WO2009113810A2 - Composition pharmaceutique, utilisation de celle-ci et procédé de traitement ou de prévention de maladies allergiques ou auto-immunes - Google Patents

Composition pharmaceutique, utilisation de celle-ci et procédé de traitement ou de prévention de maladies allergiques ou auto-immunes Download PDF

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WO2009113810A2
WO2009113810A2 PCT/KR2009/001217 KR2009001217W WO2009113810A2 WO 2009113810 A2 WO2009113810 A2 WO 2009113810A2 KR 2009001217 W KR2009001217 W KR 2009001217W WO 2009113810 A2 WO2009113810 A2 WO 2009113810A2
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allergic
disease
blood
autoimmune
immunoglobulin
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Korean (ko)
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WO2009113810A3 (fr
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전숙영
남동호
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies from serum
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • compositions for the prevention or treatment of allergic diseases and autoimmune diseases uses thereof and methods of preventing or treating allergic diseases and autoimmune diseases
  • the present invention provides a pharmaceutical composition for the prevention or treatment of allergic diseases and autoimmune diseases, including autoimmunoglobulin derived from their own blood as an active ingredient of patients suffering from allergic diseases and autoimmune diseases.
  • the present invention also provides a method for preparing the composition and a pharmaceutical use for the manufacture of a medicament for the prevention or treatment of allergic diseases and autoimmune diseases.
  • the present invention also provides a method for preventing or treating allergic diseases and autoimmune diseases comprising administering the pharmaceutical composition to a mammal. When the pharmaceutical composition of the present invention is administered to a mammal, it is possible to effectively treat allergic diseases and autoimmune diseases that are difficult to control with standard drug treatment methods currently implemented.
  • the pharmaceutical composition of the present invention its use for the prevention or treatment of allergic diseases and immune diseases, the prevention or treatment method using the same, allergic diseases and autoimmunity in which the clinical symptoms are not sufficiently improved by the current standard drug treatment alone. It can effectively improve the disease. [Background technology]
  • hypersensitivity to a particular antigenic substance has been termed an allergy, which causes harmful damage to the body of a mammal that has caused this hypersensitivity reaction (Aronson J. BMJ 1999; 319: 308). Therefore, reactions to specific antigenic substances may be applied to the mammals
  • allergic reactions in a broad sense are classified as a type of immunological hypersensitivity reactions (Gel 1 and Coombs' classification of hypersensitivity reactions). All forms of immunological reactions that may be detrimental to the host itself, and the phenomena resulting from them, are described in Bierman CW, et al. (Eds.) Allergy, asthma, and immunology from infancy to adulthood, page xvii, Saunders, Philadelphia, 1996). Allergic diseases include bronchial asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, etc., which are known to cause clinical symptoms by causing allergic reactions to damage and abnormal body organs (Bierman CW, et al.
  • allergic diseases in the broad sense include autologous allergic diseases or autologous diseases known to occur due to hypersensitivity to their proteins (including autoantibodies such as immune globulin, collagen, DNA) Rheumatoid arthritis and systemic lupus erythematosus (Vaughan JH. Med Times 1969; 97: 187-204), which are classified as immune diseases.
  • allergens antigens that can cause allergic reactions. That is, allergens such as house dust mite, pollen, animal dandruff, bear, egg albumin, milk protein, peanut, etc., which are allergens in the external environment known to cause allergic reactions, are all included.
  • allergic diseases such as atopic dermatitis, bronchial asthma, allergic rhinitis, allergic conjunctivitis, or urticaria are known to be caused by very similar pathogenesis, although their clinical manifestations are different. Accordingly, it is known that in many patients with allergic diseases, two or more allergic diseases are simultaneously suffered.
  • Allergic diseases caused by allergic reactions to foreign antigens may be caused by external allergens, regardless of whether they are house dust mites, aspiring allergens such as pollen, or food allergens such as egg albumin, milk, flour, peanuts, or allergens.
  • Allergic reactions mediated by IgE antibodies by injecting humanized monoclonal antibodies specific to human IgE have recently been shown that allergens and specific -IgE antibody reactions play a key role.
  • Has been reported to significantly improve clinical symptoms in patients with bronchial asthma, allergic rhinitis, allergic conjunctivitis, food allergy and atopic dermatitis (Chang TW et al. J Allergy Clin I ⁇ unol 2006; 117 : 1203- 12).
  • allergen-specific IgE antibodies are a target of treatment that plays a key role in the development of allergic diseases as well as allergic reactions. Oshiba A et al. J Clin Invest 1996; 97: 1398-408; Herz U et al. Clin Exp Allergy 2004; 34: 478-87).
  • allergen-immunotherapy For the treatment of allergic diseases caused by external antigens, drugs that can find and avoid the current allergen through allergic skin reaction test or suppress the allergic reaction or tissue inflammation (steroids, antihistamines, antileukotriene preparations) And allergen-immunotherapy, which selectively reduces the allergen reaction to allergens by subcutaneous administration of the allergens in small increments.
  • allergen-immunotherapy which selectively reduces the allergen reaction to allergens by subcutaneous administration of the allergens in small increments.
  • allergen-immunotherapy which selectively reduces the allergen reaction to allergens by subcutaneous administration of the allergens in small increments.
  • Allergen-immunotherapy is known to vary widely across countries, due to safety issues due to the likelihood of acute allergic reactions (including severe deaths from anaphylaxis) during treatment. Easy to treat, no side effects, specific treatment There is an urgent need for the development of effective treatments that specifically improve the disease by specifically inhibiting hypersensitivity to allergens. In recent years, it is known that the onset of allergic diseases is increasing rapidly in the world, but effective prevention methods have not been developed yet.
  • Plasma obtained from blood donors is currently tested during the manufacture of pharmaceutical compositions based on immunoglobulins and tested for the currently identified major infectious agents (hepatitis B, hepatitis C, and HIV infection). We are currently doing our best to ensure that infections do not occur even when no immunoglobulin agent is administered to patients, as long as these agents are inactivated during the manufacturing process and in the process of manufacture (Martin TD. Int Immunopharmacol 2006; 6: 517-22). . However, as most manufacturers of immunoglobulin injectables describe in their drug descriptions, side effects due to contamination with unknown viruses or infectious agents (e.g., human prion disease) that cannot be completely inactivated by current technology, are described. It is not completely excluded.
  • infectious agents e.g., human prion disease
  • the inventors have found that the immunoglobulins included in the pharmaceutical compositions of the injectable immunoglobulin or histamine-immunoglobulin complex, which are currently used for the treatment of allergic diseases and autoimmune diseases, have been found in plasma of a large number of donors Immunoglobulins isolated from pooled plasma; each donor in the manufacture of these immunoglobulins It is known that plasma is used to isolate immunoglobulins by mixing the plasma of donors who have tested negative for the presence of infectious viruses (Martin TD. Int Immunopharmacol 2006; 6: 517-22).
  • the inventors have found that foreign proteins (house dust mites) of immune antibodies present in the respective plasmas in the plasma screening process used for the isolation of immunoglobulins used for the preparation of conventional injectable immunoglobulins or histamine-immunoglobulin complexes.
  • the immunoglobulins are isolated by mixing the plasma of different health donors without analyzing the anti-ungryotypes for various antigens, including pollen) and magnetic proteins (human proteins).
  • an advanced form of the pharmaceutical composition such as the pharmaceutical composition of the present invention.
  • immunoglobulin formulations isolated from the blood of many healthy donors currently in use can be used to combat abnormally increased immune antibody response to various types of foreign substances or autoproteins seen in individual patients with allergic or autoimmune diseases.
  • various immunological mechanisms including the induction of idiotype antibody reactions were judged to be difficult to inhibit selectively and effectively.
  • foreign antigens or self-antigens that exhibit excessive immune response which are still involved in the development of the disease according to each allergic or autoimmune patient or according to different clinical forms of allergic or autoimmune diseases.
  • their autologous immunoglobulin or the same type is isolated from the blood of each patient.
  • certain external proteins or proteins may be specific to certain allergic diseases (bronch asthma, chronic rash, atopic dermatitis, etc.) or individual diseases belonging to autoimmune diseases (systemic lupus, rheumatoid arthritis, etc.). group 2 week allergens; Fc segments of rheumatoid arthritis immunoglobulin G, etc.), which show abnormally increased immune response to commonly defined antigenic proteins, including unknown antigen proteins that have not yet been identified.
  • allergic diseases or autoimmune diseases of the same type as the patient being treated eg chronic rash or ato Immunoglobulin fractions are isolated from the blood of other patients with dermatitis; bronchial asthma; rheumatoid arthritis; systemic lupus erythematosus
  • pharmaceutical compositions in the form of immunoglobulins, histamine-immunoglobulin complexes, or immunoglobulin-immune adjuvant complexes. Designed and prepared therapeutic regimens.
  • abnormal immune antibody response could be improved more effectively than conventional immunoglobulin formulations or histamine-immunoglobulin complex formulations.
  • Patients suffering from the above allergic or autoimmune diseases may also have two or more different types of external allergens (e.g., house dust mites and bears in bronchial asthma). At the same time, allergic reactions may occur simultaneously, or autoimmune reactions may occur in two or more types of autoantigens. Also, in patients with allergic or autoimmune diseases, abnormally raised immune antibody responses to unknown external allergens or autoantigens may play a more important role in the development of the disease.
  • immunoglobulin fractions are isolated from blood samples of patients with allergic or autoimmune diseases to produce immunoglobulin pharmaceutical compositions for the treatment of allergic or autoimmune diseases, or in the form of histamine-immunoglobulin complexes. No attempt was made to treat allergic or autoimmune diseases by administering to. [Detailed Description of the Invention]
  • the present inventors have made great efforts to develop more effective therapeutic drugs and treatment methods in patients with allergic diseases and autoimmune diseases in which current drug therapy alone does not completely improve clinical symptoms.
  • the present inventors have determined that the entire assortment, which was not screened by measuring the titer of specific antibodies against specific allergens collected from a number of healthy donors, included in the pharmaceutical compositions of the immunoglobulin formulations and histamine-immunoglobulin complexes currently in use.
  • the individual immunoglobulin fractions were isolated from each patient's own blood sample, prepared in the form of an immunoglobulin formulation or as a pharmaceutical composition of the histamine-immunoglobulin complex and administered to the same patient.
  • the inventors have found that the incompleteness, unpredictability and unknownness of the clinical therapeutic effect of a pharmaceutical composition mainly composed of immunoglobulins in use. Efforts have been made to find a way to solve the problem of the possibility of transmission of infectious agents. As a result of these past efforts, the onset has developed a pharmaceutical composition containing immunoglobulin (especially immunoglobulin G) protein isolated from the blood of patients suffering from allergic or chronic inflammatory diseases and injecting blood products. It was concluded that new immunoglobulin preparations could be developed to minimize the adverse effects caused by the transmission of unknown infectious agents or toxic substances that could be transmitted.
  • immunoglobulin especially immunoglobulin G
  • the inventors can logically bind to allergens present on the surface of basophil or mast cell in blood of allergic patients, which is one of the key pathogenesiss of allergic diseases.
  • Antiallergens that suppress the development of allergic reactions when other isotype antibodies, such as IgA, IgG, IgM, or IgD, which can suppress reactions between IgE antibodies and allergens by reacting reactions between allergens with IgE antibodies It was shown to be effective in the treatment of allergic diseases.
  • allergens have been isolated from the blood of each patient with an allergic disease, and their entire immunoglobulin fraction (autologus i ⁇ unoglobulin) is isolated and administered to the same patient to suppress allergic reactions arising from the IgE antibody-mediated allergic mechanism.
  • IgG autoantibodies commonly found in patients with allergic diseases, autoimmune diseases, and chronic inflammatory diseases are used to correct the autoimmune reactions, which are known to cause chronic inflammation due to reactions to their proteins.
  • Pharmaceuticals that induce the formation of antibodies (anti-idiotype antibodies) against antigenic reaction sites (idiotope) of IgG autoantibodies by isolating immunoglobulin G from their blood and administering it to the same patient No attempt has been made to make the composition ever.
  • the inventors have described the specific implementation method and embodiment of the present invention through the configuration and examples of the present invention, and are suffering from the same kind of allergic disease, autoimmune disease or chronic inflammatory disease.
  • one of the alternative therapies is autologous blood injection or autologous serum injection therapy (Schafer T. Ann Allergy Asthma Immunol. 2004; 93 (2 Sup l 1): S5—10 ).
  • Autologous injection or autologous injection therapy is performed by taking blood from patients suffering from allergic, autoimmune and chronic inflammatory diseases, and then reinjecting the whole autologous or autologous serum isolated from autologous to the same patient.
  • the inventors have previously used the above-mentioned autologous blood injection therapy or autologous serum injection therapy, which has been clinically proven in allergic diseases and chronic inflammatory diseases, and plays an important role in the development of diseases in patients' blood.
  • a specific antibody is administered through intramuscular injection Induction of anti-idiotype antibody response was expected to have a therapeutic effect.
  • a pharmaceutical composition containing an immunoglobulin fraction isolated from the blood of each patient is prepared as an active ingredient and administered by injection, allergic disease autoimmunity is the same as that of the conventional autologous blood injection therapy or autologous serum injection therapy.
  • the present invention has been devised in view of the possibility of clinically improving diseases and chronic inflammatory diseases.
  • the current autologous blood injection or autologous serum injection method collects a certain amount of blood at one time to overcome the high risk of contamination with infectious agents due to fresh intravenous blood collection and intramuscular injection every time injection. Therefore, only the immunoglobulin fractions were isolated and stored in the form of a pharmaceutical composition, and when administered, it was determined that they could be developed into more effective and safe therapeutic compositions.
  • allergic diseases comprising immunoglobulin isolated from the blood of patients suffering from allergic diseases, autoimmune diseases and chronic inflammatory diseases of the present invention as an active ingredient.
  • a pharmaceutical composition for treating autoimmune diseases and chronic inflammatory diseases was completed.
  • the histamine-immunoglobulin complex containing immunoglobulin and histamine simultaneously isolated from the blood of healthy donors is compared to the immunoglobulins isolated from the blood of many healthy donors. More effective in the treatment of allergic, autoimmune and chronic inflammatory diseases has been demonstrated by double-blind clinical studies and animal studies (Yoshii H, et al; J Allergy
  • the antiallergic effect of administration of the histamine-immunoglobulin (or gamma globulin) complex in an allergic animal model may be achieved when the same amount of histamine alone or immunoglobulin alone is administered, or when the histamine-albumin complex or the serotonin-immunoglobulin complex is administered.
  • specific combinations between the two histamine and immunoglobulin substances The synergistic effects caused by the binding may play a significant role in the treatment of allergic diseases (Yoshii H, et al .; J Allergy Clin Immunol 1997; 100: 809-16).
  • compositions comprising both immunoglobulin and histamine isolated from patients suffering from histamine and other allergic or autoimmune diseases are also compared to pharmaceutical compositions composed of immunoglobulins and histamine obtained from conventional healthy blood donors.
  • the present invention provides a pharmaceutical composition for treating allergic diseases or autoimmune diseases comprising an autologous iousunoglobulin isolated from the blood of a mammal suffering from an allergic disease or an autoimmune disease as an active ingredient. do.
  • the present invention is a pharmaceutical composition for the treatment of an allergic disease or autoimmune disease comprising an immunoglobulin (autologous i ⁇ unoglobulin) and histamine isolated from the blood of a mammal suffering from an allergic disease or autoimmune disease as an active ingredient
  • an allergic disease or autoimmune disease comprising administering to the mammal a pharmaceutical composition comprising an immunoglobulin of its own isolated from the blood of a mammal suffering from an allergic disease or autoimmune disease as an active ingredient.
  • the present invention is to treat an allergic disease or autoimmune disease comprising an autologous immunoglobulin and an adjuvant isolated from the blood of an individual mammal suffering from allergic disease or autoimmune disease as an active ingredient. It provides a pharmaceutical composition.
  • the adjuvant included in the above pharmaceutical composition is aluminum hydroxide, tyrosine, 3 De-O-acylated monophosphoryl. lipid A (3-DMPL).
  • immunoglobulins are conventional methods used for the preparation of therapeutic immunoglobulin formulations currently administered to humans from the blood of mammals suffering from allergic diseases or autoimmune diseases (eg precipitation, ion exchange).
  • Total immunoglobulin including IgG, IgA, IgM, IgD, and IgE isolated using chromatography, affinity chromatography, high pressure chromatography (Mart in TD. Int I ⁇ unopharmacol 2006; 6: 517 -22).
  • the immunoglobulin may be immunoglobulin G (IgG) isolated from the blood of a mammal suffering from an allergic disease or autoimmune disease.
  • the present invention relates to another patient suffering from the same allergic disease or autoimmune disease as the disease to be prevented because the specific mammalian subject is currently suffering from the same disease as the disease to be treated or the specific mammal is at high risk of developing the disease in the future. It provides a pharmaceutical composition for the prevention or treatment of allergic diseases or autoimmune diseases comprising an immunoglobulin isolated from the blood as an active ingredient.
  • the present invention provides a pharmaceutical composition comprising an immunoglobulin isolated from blood of a mammal suffering from an allergic disease or an autoimmune disease as an active ingredient. It provides a method for the treatment of allergic diseases or autoimmune diseases comprising administering the composition to a mammal.
  • the present invention is directed to a particular mammalian subject who is currently suffering from the same disease as the disease to be treated, or that a specific mammal is at risk of developing the disease in the future and is suffering from the same allergic or autoimmune disease as the disease to be prevented.
  • It provides a pharmaceutical composition for the prevention or treatment of allergic diseases and autoimmune diseases comprising an immunoglobulin and an adjuvant isolated from the blood of a patient as an active ingredient.
  • the adjuvant included in the above pharmaceutical composition is aluminum hydroxide, tyrosine, 3 De-O-acylated monophosphoryl, which is currently commonly used for the purpose of immunoreinforcement in vaccines or immunomodulators.
  • the present invention relates to another patient suffering from the same allergic disease or autoimmune disease as the disease to be prevented because the specific mammalian subject is currently suffering from the same disease as the disease to be treated or the specific mammal is at higher risk of developing the disease in the future. It provides a pharmaceutical composition for the prevention or treatment of allergic diseases or autoimmune diseases comprising immunoglobulin and histamine isolated from the blood of the active ingredient.
  • the allergic disease described above is not limited thereto, but is known to be caused by an allergic reaction to antigens present in the external environment, bronchial asthma, allergic rhinitis, allergic conjunctivitis, urticaria, atopic dermatitis Can be a food allergy.
  • the above-mentioned autoimmune diseases are also known to be caused by immune response to self antigens (also referred to as autoimmune reactions), rheumatoid arthritis, systemic lupus erythematosus, cystic ulcer, autoimmune thyroiditis, and autoimmune hepatitis.
  • type 1 diabetes mellitus, autoimmune nephritis, chronic inflammatory gastroenteritis, Sjogren's syndrome, and scleroderma are examples of the allergic reaction to antigens present in the external environment.
  • the present invention also provides a use for the prevention or treatment of allergic diseases or autoimmune diseases of the above pharmaceutical compositions.
  • the present invention also provides a method for preventing or treating allergic diseases or autoimmune diseases using the pharmaceutical compositions described above.
  • the present invention also provides a method of preparing the pharmaceutical compositions for the prevention or treatment of allergic diseases or autoimmune diseases.
  • the immunoglobulin may be an allergen-specific immunoglobulin G (IgG), which is physically separated using the ability to specifically bind to an allergen, and the autoantigen-specific antibody is autologous. It may be an autoantigen-specific immunoglobulin that has the ability to specifically react or specifically bind to the autoantigen to which the immune antibody is targeted.
  • IgG allergen-specific immunoglobulin G
  • allergens of the allergen-specific immunoglobulin in the above-described allergic diseases of the present invention but not limited to allergens of the external environment, egg albumin, milk, shrimp, crab, flour, It may be one or more allergens selected from peanuts, house dust mites, pollen, animal dandruff or mold.
  • autoantigen-target proteins that are targets of the antibody response of autoantigen-specific immunoglobulins are not limited thereto, but conventional systemic lupus, rheumatoid arthritis, chronic urticaria Nuclear antigen proteins, double-stranded DNA, phospholipids, beta-2 glycoprotein I, Fc segments of human IgG antibodies, type 2 collagen, alpha-enolase or It may be one or more autoantigens selected from high affinity IgE receptors.
  • the present invention comprises the steps of (a) collecting blood from a mammal suffering from an allergic disease or autoimmune disease, (b) isolating immunoglobulin from the blood of the mammal (autologous i) ⁇ unoglobulin) provides a method for producing a pharmaceutical composition for the treatment of allergic diseases or autoimmune diseases comprising as an active ingredient.
  • the present invention also comprises the steps of (a) collecting blood from a mammal suffering from an allergic disease or autoimmune disease, (b) isolating immunoglobulin from the blood of the mammal, (c) in the step (b) It provides a method for producing a pharmaceutical composition for treating allergic diseases comprising an autologous ious unoglobulin and an adjuvant as an active ingredient comprising the step of mixing the separated immunoglobulin with an adjuvant.
  • the adjuvant included in the above pharmaceutical composition is aluminum hydroxide, tyrosine, 3 De-O-acylated monophosphoryl.
  • lipid A (3— DMPL).
  • the present invention also comprises the steps of (a) collecting blood from a mammal suffering from an allergic disease or autoimmune disease, (b) isolating immunoglobulin from the blood of the mammal, (c) in the step (b) Method for producing a pharmaceutical composition for the prevention or treatment of allergic diseases or autoimmune diseases comprising an autologous immunoglobulin (hilogamine) and histamine as an active ingredient comprising the step of mixing the isolated immunoglobulin and histamine To provide.
  • the present invention also relates to (a) an allergic disease or autoimmunity of the same disease that a particular mammalian individual is currently suffering from or the same disease as the disease to be treated or the disease to be prevented due to a high risk of developing the disease in the future. (B) separating the immunoglobulin from the blood of the mammal; and (c) immunoglobulin isolated in step (b) as an active ingredient. It includes a method for producing a pharmaceutical composition for the prevention or treatment of allergic diseases or autoimmune diseases comprising.
  • the present invention (a) a particular mammalian subject is currently suffering from the same disease as the disease to treat, or the specific allergic disease or autoimmune disease that is the same as the disease to be prevented due to the high risk of the disease in the future Collecting blood from other mammals suffering from (b) Isolating immunoglobulins from the mammalian blood; (C) said
  • lipid A 3-DMPL
  • the present invention (a) a particular mammalian subject is currently suffering from the same disease as the disease to treat, or the specific allergic disease or autoimmune disease that is the same as the disease to be prevented due to the high risk of the disease in the future Collecting blood of another mammal suffering from the disease; (b) isolating immunoglobulins from the blood of the mammal; and (c) mixing the immunoglobulins and histamine isolated in step (b). It includes a method for preparing a pharmaceutical composition for the prevention or treatment of allergic diseases or autoimmune diseases.
  • composition is considered to include not only products comprising specific components, but also any products made directly or indirectly by the combination of specific components.
  • composition of the present invention may be present alone or in combination in the composition of the present invention, in an injectable preparation in which the composition of the present invention is dissolved, or in vivo.
  • an immunoglobulin and an adjuvant or histamine may exist in the form of complexes that are covalently or non-covalently bound to each other.
  • compositions of the present invention include compositions in which one of the active ingredients is in the form of a pharmaceutically or physiologically acceptable salt, compositions in which all active ingredients are in the form of pharmaceutically or physiologically acceptable salts, wherein one or more active ingredients are in the form of a pharmaceutically or physiologically acceptable salt. And in the form of acceptable salts, wherein the other active ingredients are in the form of free bases, or wherein the complex of one or more active ingredients is in the form of a pharmaceutically or physiologically acceptable salt. Salts of the active ingredient or complexes of one or more active ingredients contained in the compositions of the present invention include all pharmaceutically or physiologically acceptable salt forms.
  • compositions of the present invention include products in water-soluble, fat-soluble or insoluble forms, for example, conventionally formed from inorganic or organic acids or bases.
  • Non-toxic salts or quaternary ammonium salts include salts in water-soluble, fat-soluble or insoluble forms, for example, conventionally formed from inorganic or organic acids or bases.
  • Non-toxic salts or quaternary ammonium salts include salts in quaternary ammonium salts.
  • immunoglobulin refers to a glycoprotein that plays an important role in immunity among serum components and can be limited to specific physical, structural, and common amino acid sequences that act as antibodies.
  • a pair of L chains (light chains) having a molecular weight of about 23,000 and a pair of H chains (heavy chains) having a molecular weight of about 50,000 to 70,000 are connected by SS bonds, and by the type of H chains , a, ⁇ , ⁇ , ⁇ Are classified into IgG, IgA, IgM, IgD, and IgE, respectively ..
  • the immunoglobulins used in the compositions of the present invention may be IgG, IgA ⁇ IgM, IgD, IgE or their combinations, and their fragments having biologically equivalent activity or their It may be a complex.
  • Immunoglobulins used in the compositions of the invention can be prepared, for example, using the following methods. Ethanol is commonly used in the art to separate whole immunoglobulins from mammalian plasma by a variety of methods, including precipitation, ion chromatography and adsorption chromatography using Protein A or Protein G columns. It can be isolated and used as an immunoglobulin of the present invention. Alternatively, the immunoglobulin may be purely separated from plasma of mammals using various methods such as adsorption chromatography using agarose bead columns to which specific allergens are commonly attached, and thus may be used for preparing the pharmaceutical composition of the present invention. .
  • genetically engineered immunoglobulin from the cDNA library containing genetic information about antibody proteins obtained from peripheral blood monocytes in mammals may be used. It may be.
  • the recombinant immunoglobulin protein prepared in this way was produced by mammalian immunoglobulin. Amino acid sequences or genetically engineered recombinant immunoglobulin proteins that have been partially altered to human immunoglobulin (Vaughan TJ, et al. Human antibodies design. Nature Biotech 1998; 16: 535-539).
  • the immunoglobulin may be a part of an immunoglobulin including a portion that binds to an allergen, such as an F (ab) '2 or Fab segment capable of reacting with an allergen in an immunoglobulin protein (Vaughan TJ, et al. Human antibodies design.Nature Biotech 1998; 16: 535-539).
  • an allergen such as an F (ab) '2 or Fab segment capable of reacting with an allergen in an immunoglobulin protein
  • the immunoglobulin used in the composition of the present invention may be obtained from an animal of a different species from the mammal to which the composition of the present invention is to be administered.
  • immunoglobulins may exhibit the same pharmacological effect even when administered to humans due to high homology between heterologous species. Therefore, the prophylactic and therapeutic effects of allergic diseases or autoimmune diseases by administration of the composition of the present invention may also work in the case where the pharmaceutical composition of the present invention is obtained from a mammal of a different species than the animal to which it is finally administered.
  • immuno adjuvant includes immunoadjuvant that can enhance antibody response to specific immunogens.
  • the types of adjuvant are well known in the art (Vaccine Design I The Subunit and Adjuvant Approach, 1995, Pharmaceutical Biotechnology, Volume 6, Eds. Powell, MF, and Newman, M. J., Plenum Press, New York and London, ISBN 0-306-44867-X).
  • Preferred adjuvants included in the compositions of the present invention include aluminum salts or chaff salts (eg hydroxides or phosphates).
  • Preferred adjuvant agents included in the compositions of the present invention are the following: particulates such as aluminum salts or calcium salts (hydroxides or phosphates), oil-in-water emulsions (W0 95/17210, EP 0 399 843), or liposomes.
  • Carrier W0 96/33739.
  • Immunologically active saponin fractions eg, Quil A
  • 3 De— 0 acylated monophosphoryl lipids with adjuvant activity derived from the South American tree, Quillaja Saponaria Molina.
  • A muramyl dipeptide
  • 3D-MPL 3-deacylated Monophosphoryl lipids A
  • immunoglobulin proteins can be encapsulated in microparticles such as liposomes or present in nonparticulate suspensions of polyoxyethylene ethers (UK Patent Application No. 9807805.8).
  • Another preferred adjuvant that may be included in the compositions of the present invention is immunostimulatory oligonucleotide (W0 96/02555).
  • histamine is a compound of formula C 5 H 9 N 3 widely distributed in vivo. It is caused by decarboxylation of histidine in proteins by decayed bacteria or enterobacteriaceae. In tissues, histidine is inactivated by binding to tissue proteins and when allergic or anaphylaxis is seen by antigen antibody reaction, the inactive histamine becomes active by some action. It is thought to work on organs and tissues.
  • the histamine used in the composition of the present invention may be chemically synthesized by methods known in the art or commercially available in the art.
  • the active ingredients may be intimately mixed with various forms of pharmaceutically acceptable carriers depending on the type of preparation required for administration.
  • the pharmaceutical composition of the present invention may preferably be in unit dosage form, and may be in a form that can be diluted and used so as to adjust and use the dosage according to the judgment of a doctor.
  • composition of the present invention is preferably for subcutaneous injection.
  • the composition may also be administered in a conventional manner through intravenous, intraarterial, intramuscular, intraperitoneal, sternum, transdermal, nasal, inhalation, topical, rectal, oral, intraocular or intradermal routes. May be administered.
  • Injectable buffers and other adjuvant components used to formulate the compositions of the invention into injectable preparations are known in the art.
  • Injectable preparations for the compositions of the present invention may include, in addition to the injectable complete fluid, other auxiliaries such as, for example, dissolution aids, pH adjusters, suspensions.
  • a complete saline solution for injection may use physiological saline or the like.
  • the immunoglobulins included in the composition of the present invention can be used to counter antibody to common antigens according to the type of disease in patients with different allergic or autoimmune diseases. It was demonstrated that immunoglobulins isolated from the patient's own blood exhibited the same antigenicity as the antibodies present in their blood.
  • autologous i ⁇ unoglobulin isolated from the blood of a mammal suffering from an allergic or autoimmune disease, or immunoglobulin isolated from the blood of another patient with the same kind of allergic or autoimmune disease When administered alone or in combination with an adjuvant or histamine, it suppresses excessive immune antibody reactions through the negative feed back mechanism including anti-idiotype antibody mechanisms present in the body. It can effectively prevent or treat allergic diseases or autoimmune diseases.
  • mammal refers to a mammal that is the subject of treatment, observation or experimentation, preferably human.
  • the term "therapeutically effective amount” means the amount of an active ingredient or pharmaceutical composition that induces a biological or medical reaction in a tissue system, animal or human, as thought by a researcher, veterinarian, doctor or other clinician, This includes amounts that induce alleviation of the symptoms of the disease or disorder being treated.
  • the method for preventing or treating allergic diseases or autoimmune diseases according to the present invention can be carried out using the pharmaceutical compositions.
  • the dosage of the pharmaceutical composition of the present invention can be determined in consideration of the dosages of immunoglobulins, adjuvant, and histamine used in the treatment with the immunoglobulin formulations currently in use.
  • the dosage of the composition is determined according to the severity of symptoms, the age and weight of the patient, but in the treatment method of the present invention, allergens or autoantigens that cause allergic diseases or autoimmune diseases as well as the above conditions.
  • the dosage of immunoglobulin may be 0.001 to 100 mg, preferably 12 to 36 rag.
  • the dose of histamine may be 0.001 to 10 / g, preferably 0.15 to 0.45 jg
  • the dose of the adjuvant may be 0.001 to 10 mg, preferably 0.01 to 0.5 mg.
  • the composition is preferably present in the form of a solution or lyophilized powder, and can be used in the form contained in 0.5 to 2 injection buffers in a single administration.
  • the immunoglobulin and the adjuvant or histamine may be provided separately sealed in the form of a dry powder so that they can be dissolved and used in a buffer for injection in a separate vial.
  • the dosage can be determined and used as a dosage.
  • the single dose of the active ingredients in the treatment of the diseases is not fixed, and may be gradually increased in consideration of the sensitivity of the patient to the initial dose.
  • the dosage of the composition of the present invention can be determined by adjusting according to the rich experience of the doctor according to the symptoms of the patient following the administration of the composition of the present invention.
  • the effective dosage and frequency of administration of the active ingredients of the present invention or pharmaceutical compositions containing them will vary depending on the desired effect. Therefore, the optimal dosage to be administered may be readily determined and may vary depending on the particular active ingredient used, the mode of administration, the effect of the formulation and the development of the disease state. In addition, dosage adjustment according to the appropriate therapeutic level will be needed depending on factors of the individual being treated, including the patient's age, weight, diet and time of administration. Advantages and features of the present invention and methods of achieving them will be apparent with reference to the embodiments described below in detail.
  • Example 2 Isolation of immunoglobulins from the blood of patients with allergic or autoimmune diseases Comparative analysis of reactions against external allergens or autoantigens
  • target patient We examined serum samples from three bronchial asthma patients, one atopic dermatitis patient, one rheumatoid arthritis patient, and one systemic lupus erythematosus patient.
  • the PVDF membrane strip was cut to 3-4 mm wide and then diluted with l: 100 (v / v) in the same buffer solution by 1 ml per strip or by serum protein A column using protein A column.
  • the isolated human immunoglobulin was diluted to a concentration of 0.1 mg / ml and reacted for 2 hours at room temperature with 1 ml per strip.
  • the membrane was reacted with alkaline phosphatase-attached high Haut anti human IgG antibody (Sigma Chemical Co., St. Louis, M0) for 2 hours at room temperature. After final washing, the membrane was stained with 5_bromo-4_chloro-3 indoyl phosphate / nitro blue tetrazolium solution.
  • the immunoblot method was performed by immunoglobulin isolated from the blood of each allergic patient and autoimmune disease patient. Antibody reactions against external allergen proteins (house dust mite extract proteins) and human own proteins (airway epithelial cell extract proteins) showed the best match between their blood and their immunoglobulins isolated therefrom. (FIG. 1, FIG. 2). In contrast, the currently commercialized therapeutic immunoglobulin formulations showed a different response pattern than the antigen response pattern recognized by the immunoglobulin of each patient (FIGS. 1 and 2). These results were isolated from each patient's own blood to suppress, by immunological mechanism, abnormally increased pathogenic antibody response to external allergens or internal autoantigens in each allergic or autoimmune disease patient.
  • Human immunoglobulin and commercialized immunoglobulin formulations isolated by adsorption chromatography using protein A column in serum of patients with allergic or autoimmune diseases used in the embodiment of the present invention
  • immunoglobulins isolated from blood by patients with allergic or rheumatic diseases using Protein A used in Example 2 of the present invention were heavy chains of 50-kDa in the same manner as immunoglobulins included in commercially available immunoglobulin formulations.
  • immunoglobulin G consisting of a light chain
  • IgG 25-kDa light chain
  • the pharmaceutical composition of the present invention can be prepared by separating (FIG. 3).
  • Example 3 Demonstrating the antiallergic effect of immunoglobulin G isolated from patients suffering from allergic diseases
  • Example 3 of the present invention immunoglobulin G isolated from the blood of patients with allergic diseases, which is the pharmaceutical composition of the present invention, suppresses the reaction between allergens and allergen-specific IgE antibodies, It has been demonstrated that it has anti-allergic effect that can suppress the development of allergy as follows.
  • Example 3-1 Isolation and Purification of Immunoglobulins from Blood of Patients with Allergic Diseases
  • North American house dust mite (D. farinae) in the serum samples of two patients with allergic rhinitis and atopic dermatitis who are allergic to D. farinae described in Example 3.
  • Specific IgE antibody titers were measured by an enzyme immunoassay (enzyme-1 inked i ⁇ unosorbent assay (ELISA)) by modifying a previously reported method (Saloga J, et al. J Clin Invest 1993; 91: 133-40).
  • ELISA enzyme immunoassay
  • ELISA enzyme immunoassay
  • 1 / g of North American house dust mite precursor extract antigen was reacted per well, followed by a phosphate buffered saline containing 3% bovine serum albumin and 0.1% Tween-20.
  • Example 3-3 Inhibition of reaction between allergen-specific IgE antibodies and allergens present in the blood of each patient using immunoglobulins isolated from the blood of patients with allergic diseases
  • the inventors found that their autologous i ⁇ unoglobulin isolated from the blood of the patient suffering from the allergic disease of the present invention plays a key role in the development of allergic disease in the blood of the patient. It has been shown that it is possible to suppress reactions between allergen-specific IgE antibodies and allergens, which are known to be known, and by applying these newly discovered principles, significantly more than immunoglobulin preparations isolated from the blood of many existing normal healthy blood donors.
  • a pharmaceutical composition for preventing and treating allergic diseases of the present invention has been developed, which has a high anti-allergic effect and minimizes the risk of transmission of unknown infectious agents.
  • a pharmaceutical composition for the treatment or prevention of allergic diseases or autoimmune diseases of the present invention When administering a pharmaceutical composition for the treatment or prevention of allergic diseases or autoimmune diseases of the present invention to patients with allergic diseases or autoimmune diseases, allergic diseases or autoimmune diseases through the immunomodulatory effect of the pharmaceutical composition of the present invention It can have the effect of preventing and treating it.
  • Pharmaceutical compositions for the treatment or prevention of allergic diseases or autoimmune diseases of the present invention and methods for their preparation can be industrially used in the manufacture of a medicament for the treatment or prevention of allergic diseases or autoimmune diseases. Therefore, according to the pharmaceutical composition of the present invention, the use of the prophylaxis or treatment of allergic diseases or autoimmune diseases, the prevention or treatment method using the same, refractory allergic diseases in which clinical symptoms are not sufficiently improved by the current standard drug treatment alone. Or effectively improve patients with autoimmune diseases.
  • 1 is an immunoblotting method in which blood samples of patients suffering from allergic diseases and autoimmune diseases and antibodies present in their immunoglobulins separated from the blood of each patient are reacted with human airway epithelial proteins. i ⁇ unoblot) shows the result.
  • FIG. 2 shows an immunoblot in which blood samples of patients suffering from allergic diseases and autoimmune diseases and antibodies present in their immunoglobulins separated from the blood of each patient are reacted with house dust mite proteins. The analysis results are shown.
  • Figure 3 shows the results of analysis of blood samples of patients suffering from allergic diseases and autoimmune diseases and their immunoglobulin proteins isolated from the blood of each patient by polyacrylamide gel electrophoresis (SDS-PAGE) and protein staining. Shows. 3-1 (left figure of FIG.
  • lane 1 molecular weight marker
  • lane 2 serum of systemic lupus erythematosus 1 patient
  • lane 3 immunoglobulin isolated from the serum of systemic lupus erythematosus Patient 1; sera of lane 4- rheumatoid arthritis patient 1; immunoglobulins isolated from serum of ane 5-rheumatic arthritis patient 1
  • lane 6 serum of bronchial asthma patient 1
  • lane 8- serum of bronchial asthma patient 2 were analyzed by electrophoresis and protein staining.

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Abstract

La présente invention concerne une composition pharmaceutique destinée à la prévention ou au traitement de maladies allergiques ou auto-immunes, qui contient une immunoglobuline comme principe actif, isolée du sang d'un patients souffrant d'une maladie allergique ou auto-immune. Par ailleurs, l'invention concerne une autre composition pharmaceutique destinée à prévenir ou à traiter des maladies allergiques ou auto-immunes, qui contient une immunoglobuline, comme principe actif, isolée du sang d'un autre patient souffrant d'une maladie allergique ou auto-immune. La présente invention concerne aussi un procédé de fabrication et une utilisation médicinale et pharmaceutique de cette composition médicinale destinée à prévenir ou traiter des maladies allergiques ou auto-immunes. L'invention concerne aussi un procédé de prévention et de traitement de maladies allergiques ou auto-immunes, qui consiste à administrer la composition pharmaceutique à des mammifères. Par l'administration de la composition pharmaceutique de l'invention, des maladies allergiques auto-immunes contre lesquelles il est difficile de lutter avec un procédé de traitement médicamenteux standard, peuvent être traitées. Par conséquent, par cette composition pharmaceutique, l'utilisation de celle-ci pour prévenir ou traiter une maladie allergique ou auto-immune, et le procédé de prévention et de traitement utilisant cette composition, des maladies allergiques ou auto-immunes dont les symptômes ne sont pas facilement traités avec des procédés de traitement médicamenteux standards peuvent être traitées plus efficacement.
PCT/KR2009/001217 2008-03-11 2009-03-11 Composition pharmaceutique, utilisation de celle-ci et procédé de traitement ou de prévention de maladies allergiques ou auto-immunes Ceased WO2009113810A2 (fr)

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KR1020090019625A KR100946747B1 (ko) 2008-03-11 2009-03-09 알레르기질환 및 자가면역질환의 예방 또는 치료를 위한 약학적 조성물, 그의 용도 및 알레르기질환 및 자가면역질환의 예방 또는 치료 방법

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CN112638442A (zh) * 2018-06-29 2021-04-09 爱德芳世株式会社 血液透析用经皮端子及个体差别血液透析系统

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JPS5653623A (en) * 1979-10-09 1981-05-13 Mochida Pharmaceut Co Ltd Remedy for allergic disease
JPH07133229A (ja) * 1993-11-09 1995-05-23 Fumakilla Ltd ダニアレルゲン
KR100756974B1 (ko) * 2006-03-16 2007-09-07 전숙영 알레르기 질환 및 만성염증성 질환의 치료를 위한 약학적 조성물 및 키트
KR20070108320A (ko) * 2006-03-20 2007-11-09 전숙영 알레르기질환 및 자가면역질환의 치료를 위한 약학적조성물, 그의 용도 및 알레르기질환 및 자가면역질환의치료방법
KR100850416B1 (ko) * 2006-06-21 2008-08-04 남상윤 자가세포 파괴에 의해 야기되는 자가면역질환의 치료를위한 세포치료제 및 그 제조 방법

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112638442A (zh) * 2018-06-29 2021-04-09 爱德芳世株式会社 血液透析用经皮端子及个体差别血液透析系统

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