH 2.0)
Washing liquid flow rate: 30 μl / min
Cleaning liquid injection time: 30 seconds Stabilization time: 2 minutes

  As can be understood from the results of Example 2 shown in FIG. 5, the liposomes conjugated with DSPE-PEG-MOG35-55 did not show the binding property to the control antibody and showed high binding property to the anti-MOG35-55 antibody. On the other hand, as can be understood from the result of Comparative Example 1 shown in FIG. 5, the liposome not bound with DSPE-PEG-MOG35-55 did not show binding properties to the control antibody and the anti-MOG35-55 antibody. From these results, the liposome conjugated with DSPE-PEG-MOG35-55 is a reverse targeting liposome that retains the binding property to the anti-MOG35-55 antibody and retains the antigenicity as a self-antigen on the drug carrier surface. I understood that.

<Test Example 2: Treatment Test 1 for Multiple Sclerosis>
In order to create a multiple sclerosis model, C57BL / 6J mice (female, 9 weeks old) were immunized to develop experimental autoimmune encephalomyelitis (hereinafter also referred to as “EAE”). Specifically, 500 μl of PBS containing 1 mg of MOG35-55 was mixed with 500 μl of complete Freund's adjuvant (manufactured by Chondrex) containing 2.5 mg of tuberculosis-killed bacteria, and this was used as an inducing agent. did. 200 μl of this inducer was administered subcutaneously to the back of the mouse. Furthermore, 200 μl of PBS containing 200 ng pertussis toxin (manufactured by Wako Pure Chemical Industries, Ltd.) was administered to the tail vein on the treatment day with the inducer and on the 2nd and 4th days after that.

  As Example 3, the reverse-targeted liposome of Example 1 was administered so that 0.05 mg of doxorubicin per kg body weight of the mouse was administered 10 days, 12 days, 14 days, and 16 days after the treatment with the inducer. Mixed PBS was administered into the tail vein of 7 immunized mice.

  As Example 4, the reverse-targeted liposome of Example 1 was administered so that 0.01 mg of doxorubicin per 1 kg body weight of mice was administered 10 days, 12 days, 14 days, and 16 days after the treatment with the inducer. Mixed PBS was administered into the tail vein of 7 immunized mice.

  As Comparative Example 2, PBS was administered to the tail vein of 7 mice immunized 10 days, 12 days, 14 days, and 16 days after the treatment with the inducer. PBS was administered in the same amount as in Example 3.

From the treatment day with the inducer, the neurological symptoms of each mouse were evaluated according to the following criteria. The results are shown in FIG.
Grade 0: Normal Grade 0.5: Abnormal tail (the tip of the tail does not reach the floor)
Grade 1: Decreased muscle tone in the tail (the tip of the tail always reaches the floor)
Grade 1.5: More than half of the tail always reaches the floor Grade 2: Complete tail droop (the entire tail always reaches the floor)
Grade 2.5: Abnormal gait (abdomen does not reach the floor)
Grade 3: Abnormal gait (the abdomen is always on the floor) and hemiplegia of the hind limb (one hind limb does not move completely)
Grade 3.5: Both paralysis of the hind limbs (both hind limbs cannot be used for walking but can be moved)
Grade 4: Complete hind limb paralysis (both hind limbs do not move completely)
Grade 4.5: Complete hind limb paralysis and forelimb abnormalities (both forelimbs can be moved)
Grade 5: Complete paralysis of hind limbs and paralysis of forelimbs (one forelimb does not move completely)
Grade 5.5: Drowning (complete paralysis of hind limbs + complete paralysis of forelimbs)
Grade 6: Death

  As can be understood from the results of Comparative Example 2 shown in FIG. 6, the mice not administered with liposomes showed grade 4 or higher neurological symptoms 18 days after the treatment with the inducer. On the other hand, as can be understood from the results of Examples 3 and 4 shown in FIG. 6, mice administered with liposomes bound with DSPE-PEG-MOG35-55 are about grade 1 after 18 days from the treatment with the inducer. Only showed neurological symptoms. From these results, it was understood that the therapeutic agent of this embodiment including a drug delivery body can treat EAE, that is, multiple sclerosis.

<Test Example 3: Treatment Test 2 for Multiple Sclerosis>
Under the same conditions as in Test Example 2, C57BL / 6J mice were immunized to develop EAE.

  As Example 5, the reverse-targeted liposome of Example 1 was administered so that 0.4 mg of doxorubicin was administered per 1 kg of the body weight of the mouse 10 days, 14 days, 18 days, and 22 days after the treatment with the inducer. Mixed PBS was administered into the tail vein of 6 immunized mice.

  Liposomes produced without applying DSPE-PEG-MOG35-55 in the step of producing liposomes of Example 1 and not bound with DSPE-PEG-MOG35-55 (liposomes in which doxorubicin is encapsulated) ) Was prepared. As Comparative Example 3, DSPE-PEG-MOG35-55 was bound so that 0.4 mg of doxorubicin was administered per 1 kg body weight of the mouse 10 days, 14 days, 18 days, and 22 days after the treatment with the inducer. PBS mixed with unreacted liposomes was administered into the tail vein of 6 immunized mice.

  As Comparative Example 4, the tail vein of 7 mice immunized with PBS mixed with 0.4 mg of doxorubicin per kg body weight of the mice 10 days, 14 days, 18 days and 22 days after the treatment with the inducer Administered.

  In the step of producing the liposome of Example 1, a liposome that was produced without using doxorubicin and in which doxorubicin was not encapsulated (DSPE-PEG-MOG35-55 was bound) was prepared. As Comparative Example 5, doxorubicin was administered so that DSPE-PEG-MOG35-55 bound to liposomes was administered in the same amount as in Example 5 after 10 days, 14 days, 18 days, and 22 days after the treatment with the inducer. PBS mixed with unencapsulated liposomes was administered into the tail vein of 6 immunized mice.

  As Comparative Example 6, PBS was administered to the tail vein of 6 mice immunized 10 days, 14 days, 18 days, and 22 days after the treatment with the inducer. PBS was administered in the same amount as in Example 5.

  After the treatment day with the inducer, the neurological symptoms of each mouse were evaluated according to the criteria used in Test Example 2, and the neurological symptom grade of each mouse was arithmetically averaged for each of Example 5 and Comparative Examples 3-6. The calculated value was calculated. The results for 36 days from the treatment day with the inducer are shown in FIG. 7, and the results 101 days after the treatment day with the inducer are shown in FIG.

For each of Example 5 and Comparative Examples 3 to 6, the number of mice that died for 101 days from the treatment day with the inducer was measured, and the transition of the survival rate of the mice was confirmed based on the following formula (1). . In addition, for each of Example 5 and Comparative Examples 3 to 6, the body weight of each mouse was measured for 57 days from the treatment day with the inducer, and the transition of the average body weight of the mouse was confirmed. FIG. 9 shows the survival rate, and FIG. 10 shows the average body weight.

  As can be understood from the results of FIG. 7, in Comparative Examples 3 to 6, even in Comparative Example 5 with the best neurological symptoms (low grade), about 16 grades after the treatment day with the inducer. Showing neurological symptoms. In particular, in Comparative Examples 3, 4, and 6, the neurological symptoms worsened after 16 days from the treatment day with the inducer (grade increased), and after about 22 days from the treatment day with the inducer, a grade 4 nerve Was showing symptoms. On the other hand, in Example 5, only neurological symptoms less than grade 2 were shown even 16 days after the treatment with the inducer. Further, in Example 5, the neurological symptoms were improved (grade decreased) after 16 days from the treatment day with the inducing agent, and only grade 1 neurological symptoms were shown after 22 days from the treatment day with the inducing agent. There wasn't. From these results, it was understood that the therapeutic agent of this embodiment including a drug delivery body can treat EAE, that is, multiple sclerosis.

  Further, as can be understood from the results of FIG. 8, even in Comparative Example 5 having the best neurological symptoms (low grade) among Comparative Examples 3 to 6, Grade 3. It showed 5 or more (average value) neurological symptoms. On the other hand, Example 5 showed only less than grade 1 (average value) neurological symptoms even 101 days after the treatment day with the inducer. In particular, EAE was completely cured in 2 out of 6 mice used in Example 5. Further, as can be understood from the results of FIG. 9, in Example 5, the survival rate of the mice was 100% even after 101 days from the treatment day with the inducer. From this result, it can be understood that the therapeutic agent of the present embodiment including a drug delivery body is useful for short-term and long-term treatment of EAE, that is, multiple sclerosis.

  In addition, as can be understood from the results of FIG. 10, weight loss due to administration of the therapeutic agent or progression of the disease state was not observed during the 57 days from the treatment day with the inducer. From these results, it can be understood that the therapeutic agent of the present embodiment including a drug delivery body is a safe therapeutic agent capable of treating EAE, that is, multiple sclerosis.

DESCRIPTION OF SYMBOLS 1 Drug delivery body 2 Drug carrier 3 Drug 4 Linker molecule 5 Autoantigen 50 T cell 100 Neuron cell 101 Cell body 102 Axon 103 Myelin sheath

Claims (8)

A therapeutic or preventive agent for autoimmune diseases caused by autoantigens,
A drug that damages immune cells that respond to the self-antigen;
A drug delivery body comprising a drug carrier in which the drug is encapsulated, a linker molecule bonded to the surface of the drug carrier, and the self-antigen held on the surface of the drug carrier via the linker molecule And a therapeutic or prophylactic agent for autoimmune diseases.   The therapeutic or prophylactic agent for autoimmune diseases according to claim 1, wherein the drug carrier is a liposome.   The therapeutic or prophylactic agent for autoimmune diseases according to claim 1 or 2, wherein the immune cells are T cells.   The autoimmune disease treatment or prevention agent according to any one of claims 1 to 3, wherein the autoimmune disease is an organ-specific autoimmune disease. The organ-specific autoimmune disease is multiple sclerosis;
The therapeutic or preventive agent for autoimmune diseases according to claim 4, wherein the self-antigen is a peptide having the same amino acid sequence as at least a part of the amino acid sequence of myelin oligodendrocyte glycoprotein represented by SEQ ID NO: 2 in the sequence listing.   The therapeutic or prophylactic agent for autoimmune disease according to claim 5, wherein the autoantigen is MOG35-55 having an amino acid sequence represented by SEQ ID NO: 4 in the sequence listing. The organ-specific autoimmune disease is multiple sclerosis or experimental autoimmune encephalomyelitis;
The therapeutic or preventive agent for autoimmune diseases according to claim 4, wherein the self-antigen is a peptide having the same amino acid sequence as at least a part of the amino acid sequence of myelin oligodendrocyte glycoprotein represented by SEQ ID NO: 1 in the sequence listing. The therapeutic or preventive agent for autoimmune diseases according to claim 7, wherein the autoantigen is MOG35-55 having an amino acid sequence represented by SEQ ID NO: 3 in the sequence listing.