WO2009113810A2

WO2009113810A2 - Pharmaceutical composition, use thereof, and method for the treatment or prevention of allergic and autoimmune diseases

Info

Publication number: WO2009113810A2
Application number: PCT/KR2009/001217
Authority: WO
Inventors: 전숙영; 남동호
Original assignee: Jeon Sook Yeong; Nahm Dong Ho
Priority date: 2008-03-11
Filing date: 2009-03-11
Publication date: 2009-09-17
Also published as: WO2009113810A3

Abstract

The present invention provides a pharmaceutical composition for preventing or treating allergic or autoimmune diseases, which contains immunoglobulin, as an active ingredient, isolated from the blood of a patient who is suffering from an allergic or autoimmune disease. In addition, the disclosed invention provides another pharmaceutical composition for preventing or treating allergic or autoimmune diseases, which contains immunoglobulin isolated from the blood of another patient who is suffering from an allergic or autoimmune disease as an active ingredient. The present invention also provides a manufacturing method and a medicinal and pharmaceutical use of the composition of a medicine for preventing or treating allergic or autoimmune diseases. Also, the disclosed invention provides a method for preventing and treating allergic or autoimmune diseases, which includes administering the pharmaceutical composition to mammals. By administering the disclosed pharmaceutical composition to mammals, allergic or autoimmune diseases, which are hard to control with a current standard drug treatment method, can be treated. Therefore, through the pharmaceutical composition, the use thereof for preventing or treating allergic or autoimmune disease, and the prevention and treatment method using the same, allergic or autoimmune diseases whose symptoms are not easily treated with current standard drug treatment methods can be more effectively treated.

Description

【Specification】

[Name of invention]

Pharmaceutical 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

[Technical field]

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. Therefore, according to 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]

Historically, 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

1 Alternative Response (Article 26) It is the opposite of immunity, which refers to the favorable case (Aronson J. BMJ 1999; 319: 308). Recently, the IgE antibody-mediated immediate type hypersensitivity reaction type I to antigens present in the mammal's external environment has been referred to as an allergic reaction in a narrow sense. And all hypersensitivity reactions to antigens present therein, and hence hypersensitivity to its own protein (autoantigen) is termed autoallergy (Aronson J. BMJ 1999; 319 : 308) However, in recent years, such auto-allergic diseases have been named autoimmune disease in the sense that they show harmful immune response to their proteins. However, 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. (Eds) Allergy, asthma, and immunology from infancy to adulthood, page xvii, Saunders, Philadelphia, 1996). In addition, 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. Rheumatoid arthritis, systemic lupus erythematosus and pemphigus, which have traditionally been classified as an allergic disease, As noted above, due to poor practice in the art (although immunity means beneficial reactions), a phenomenon called autoi- une diseases is becoming more common, leading to the reduction of disease among some scholars. Despite pointing out the necessity of correcting the name, it is hardened by the practice of academia and industry (Aronson J. BMJ 1999; 319: 308; Davidson, A. et al., N Engl J Med 2001 345: 340-350. Some people have suggested a disease name called autoaggresive diseases to solve the problem of this name, but this is also rarely used.

In general, the current art is defined as 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.

On the other hand, 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 隱 unol 2006; 117 ： 1203- 12). In addition, allergic reactions to certain allergens (regardless of food allergens such as egg albumin or aspirable allergens such as house dust mites) induced in mammals and the resulting allergens—specific IgE antibodies to other mammals Transfer to other mammals during passive transfer is considered evidence to confirm that 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). Taken together, these findings suggest that specific IgE-antibodies to allergens play a key role in the pathogenesis of allergic diseases caused by external allergic reactions (Platts-Mills TA. Am. J Respir Crit Care Med 2001; 164: Sl-5).

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. However, although the above treatments can improve clinical symptoms in a large number of allergic patients, it is very common that a large number of patients cannot fully control the clinical symptoms. In particular, there are very few ways to effectively avoid external allergens in real life, and some reports of allergen-immunotherapy that are currently in use sometimes cause severe allergic reactions and deaths of patients who have undergone it. 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.

Meanwhile, systemic lupus, rheumatoid arthritis, pemphigus, dilated cardiomyopathy

Many chronic inflammatory diseases, including dilated cardiomyopathy, are associated with antigen-specific -IgG antibodies that react with antigens (autoantigens) present in one's body due to hypersensitivity to their proteins in the human body. It is known to cause damage and inflammation, and thus is classified as an autoallergic disease or autoimmune disease. (Vaughan JH. Med Times 1969; 97: 187-204; Albin RJ. Lancet 1968; 2 (7583): 1397; Davidson, A. et al., N Engl J Med 2001; 345: 340—350). Currently, the main treatment of these autoimmune diseases is a treatment that reduces inflammation or antigen-specifically reduces immunity irrespective of causative autoantigens such as steroids or immunosuppressants. However, a significant number of patients with autoimmune disease have not been sufficiently clinically improved by the drug treatment. Clinical Effects of Current Pharmaceutical Compositions Based on Immunoglobulins

It is well known that immunoglobulins isolated from the blood of healthy blood donors have anti-inflammatory and anti-allergic effects, thus preventing intractable allergic diseases, autoimmune diseases, or chronic inflammatory diseases not controlled by current standard medications. It has been reported that some patients may experience significant therapeutic effects when they are treated with a pharmaceutical composition based on immunoglobulins isolated from plasma from a number of healthy blood donors (Gelfand EW. J). Allergy Clin Immunol 2001; 108 (4 suppl): Slll-6.) Mechanism of Action of Pharmaceutical Composition Based on Current Immunoglobulins However, immunoglobulin injectables isolated from the plasma of many healthy blood donors currently in use have no clear mechanism of action in allergic, autoimmune or chronic inflammatory diseases. Therefore, there is a limit to further development in terms of efficacy. However, some researchers have reported that anti-idiotype antibodies, which can react with certain antigens (allergens or autoantigens), to inhibit the action of autoantibodies, which are likely to affect the onset and exacerbation of the disease, have been applied to current immunoglobulin injections Potential therapeutic effects have been suggested (Gelfand EW. J Allergy Clin Immunol 2001; 108 (4 suppl): Slll-6.). Current Efficacy Problems of Pharmaceutical Compositions Based on Immunoglobulins However, current immunoglobulin injection formulations present the presence of antibodies to specific antigens (or allergens) in the individual plasmas used to separate the immunoglobulins, or Immunoglobulins were not isolated by selecting specific plasma by measuring titers of antibodies to specific antigens. In particular, in order to make immunoglobulin preparations, the blood of healthy blood donors who do not have a specific disease is used as a raw material (Mart in TD. Int Immunopharmacol 2006; 6: 517-22). Therefore, it is obvious that certain patients or blacks cannot effectively suppress pathogenic autoantibodies involved in disease development by reacting with certain antigens commonly overproduced in patients with certain kinds of diseases. This logical problem with currently used immunoglobulin agents is that the extent of clinical improvement in patients with intractable allergic disease, autoimmune disease and chronic inflammatory disease varies widely depending on the patient. And shortcomings (unforeseen of clinical treatment effects) that are difficult to predict in advance. Possibility of Side Effects of Current Pharmaceutical Compositions Based on Immunoglobulins

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. It also does not completely rule out the possibility of unknown unknown infectious agents or factors that may be adversely affecting those transmitted or transmitted through the blood in the currently used immunoglobulin preparations isolated from multiple blood donors. I can't. Due to the unpredictability of these therapeutic effects and concerns about infections caused by biologically formulated points separated from the blood of many people, they suffer from intractable allergic diseases, autoimmune diseases and chronic inflammatory diseases that are not well controlled by conventional medications. Treatment with immunoglobulins is not actively performed by clinicians treating patients. Improvement of Pharmaceutical Composition Based on Current Immunoglobulins

In particular, 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). Accordingly, 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. B) 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). In view of the manufacture, it solved this problem to devise an advanced form of the pharmaceutical composition, such as the pharmaceutical composition of the present invention.

Indeed, 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. In particular, 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. Considering the situation in which proteins are not fully identified and new foreign allergens or autoantigens are still being identified, their autologous immunoglobulin or the same type is isolated from the blood of each patient. Administration of immunoglobulins isolated from the blood of other patients with allergic diseases or autoimmune diseases, suppresses abnormally increased immune antibody response to unknown external allergens or internal autoantigens, which have not yet been identified. Logical It was judged to be represented a more effective immune control, and treatment effects. Therefore In order to treat the disease by selectively and effectively inhibiting abnormally increased immune antibody responses to foreign proteins or their proteins that play an important role in the development of the disease in patients suffering from allergic or autoimmune diseases. Blood samples are collected from individual patients with the disease, and their immunoglobulins are isolated from the immunoglobulin alone or in combination with immunoglobulins and immunoadjuvant or histamine. The present invention was devised to administer the same patient to administer again. In addition, certain external proteins or proteins (eg, atopic dermatitis-house dust mite) 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. (Bierman CW, et al. (Eds.) Allergy, asthma, and immunology from infancy to adulthood, page xvi i, Saunders, Philadelphia, 1996; Davidson, A. et al., N Engl J Med 2001; 345: 340-350), in fact 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) to prepare pharmaceutical compositions in the form of immunoglobulins, histamine-immunoglobulin complexes, or immunoglobulin-immune adjuvant complexes. Designed and prepared therapeutic regimens. In the case of treatment with the composition, it was determined that 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. Attempts to create an immunoglobulin from blood selected solely for antibody titers or to separate only immunoglobulins that can react with specific allergens or autoantigens from the patient's blood may be incomplete and less effective. have. The inventors have therefore isolated immunoglobulins from the blood of patients suffering from allergic or autoimmune diseases or from other patients suffering from the same type of disease to overcome the imperfections and limitations of these current immunoglobulin therapeutic formulations in the present invention. In the form of immunoglobulin alone, immunoglobulin-histamine complexes, or immunoglobulin-immune adjuvant complexes, an attempt was made to develop pharmaceutical compositions for more effective prophylaxis or treatment for allergic or autoimmune diseases.

In order to improve the unpredictability and incompleteness of the clinical therapeutic effects of immunoglobulin preparations and histamine-immunoglobulin complexes, which are currently used for the treatment of allergic diseases and autoimmune diseases in humans, More advanced than the immunoglobulin formulations, the more fully antigen-producing immunoglobulin involved in developing abnormally increased disease present in each of the allergic and autoimmune patients. We devised a way to specifically inhibit.

To date, 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]

[Technical problem]

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. As part of this effort, 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. Instead of immunoglobulins isolated from pooled plasma, 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 hypothesis that it will exert an immunomodulatory treatment effect against allergic diseases or autoimmune diseases significantly superior to existing immunoglobulin formulations or histamine-immunoglobulin complexes, and this hypothesis is demonstrated through the examples of the present invention. W, thereby completing the present invention. In addition, the inventors also found that a limited number of specific foreign proteins or magnetic proteins in common, depending on the type of individual diseases belonging to a particular allergic disease (bronchial asthma, chronic rash, atopic dermatitis, etc.) or autoimmune diseases (systemic lupus, rheumatoid arthritis, etc.). In view of the fact that it shows an abnormally increased immune antibody response (even for proteins that have not yet been detected), allergic or autoimmune diseases of the same type as the patient being treated. Invented a therapeutic method of isolating immunoglobulins from the blood of other patients, preparing them with pharmaceutical compositions formulated in the form of immunoglobulins or histamine—immunoglobulins and administering them to a patient to be treated, as demonstrated by examples of the present invention. Completed the invention .

In addition, 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. In particular, 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. However, allergens have been isolated from the blood of each patient with an allergic disease, and their entire immunoglobulin fraction (autologus i 隱 unoglobulin) is isolated and administered to the same patient to suppress allergic reactions arising from the IgE antibody-mediated allergic mechanism. No attempt has been made to use the disease as a pharmaceutical composition for treatment. In addition, 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. Patients were found to be very similar in terms of antigenicity of IgG antibodies, and distinctly different from those of healthy normal blood donors who did not suffer from specific diseases. Thus, pathogenic specific antibodies directed against specific antigens, which are important for the development of certain diseases, can be induced to form anti-idiotype antibodies, thereby treating patients suffering from allergic diseases, autoimmune diseases and chronic inflammatory diseases. In the present invention, it is logically obvious that immunoglobulin fractions obtained from patients suffering from the same disease are more effective than commercialized immunoglobulin fractions obtained from blood of normal healthy donors currently being clinically used. The composition was devised. As another basis to support the pharmaceutical composition of the present invention and the possibility of a new treatment using the same, allergic diseases, autoimmune diseases and chronic diseases that have not been responded to conventional drug treatment in many countries around the world for the last about 50 years. For the treatment of patients with inflammatory diseases, 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. It has been scientifically proven in double-blind studies and placebo-controlled studies to have therapeutic effects in chronic moles and atopic dermatitis (Pittler MH, et al. Br J Dermatol. 2003; 148: 307-13; Staubach P et al. Dermatology. 2006; 212: 150-9; Bajaj AK et al. Indian J Dermatol Venereol Leprol. 2008; 74: 109-113). However, it is not yet known which components in the whole autologous blood or plasma have a clinical effect. Therefore, 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. When a specific antibody is administered through intramuscular injection Induction of anti-idiotype antibody response was expected to have a therapeutic effect. Accordingly, when 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. In addition, 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.

Therefore, the inventors through the above-described logical basis and the implementation of the present specification and examples, 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.

In addition, in the treatment of allergic diseases, autoimmune diseases and chronic inflammatory diseases, 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

Clin Immunol 1997; 100: 809-16, United State Patent 6,627,194). In particular, 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). Therefore, if the immunoglobulin component included in the histamine-immunoglobulin complex is replaced with an immunoglobulin isolated from a patient suffering from an allergic disease or an autoimmune disease, a histamine-autoimmunoglobulin complex is prepared and administered. In addition to the therapeutic effect of globulin itself, it is clear that the synergistic effect generated by forming a complex with histamine can be exerted at the same time, which is superior to the existing histamine-immunoglobulin complex. In addition, 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. It is highly likely to be more effective. Therefore, the inventors have allergies comprising immunoglobulin and histamine isolated from the blood of patients suffering from allergic diseases, autoimmune diseases and chronic inflammatory diseases of the present invention through the implementation of the present invention as in the present specification and examples. The pharmaceutical composition for the treatment of diseases, autoimmune diseases and chronic inflammatory diseases has been completed. [Technical problem solution]

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 隱 unoglobulin) and histamine isolated from the blood of a mammal suffering from an allergic disease or autoimmune disease as an active ingredient To provide. The present invention is 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. Provides a treatment method.

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).

In the present invention, 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 画 unopharmacol 2006; 6: 517 -22). In the present invention, 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. lipid A (3-DMPL).

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.

In one embodiment of the invention, 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. In one embodiment of the present invention, 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. And type 1 diabetes mellitus, autoimmune nephritis, chronic inflammatory gastroenteritis, Sjogren's syndrome, and scleroderma.

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.

In one embodiment of the invention, 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.

In one embodiment of the present invention, 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. In addition, in one embodiment of the present invention, in the above-described autoimmune diseases of the present invention, 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.

In another aspect, 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)隱 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.

In addition, 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

It includes a method for producing a pharmaceutical composition for the prevention or treatment of allergic diseases or autoimmune diseases comprising the step of mixing with the immunoglobulin and the adjuvant isolated in step (b). The adjuvant included in the above pharmaceutical composition is aluminum hydroxide, tyrosine, 3 De-0-acylated monophosphoryl, which is currently commonly used for immunoadjuvant purposes in vaccine formulations or immunomodulators. lipid A (3-DMPL).

In addition, 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.

As used herein, the term "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.

Each active ingredient used in the 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. For example, 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. Pharmaceutically or physiologically acceptable salts of the active ingredient or complexes of one or more active ingredients contained in the 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. The term “immunoglobulin” of the present invention 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, μ, δ, ε Are classified into IgG, IgA, IgM, IgD, and IgE, respectively .. The immunoglobulins used in the compositions of the present invention may be IgG, IgA ᅳ 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. . Alternatively, according to methods known in the art, 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). In addition, 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).

In addition, 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. In particular, it is well known in the art that 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.

One of the active ingredients of the compositions of the present invention, "immune 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 (3-0-deacylated Monophosphoryl lipids A), but are not limited to these. As a further typical alternative, 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).

One of the active ingredients of the composition of the present invention "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.

In order to prepare a pharmaceutical composition of the present invention, 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.

The composition of the present invention is preferably for subcutaneous injection. However, in embodiments of the present invention, 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. For example, a complete saline solution for injection may use physiological saline or the like. As can be seen in the examples of the present invention, 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. Therefore, autologous i 隱 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.

As used herein, the term "mammal" refers to a mammal that is the subject of treatment, observation or experimentation, preferably human.

As used herein, 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. In the case of a general pharmaceutical composition, 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. Patient's sensitivity to And / or the patient's sensitivity to immunoglobulins, adjuvant, or histamine.

In the pharmaceutical composition of the present invention comprising immunoglobulin alone or immunoglobulin and an adjuvant or histamine, 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.

Preferably, 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.

It will be apparent to those skilled in the art that 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. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms, and only the embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the art to which the present invention pertains. It is provided to fully convey the scope of the invention to those skilled in the art, and the invention is defined only by the scope of the claims. Example 1

Formulation Example 1

12 nig of autologous immunoglobulin isolated from the blood of a mammal suffering from an allergic or autoimmune disease

Aluminum hydroxide lmg

Sodium chloride 4mg

Amino Acetic Acid 45 mg

D 一 mantle 4 nig

Sodium Hydroxide

Water for Injection 0.8-2 m.C Formulation Example 2

12 nig of autologous i 隱 unoglobuHn isolated from the blood of a mammal suffering from an allergic or autoimmune disease

Histamine dihydrochloride 0.15 // g

Sodium chloride 4mg

45 nig aminoacetic acid

4mg D-Mani

Sodium Hydroxide

Water for Injection 0.8-2 ιι

(Injectable water is supplied in a separate vial different from the other ingredients) Formulation Example 3

12 mg of immunoglobulin isolated from blood of other mammals suffering from allergic or autoimmune diseases

Aluminum hydroxide lmg

Sodium chloride 4 mg

45 nig aminoacetic acid

4 mg of D-mann

Sodium Hydroxide

Water for injection 0.8-2 mi Formulation Example 4

Histamine dihydrochloride 0.15 / g

Sodium chloride 4mg

45 nig aminoacetic acid

D-mantle 4mg

Sodium Hydroxide

Water for Injection 0.8-2 m «

(Injection number is supplied in a separate vial different from the other components) Example 2: Isolation of immunoglobulins from the blood of patients with allergic or autoimmune diseases Comparative analysis of reactions against external allergens or autoantigens

(1) 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. (2) immunoblot analysis

Cultured human airway epithelial cell (A549 cell line; ATCC CCL-185) extract or whole extract extract of North American Dermatophagoides farinae was isolated by discontinuous sodium dodecyl sulfate / polyacrylamide electrophoresis (SDS-PAGE). . After electrophoresis, the protein was translocated into a polyvinylidine di f luoride (PVDF; Bio- Rad Laboratories, Hercules, CA) membrane. After translocation, PVDF membranes were first reacted with Tris buffered saline (TBS) containing 10% bovine serum, 10% skim milk powder, and 0.1% Tween 20 for at least 1 hour. Next, 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. After washing, 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. For control experiments, antibodies specific for human alpha-enolase protein, monoclonal antibodies against human cytokeratin 18 protein and monoclonal antibodies against house dust mite group 2 week allergens were used as positive controls and then the appropriate alkaline phosphate for each antibody. The color was developed as above after treatment with the acetylase-binding secondary antibody. In addition, two types of purely isolated intravenous human immunoglobulins (trade name: IVglobulin- Green Cross, Korea; trade name: Livga® a—Dongshin Pharmaceutical, Korea) and commercialized intramuscular human immunoglobulins (trade name: gamma) Globulin, green cross, Korea) and commercialized histamine-human immunoglobulin complex (trade name: histobulin, green cross Korea) were diluted to a concentration of O.lmg / ml, followed by 1 ml per PVDF strip. The color was developed after the secondary antibody treatment. As a negative control, the case of treatment with diluent instead of serum or immunoglobulin diluent was developed as described above. 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. The preparation of pharmaceutical formulations for the prevention or treatment of allergic or autoimmune diseases more logically reasonable compared to immunoglobulins isolated from a large number of assorted plasmas of normal healthy blood donors, which are currently in use. Prove that the material can be. In addition, in the case of patients suffering from the same type of allergic disease or autoimmune disease, it was confirmed that antigens commonly recognized by antibodies present in immunoglobulins separated from blood (FIGS. 1 and 2). In particular, in patients suffering from bronchial asthma, two of three patients showed common autoantibody reaction against alpha-enolase protein (FIG. 1). One bronchial asthma (Bronchial Asthma patient 3 of FIG. 2) and one patient suffering from atopic dermatitis were observed to have an immune antibody in common against the same house dust mite allergen (FIG. 2). In contrast, immunoglobulin formulations isolated from commercially available healthy donors did not detect antibody reaction against house dust mite group 2 main allergen (Der f2), which is known to be important for the development of allergic diseases (FIG. 2). The results of immunoblot analysis showed that patients suffering from allergic diseases or autoimmune diseases Assorted immunoglobulins from patients' own blood or other patients suffering from the same type of disease, prepared from a number of normal healthy blood donors, which are prepared by administering pharmaceutical compositions to these patients. Compared to immunoglobulins isolated from pooled plasma, abnormally increased antibody responses to various antigens observed in allergic or autoimmune diseases can be achieved through negative feed back immunomodulatory mechanisms, including anti-idiotype antibody mechanisms. It shows that allergy disease or autoimmune disease can be prevented or treated more effectively.

(3) Protein analysis using polyacrylamide gel electrophoresis

Human immunoglobulin and commercialized immunoglobulin formulations (histamine and immunoglobulin) 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 In order to analyze the immunoglobulin protein contained in the formulation included simultaneously, electrophoresis using polyacrylamide gel (sodium dodecyl sulphate / polyacryl amide gel electrophoresis = SDS-PAGE) and protein analysis by Coomassie staining were performed. As a result, 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) and a 25-kDa light chain (IgG) has been found to be a major component, and therefore, successful treatment of autologous immunoglobulin or immunoglobulins from other patients with the same type of allergic or autoimmune disease from patients with allergic or rheumatic diseases. It was confirmed that 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

Previous studies have shown that allergic reactions that begin with the reaction of causative allergens and specific IgE antibodies in patients with asthma, rhinitis, conjunctivitis, urticaria and atopic dermatitis, which are clinical manifestations of allergic disease, play a key role in the development of allergic disease. (Platts—Mills TA. Am J Respir Crit Care Med 2001; 164; 1-5). Therefore, the inventors of 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

Allergic disease in North American type dust mites (Dermatophagoides farinae, abbreviated in the following sentence, abbreviated as D. farinae) shows allergic reaction test results and clinically diagnosed allergic rhinitis and atopic dermatitis Venous blood was collected from the patients and serum was isolated. Immunoglobulins from the blood of patients with allergic diseases corresponding to the pharmaceutical composition of the present invention by an adsorption chromatography method using a protein A column from serum isolated from the patients (as confirmed in Example 2). Similarly, the main component was immunoglobulin G), and the anti-allergic effect was verified. Example 3-2: Allergen-Specific IgE Antibody Titers

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 隱 unosorbent assay (ELISA)) by modifying a previously reported method (Saloga J, et al. J Clin Invest 1993; 91: 133-40). In a 96-well plate, 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. , PBS), reacted for 1 hour to block nonspecific reactions, and then the serum of the patients diluted with l: 50 (v / v) in the same buffer for 2 hours, followed by biotin-attached anti-human The reaction of IgE antibody (affinity purified goat specific antibody to human IgE) for 2 hours and 30 minutes of alkaline phosphatase conjugated streptavidin followed by P-nitrophenyl phosphate ( p-nitrophenyl phosphate) was used for color development. Between each reaction step described above, the ELISA plate was washed five times with PBS (PBST) containing 0.1% Tween-20. The measured results were expressed as absorbance measured at 405 nm, and the average of the measured values (quadruplicate) was repeated four times for each sample and used as an experimental result. In the negative control experiment, only the diluted solution was reacted to four wells instead of blood samples, and the rest of the procedure was performed in the same manner as described above to confirm the absorbance measured. 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 experiments below whether immunoglobulins isolated from the blood of two patients with allergic diseases isolated in Example 3-1 could inhibit IgE antibody reaction against house dust mites present in the blood of each same patient. It was confirmed. The serum of the two patients was diluted 1:50 (v / v) with 3% bovine serum albumin and phosphate buffered saline (PBS) containing 0 · 1¾> Tween-20. After each Commercialized intravenous immunoglobulin isolated from multiple healthy blood donors with immunoglobulins or negative controls isolated from the same patients

IVglobul in; Green Cross Co, Korea) was added to a concentration of 4 microgram / ml and reacted for 16 hours at 4 degrees Celsius, and then to the North American house dust mite (D. farinae) as in Example 3-2. Titers of allergen-specific IgE antibodies against were determined. In addition, as a negative control experiment, the serum of the two allergic patients was diluted to the same dilution factor (1:50 v / v) with only the diluent, and then reacted at 4 degrees Celsius for 16 hours, and then the same conditions as the immunoglobulin-added specimens. The titer of North American house dust mite (D. farinae) allergen-specific IgE antibody was measured and compared with the results of the above experiment. Through the above experiment, the reaction between the patient's own autologous immunoglobulin and the intravenous immunoglobulin isolated from normal healthy blood donor between house dust mite antigen and the house dust mite specific to the house dust mite in each patient's serum It was confirmed whether or not to inhibit (inhibition).

Results of the above inhibitory experiments Experimental results of commercialized intravenous immunoglobulin isolated from healthy blood donors in patients 1 showing allergen-specific IgE antibody response to North American dust mites (D. farinae) as shown in Table 1 below. Compared to intravenous i 画 unoglobulin, autologous i 隱 unoglobulin isolated from patient's own blood was more significantly statistically related to specific -IgE antibodies to house dust mite antigen and house dust mite present in his blood. It can be seen that significantly more inhibition (P <0.05).

Table 1.Self-immunoglobulins isolated from patient 1's blood in response to specific -IgE antibodies to North American dust mite (Ι farinae) present in the blood of patient 1 suffering from allergic disease Demonstration of inhibitory effect

SD = standard deviation; * A statistically significant difference was considered when the p value was less than 0.05 compared to the Student t-test (independent sample test). In addition, as shown in Table 2 below, in the case of patients 2 showing allergen-specific IgE antibody response to North American house dust mites (D. farinae) as shown in Table 2 below, commercialized intravenous immunization isolated from healthy blood donors Compared to globulin (intravenous i 睡 unoglobul in), patient 2's own autologous immunoglobulin was significantly more sensitive to house dust mite antigen and house dust mites present in their blood. It can be seen that the statistically significant inhibition (p <0.05). Table 2. Specific _IgE antibodies against North American type dust mites (D. farinae) present in the blood of Patient 2 suffering from allergic disease Demonstration of the effect of the immunoglobulin isolated from patient 2's blood on suppressing reaction with North American type dust mite antigen

S.D. = standard deviation; * If the p value is less than 0.05 compared to the Student t_test (independent sample test), it is regarded as showing statistically significant difference. Experimental results of Table 1 and Table 2 shows that the immunoglobulin G (autologous immunoglobulin G) isolated from the blood of a patient suffering from an allergic disease, which is the pharmaceutical composition of the present invention, shows an antiallergic effect. Confirm that it can be used as.

In other words, the inventors found that their autologous i 隱 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.

【Effects of the 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.

[Brief Description of Drawings]

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 隱 unoblot) shows the result. lane 1-Serum from systemic lupus erythematosus 1; lane 2-immunoglobulins isolated from serum of systemic lupus erythematosus Patient 1; lane 3-serum of rheumatoid arthritis patient 1; lane 4—immunoglobulins isolated from the sera of rheumatoid arthritis patient 1; lane 5-serum from bronchial asthma patient 1; lane 6- immunoglobulins isolated from serum of bronchial asthma patient 1; lane 7- serum of bronchial asthma patient 2; immunoglobulins isolated from the serum of lane 8-bronchial asthma patient 2, serum of lane 9- bronchial asthma patient 3; lane 10- immunoglobulins isolated from serum of bronchial asthma patient 3; lane 11- serum of atopic dermatitis patient 1; lane 12- immunoglobulins isolated from serum of atopic dermatitis patient 1; lane 13-Commercial intravenous human immunoglobulin (trade name: Ivy-globulin S, Green Cross, Korea); lane 14-commerized intravenous human immunoglobulin (trade name: Ribgamma, Dongshin Pharmaceutical, Korea); lane 15—commercial intramuscular injectable human immunoglobulin (trade name: gamma-globulin, green cross, Korea); lane 16—commercialized histamine-human immunoglobulin complex (trade names: histobulin, green cross, Korea); lane 17—cytokeratin 18 specific antibody; lane 18- Alpha ᅳ enolase specific antibody lane 19-Shows the result of reaction with diluent in negative control.

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. lane 1- Sera of systemic lupus erythematosus Patient 1; lane 2-immunoglobulins isolated from serum of systemic lupus erythematosus Patient 1; lane 3-serum of rheumatoid arthritis patient 1; immunoglobulins isolated from serum of lane 4- rheumatoid arthritis patient 1; lane 5-serum from bronchial asthma patient 1; lane 6- Bronchial Asthma Immunoglobulins isolated from serum of Patient 1; lane 7—serum of bronchial asthma patient 2; lane 8- immunoglobulins isolated from serum of bronchial asthma patient 2; lane 9—serum of bronchial asthma patient 3; lane 10—immunoglobulin isolated from serum of bronchial asthma patient 3; lane 11—serum of atopic dermatitis patient 1; lane 12- immunoglobulins isolated from serum of atopic dermatitis patient 1; lane 13-Commercial intravenous human immunoglobulin (trade name: Ivy-globulin S, Green Cross, Korea); lane 14-commerized intravenous human immunoglobulin (trade name: Ribgamma, Dongshin Pharmaceutical, Korea); lane 15-merged intramuscular injectable human immunoglobulin (trade name: gamma-globulin, green cross, Korea); lane 16—commercialized histamine-human immunoglobulin complex (trade names: histobulin, green cross, Korea); lane 17- monoclonal antibody against house dust mite group 2 major antigen; lane 18 一 The result of reaction with diluent was shown as negative control.

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. 3), 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 immunoglobulins isolated from the serum of bronchial asthma patient 1; lane 8- serum of bronchial asthma patient 2; lane 9 면역 Immunoglobulins isolated from serum of bronchial asthma patient 2 were analyzed by electrophoresis and protein staining. 3-2 (right side of FIG. 3), sera of lane 1-bronchial asthma patient 3; immunoglobulins isolated from the serum of lane 2-bronchial asthma patient 3; lane 3-serum of atopic dermatitis patient 1; immunoglobulins isolated from the sera of lane 4- atopic dermatitis patient 1; lane 5—commercial intravenous human immunoglobulin (trade name: Ivy-globulin S, Green Cross, Korea); lane 6-commerized intravenous human immunoglobulin (trade name: Ribgamma, Dongshin Pharmaceutical, Korea); lane 7-commercial intramuscular injectable human immunoglobulin (trade names: gamma—globulin, green cross, Korea); lane 8-commercialized histamine-human immunoglobulin complex (trade names: histobulin, green cross, Korea); lane 9- Molecular weight marker was analyzed by electrophoresis and protein staining.

Claims

[Range of request]

[Claim 11

A pharmaceutical composition for treating allergic diseases or autoimmune diseases comprising an immunoglobulin isolated from the blood of a mammal suffering from an allergic disease or an autoimmune disease as an active ingredient.

[Claim 2]

A pharmaceutical composition for treating allergic disease or autoimmune disease, comprising an immunoglobulin and hastamine isolated from the blood of a mammal suffering from an allergic disease or an autoimmune disease as an active ingredient.

[Claim 3]

A pharmaceutical composition for treating allergic diseases or autoimmune diseases comprising an immunoglobulin and an adjuvant as an active ingredient isolated from the blood of a mammal suffering from an allergic disease or an autoimmune disease as an active ingredient.

[Claim 4]

4. The pharmaceutical composition of claim 3, wherein the adjuvant is at least one adjuvant selected from the group consisting of aluminum hydroxide, tyrosine, and 3 De-O-acylated monophosphoryl lipid A (3-DMPL).

[Claim 5]

A pharmaceutical composition for treating allergic diseases or autoimmune diseases comprising an immunoglobulin isolated from blood of a mammal suffering from allergic diseases or autoimmune diseases as an active ingredient.

[Claim 6] A pharmaceutical composition for treating allergic diseases or autoimmune diseases comprising immunoglobulin and histamine isolated from blood of a mammal suffering from allergic diseases or autoimmune diseases as an active ingredient.

[Claim 7]

A pharmaceutical composition for treating allergic diseases or autoimmune diseases comprising an immunoglobulin and an adjuvant as an active ingredient isolated from blood of a mammal suffering from an allergic disease or an autoimmune disease.

[Claim 8]

8. The pharmaceutical composition of claim 7, wherein the adjuvant is at least one adjuvant selected from the group consisting of aluminum hydroxide, tyrosine and 3 De-O-acylated monophosphoryl lipid A (3-DMPL).

[Claim 9]

The method according to claim 1, 2, 3, 5, 6 or 7, wherein the allergic disease is atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, food allergy, or bronchial asthma. Pharmaceutical compositions.

[Claim 10]

8. The method of claim 1, 2, 3, 5, 6 or 7, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, pemphigus, autoimmune thyroiditis, autoimmune hepatitis, A pharmaceutical composition that is type 1 diabetes mellitus, autoimmune nephritis, chronic inflammatory gastroenteritis, Schengen syndrome, or scleroderma.

[Claim 111]

8. A pharmaceutical composition according to claim 1, 2, 3, 5, 6 or 7, wherein said immunoglobulin is immunoglobulin G.

[Claim 12]

(a) extracting blood from a mammal suffering from an allergic or autoimmune disease, (b) isolating immunoglobulins from the blood of the mammal for treating allergic disease or autoimmune disease of claim 1 Method of Preparation of Pharmaceutical Composition.

[Claim 13]

(a) collecting blood from a mammal suffering from an allergic or autoimmune disease; (b) isolating immunoglobulins from the mammal's blood; (C) immunoglobulins isolated in step (b) A method for preparing a pharmaceutical composition for treating allergic diseases or autoimmune diseases according to claim 2, comprising the step of mixing with histamine.

[Claim 14]

(a) extracting blood from a mammal suffering from an allergic or autoimmune disease, (b) isolating immunoglobulins from the blood of the mammal, (c) immunoglobulins isolated in step (b) A method for preparing a pharmaceutical composition for treating allergic diseases or autoimmune diseases according to claim 3, comprising the step of mixing an adjuvant with an adjuvant.

[Claim 15]

(a) collecting blood from a mammal suffering from an allergic or autoimmune disease; (b) isolating immunoglobulins from the blood of the mammal; Method for the preparation of a therapeutic pharmaceutical composition.

[Claim 16]

(a) collecting blood from a mammal suffering from an allergic or autoimmune disease; (b) obtaining immunoglobulins from the mammal's blood; A method of preparing a pharmaceutical composition for preventing or treating allergic disease or autoimmune disease according to claim 6, comprising the step of: separating (C) the immunoglobulin and histamine separated in step (b).

[Claim 17]

(a) collecting blood from a mammal suffering from an allergic or autoimmune disease; (b) isolating immunoglobulins from the blood of the mammal; (c) immunoglobulins isolated in step (b). Method of producing a pharmaceutical composition for preventing or treating allergic diseases or autoimmune diseases of claim 7 comprising the step of mixing with an adjuvant.

[Claim 18]

A method for treating an allergic disease or autoimmune disease comprising administering to a mammal a pharmaceutical composition comprising an immunoglobulin isolated from the blood of a mammal suffering from an allergic disease or an autoimmune disease as an active ingredient. .

[Claim 19]

The method of claim 18, wherein the active ingredient further comprises histamine.

[Claim 20]

The method of claim 18, wherein the active ingredient further comprises an adjuvant.

[Claim 21]

The method of claim 20, wherein the adjuvant is at least one adjuvant selected from the group consisting of aluminum hydroxide, tyrosine and 3 De-O-acylated monophosphoryl lipid A (3-DMPL).

[Claim 22]

A method for treating allergic disease or autoimmune disease, comprising administering to a mammal a pharmaceutical composition comprising an immunoglobulin isolated from blood of a mammal suffering from allergic disease or autoimmune disease as an active ingredient.

[Claim 23]

23. The method of claim 22, wherein the active ingredient further comprises histamine.

[Claim 24]

The method of claim 22, wherein the active ingredient further comprises an adjuvant.

[Claim 25]

The method of claim 24, wherein the adjuvant is at least one adjuvant selected from the group consisting of aluminum hydroxide, tyrosine and 3 De-O-acylated monophosphoryl lipid A (3-DMPL).

[Claim 26]

23. The method of claim 18 or 22, wherein the allergic disease is atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, food allergy, or bronchial asthma.

[Claim 27]

23. The method of claim 18 or 22, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, pemphigus, autoimmune thyroiditis, autoimmune hepatitis, Type 1 diabetes mellitus, autoimmune nephritis, chronic inflammatory gastroenteritis, Schagren's syndrome, or scleroderma.

[Claim 28]

23. The method of claim 18 or 22, wherein said immunoglobulin is immunoglobulin G.