Sublingual immunotherapy preparation for the treatment of egg allergy

Abstract

To provide a sublingual immunotherapy formulation for the treatment of egg allergy that is highly safe and allows for the appropriate dosage to be administered to the sublingual mucosa. [Solution] The present invention provides a sublingual immunotherapy preparation for the treatment of egg allergy, which contains a heat-dried chicken egg-derived powder containing 90 mg to 130 mg of egg-derived protein, the causative antigen of egg allergy. It is also administered to patients whose oral intake of heat-dried chicken egg-derived powder is 0.1 g or less in a challenge test. The preparation is administered according to the sublingual immunotherapy administration schedule, in which 0.8 ml to 1.2 ml of the preparation is suspended in water or buffer solution, brought into contact with the sublingual mucosa, held for at least 2 minutes, and then vomited up.

Description

Technical Field

[0001] The present invention relates to a preparation for sublingual immunotherapy for the treatment of egg allergy.

Background Art

[0002] Conventionally, as a treatment method for food allergy, an elimination diet therapy is known. The elimination diet therapy is to give an allergy patient a diet from which substances (antigens) that cause allergies have been removed, so as not to cause allergy symptoms. However, the elimination diet therapy is not an approach to the immune abnormality itself, but rather leaves it to spontaneous remission, so the period of implementation becomes long. In addition, the elimination diet therapy places a high burden on the patient himself and his family, and has a chronic risk of anaphylaxis associated with accidental ingestion. In children, remission often occurs by the age of about 6 years, but in severe cases, spontaneous remission is difficult. Therefore, the establishment of a radical treatment method is desired worldwide.

[0003] Therefore, as a treatment method for food allergy, desensitization therapy (immunotherapy) has been attempted. Immunotherapy is generally a treatment method for acquiring immune tolerance by orally administering antigens little by little to allergy patients by oral immunotherapy (OIT). Different from the elimination diet therapy, immunotherapy has a high possibility that the allergy itself becomes immunotolerant and the patient can eat foods containing antigens.

[0004] Particularly, as a food for immunotherapy or an immunotherapeutic agent for chicken egg allergy, it has been proposed to heat-denature eggs, powder them, and further mix them with other specific components and fill them into small packaging containers, so as to implement an immunotherapy with less burden on patients, easy grasp of the antigen amount, and safety (see Patent Document 1).

[0005] On the other hand, oral immunotherapy has safety concerns, and according to one study, 8.4% of patients experienced a serious adverse reaction (anaphylaxis) requiring epinephrine. Therefore, sublingual immunotherapy (SLIT) has been proposed as a safer treatment method. Sublingual immunotherapy for chicken egg allergy is performed by administering a suspension of heated whole egg powder and water under the tongue, holding it for two minutes, and then vomiting it up. In this method, the amount of heated whole egg powder administered sublingually is gradually increased starting from 0.04 g (see Non-Patent Literature 1). [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2015-105234

[0007] [Non-Patent Document 1] Sagara et al. “Successful sublingual immunotherapy for severe egg allergy in children: a case report” 06 January 2021, Allergy, Asthma & Clinical Immunology [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] The immunotherapy agent disclosed in Patent Document 1 involves administering powdered eggs orally to patients. When administered to severely ill patients, there is a risk of serious adverse reactions, raising safety concerns.

[0009] According to the sublingual immunotherapy disclosed in Non-Patent Document 1, the dosage for treating chicken egg allergy is not clearly defined, and the safe range of egg-derived protein dosage at the start of treatment is unknown. 1Sublingual immunotherapy, as disclosed in [publication name], has the challenge of lacking a reproducible dosage design that balances therapeutic efficacy and safety.

[0010] The present invention aims to provide a sublingual immunotherapy formulation for the treatment of egg allergy that is highly safe and allows for the appropriate dosage to be administered to the sublingual mucosa from the start of treatment. [Means for solving the problem]

[0011] The present invention provides a sublingual immunotherapy preparation for the treatment of egg allergy, which contains a heat-dried chicken egg-derived powder containing 90 mg to 130 mg of egg-derived protein, the causative antigen of egg allergy. In the challenge test, the heat-dried chicken egg-derived powder can be administered to patients whose oral intake is 0.1 g or less. This method is characterized by being administered according to the administration schedule for sublingual immunotherapy, in which a suspended amount of 0.8 ml to 1.2 ml per dose is applied to the sublingual mucosa in water or buffer solution, held for at least 2 minutes, and then vomited up. [Effects of the Invention]

[0012] According to the above method, a sublingual immunotherapy formulation for the treatment of egg allergy can be obtained that suppresses adverse reactions, is highly safe, and can be effectively administered to induce allergy-suppressing immunity. [Brief explanation of the drawing]

[0013] [Figure 1] This is an explanatory diagram illustrating the overview of the SLAEL (Sublingual immunotherapy for egg allergy in children) trial. [Figure 2] This figure shows the trend in the number of participants enrolled in the SLAEL trial. [Figure 3] This flowchart shows the process of participant registration, group assignment, and trial progress. [Figure 4] This is a diagram illustrating the outline of a double-blind load test. [Figure 5] A graph showing changes in ovalbumin, ovomucoid, and ovalbumin-specific IgG4 antibody titers at 0, 16, and 32 weeks. [Figure 6] A graph showing changes in the specific IgG4 / IgE ratios of ovalbumin, OVM, and OVA at 0, 16, and 32 weeks. [Figure 7] An image diagram showing changes in immunoglobulin values and intake thresholds by immunotherapy using a preparation for sublingual immunotherapy. [Figure 8] A graph showing the time-series changes of individual subjects in specific IgE antibody titers against ovalbumin, ovomucoid, and ovalbumin at 0, 16, and 32 weeks. [Figure 9] It summarizes the results of the double-blind challenge test of the subjects.

Mode for Carrying Out the Invention

[0014] The preferred embodiments of the present invention are described in detail below. The embodiments described below are preferred specific examples of the present invention, and various technically preferable limitations are imposed. However, the scope of the present invention is not limited to these aspects unless there is a description to specifically limit the present invention in the following description.

[0015] Embodiment 1. 1. Regarding egg allergy Egg allergy is one of the most common food allergies in children, and ingestion may cause severe symptoms such as urticaria, respiratory symptoms, digestive symptoms, and even anaphylaxis. Conventionally, an egg-elimination diet therapy has been carried out, but this method cannot act on the immune abnormality itself, and the improvement of symptoms is left to spontaneous remission. Therefore, the treatment period tends to be long and it is not a radical treatment. The egg allergy according to this embodiment generally refers to an allergy to the proteins contained in chicken eggs. However, it is not limited to this, and may include allergies to proteins contained in eggs of other poultry such as quail and duck.

[0016] In addition, the elimination diet therapy has significant restrictions in daily life. The patient himself / herself has limited freedom in diet and always has to be aware of the risk of accidental ingestion in the situations of school meals or eating out. Furthermore, the family has to pay meticulous attention to the selection of food ingredients and cooking environment at the cooking stage, and always bears the uneasiness of accidental ingestion, thus chronically bearing the anaphylaxis risk. As a result, the mental and economic burdens are heavy, and the quality of life of the whole family declines. Especially in severe cases, spontaneous remission is difficult, so the establishment of a radical treatment method is strongly desired worldwide.

[0017] 2. Sublingual immunotherapy (SLIT) for egg allergy In recent years, immunotherapy for egg allergy has attracted attention. Immunotherapy includes oral immunotherapy (OIT) and sublingual immunotherapy (SLIT). Oral immunotherapy is a method of gradually increasing the oral administration of an antigen, but there are problems with safety, such as severe side effects (anaphylaxis) requiring epinephrine administration occurring at a certain rate.

[0018] In contrast, sublingual immunotherapy (SLIT) is a method of inducing immune tolerance by retaining an antigen on the sublingual mucosa, and is considered to be safer than oral immunotherapy. This embodiment relates to a preparation suitable for this sublingual immunotherapy.

[0019] 3. Preparation for sublingual immunotherapy for egg allergy (1) Composition of the preparation for sublingual immunotherapy The preparation for sublingual immunotherapy according to this embodiment contains heat-dried chicken egg-derived powder as an active ingredient. Generally, chicken eggs are used as the raw material eggs. As chicken eggs, for example, in addition to eggs with shells, commercially available liquid whole eggs obtained by industrially cracking eggs and removing the shells, or mixtures of liquid egg white and liquid egg yolk can be used. The heat-dried chicken egg-derived powder contained in the preparation for sublingual immunotherapy can contain egg proteins including yolk protein and egg white protein. Yolk protein is the protein contained in egg yolk, and examples include phosvitin, α-lipovitellin, β-lipovitellin, etc. Egg white protein is the protein contained in egg white, and examples include ovalbumin (OVA), ovomucoid (OVM), lysozyme, ovotransferrin, ovomucin, etc.

[0020] The sublingual immunotherapy preparation according to this embodiment may contain 0.48 g to 0.72 g of heat-dried chicken egg-derived powder. Furthermore, the sublingual immunotherapy preparation according to this embodiment contains 90 mg to 130 mg of egg-derived protein, which is the causative antigen of egg allergy, per single dose. It is desirable that the sublingual immunotherapy preparation contains approximately 110 mg of the egg-derived protein antigen. However, the amount of egg-derived protein antigen may be within the range of any two of the examples given, such as 90, 100, 110, 120, and 130 mg. This ensures a sufficient amount of antigen for inducing immune tolerance without inducing an excessive IgE response. In this specification, the egg-derived protein that is the causative antigen of egg allergy can be quantified using a complex antigen ELISA (e.g., FASTKIT ELISA Ver. III) (in some cases, the total amount of protein may include trace amounts derived from egg yolk). Based on the typical ELISA-reactive antigen protein content in heat-dried chicken egg-derived powder, the powder weighing range to obtain a total antigen amount of 90-130 mg per dose is approximately 0.48-0.72 g per dose.

[0021] The egg allergens contained in sublingual immunotherapy preparations are mainly derived from egg white components. Eggs consist of shell, egg white, and yolk, and contain multiple proteins. Among them, ovalbumin is known as the main component, making up the majority of egg white protein, and plays a central role in functional aspects such as gelation, foaming, and emulsification. In contrast, ovomucoid is a glycoprotein with serine protease inhibitory activity and is one of the main components in egg white. The composition of unheated egg white is stated in standard chemical composition tables as approximately 54% ovalbumin and approximately 11% ovomucoid. The sublingual immunotherapy preparation according to this embodiment contains heat-dried egg-derived powder as an active ingredient. The effect of the heating process differs depending on the antigen; generally, ovomucoid (OVM) retains its antigenicity relatively well, while ovalbumin (OVA) is susceptible to heat. On the other hand, even after heat drying, OVA may remain at a detectable and quantifiable level. The sublingual immunotherapy preparation according to this embodiment may be formulated to contain a total of 90 mg to 130 mg of OVA and OVM as the proteins that cause egg allergy. In this case, proteins other than OVA and OVM that act as antigens may be included outside the above-mentioned range. Furthermore, the sublingual immunotherapy preparation according to this embodiment may be formulated to contain a total of 90 mg to 130 mg of OVA, OVM, and other antigenic proteins. More preferably, the sublingual immunotherapy preparation according to this embodiment is formulated to contain antigenic proteins in a range of 100 mg to 120 mg. Even more preferably, the sublingual immunotherapy preparation according to this embodiment is formulated to contain antigenic proteins in a range of 105 mg to 115 mg.

[0022] The egg-derived proteins that act as antigens in the sublingual immunotherapy preparation according to this embodiment are not limited to OVA and OVM. In addition to OVA and OVM, other egg white-derived allergens (e.g., conalbumin / ovotransferrin (Gal d 3), lysozyme (Gal d 4), ovomucin, etc.) and, if necessary, egg yolk-derived allergens (e.g., α-ribetin (Gal d 5), YGP42 (Gal d 6)) may be included in trace amounts. The sublingual immunotherapy preparation according to this embodiment only needs to be adjusted so that the total amount of egg-derived proteins that act as causative antigens for egg allergy is between 90 mg and 130 mg, and it is desirable that the sum of OVA and OVM constitutes the main part of this total. For example, the sum of OVA and OVM may be adjusted to account for 70-100% of the total amount of proteins that act as causative antigens for egg allergy. On the other hand, considering compositional variations due to differences in raw material lots and heating conditions, the remainder of OVA and OVM may consist of other antigens. The egg-derived protein that acts as the antigen is quantified using the ELISA method.

[0023] Among the major allergens contained in heat-dried egg-derived powder, ovalbumin (OVA) is known to lose antigenicity after heat treatment, while ovomucoid (OVM) retains its antigenicity even after heat treatment. Therefore, heat-dried egg-derived powder has the characteristic of being able to induce an immune response while appropriately controlling the total amount of antigen. This makes it possible to induce immune tolerance while reducing the risk of severe immediate-type reactions. Furthermore, the amount of antigen contained in the powder can be measured using methods such as ELISA (Enzyme-Linked Immunosorbent Assay), enabling reproducible dosage design. However, in actual pharmaceutical manufacturing, the amount of antigen is not always perfectly constant due to lot-to-lot variations in egg powder, weighing errors during formulation, and analytical errors in allergen measurement, and it is necessary to maintain a stable antigen concentration.

[0024] Therefore, the sublingual immunotherapy preparation according to this embodiment is formulated to contain an egg-derived protein antigen in a range of 90 mg to 130 mg. This range corresponds to a variation of ±20% centered around 110 mg, and loading test results have confirmed that it does not impair the clinical effect of inducing an immune response and does not induce an excessive IgE response. In other words, by allowing a range of 90 to 130 mg, it is possible to achieve stable therapeutic effects while balancing actual manufacturing reproducibility and safety. The safety of this 90 to 130 mg range is further supported by the fact that no serious reactions occurred in the SLAEL test described in the examples, and that, compared to double-blind loading tests, sublingual immunotherapy avoids massive absorption of the antigen and allows control of the rate and amount of antigen delivered to the body.

[0025] (Ratio of antigen content in heat-dried chicken egg-derived powder) The sublingual immunotherapy preparation according to this embodiment is prepared by adjusting the dose of egg-derived antigen (mainly derived from egg white) to 90 mg to 130 mg per dose. Here, "egg-derived antigen" refers to a protein containing at least ovomucoid (OVM) and ovalbumin (OVA). In addition to ovomucoid (OVM) and ovalbumin (OVA), "egg-derived antigen" may also contain other antigenic proteins (e.g., ovotransferrin, lysozyme, ovomucin, α-ribetin, YGP42). Since the soluble and immunoreactive fractions of OVA tend to decrease with heat treatment, while OVM is relatively well retained, the contribution ratio of OVM tends to be relatively higher in heated egg powder.

[0026] (Variations of heat-dried chicken egg-derived powder) The heat-dried egg-derived powder contained in the sublingual immunotherapy preparation according to this embodiment is basically a heat-dried powder made from whole eggs, but this does not exclude products made from egg powder made from egg whites only, for example. Generally, the proteins that are allergens in egg allergies are derived from egg whites, and as long as the egg-derived protein that acts as an antigen is adjusted to 90 mg to 130 mg per dose, it does not have to be a heat-dried powder made from whole eggs.

[0027] (Quantitative methods and lot-to-lot variation management) For OVM and OVA, quantitative analysis is preferably performed lot by lot using the ELISA method. For ovotransferrin, lysozyme, ovomucin, α-ribetin, etc., if specific antibodies are available, they are similarly quantified by ELISA. For components for which appropriate antibodies are difficult to obtain, the relative or absolute amount may be measured by other measurement methods.

[0028] Since OVM tends to retain its epitopes even after heating, while OVA is susceptible to the effects of heating, the above ratio design provides a practical balance that promotes immunological tolerance, such as IgG4 induction, while avoiding excessive IgE-mediated immediate reactions. Furthermore, by including other components in appropriate amounts, a broad antigenic spectrum is ensured, and a certain level of effectiveness can be expected even for individual-variable reactivity.

[0029] The above ratios and specifications are presented as examples of embodiments to ensure both manufacturing feasibility and clinical rationality, but do not preclude modifications by those skilled in the art as necessary. The ratio of antigens contained in the chicken egg powder used in the sublingual immunotherapy preparation according to this embodiment can be appropriately optimized within the range by those skilled in the art, depending on the results of clinical trials and the findings of safety monitoring.

[0030] (Particle size of heat-dried chicken egg-derived powder) The sublingual immunotherapy preparation according to this embodiment is administered suspended in water or a buffer solution maintaining a pH range close to physiological conditions in order to ensure the amount of antigen necessary for inducing immune tolerance and to contact the sublingual mucosa. Therefore, the heat-dried chicken egg-derived powder contained in the sublingual immunotherapy preparation is manufactured, for example, by spray drying or freeze-drying, and is preferably formed to have a particle size of 1 μm to 100 μm so that it disperses easily in liquid. Alternatively, the particle size of the heat-dried chicken egg-derived powder may be within the range of any two of the example values ​​such as 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, and 100 μm.

[0031] (Adjuncts included in sublingual immunotherapy preparations) Because heat-dried egg-derived powder has relatively small particle size and is easily dispersed, it is advisable to stabilize the powder by mixing it with auxiliary components such as maltose, dextrin, or mannitol. This improves the weighability and suspendability of the sublingual immunotherapy preparation. Maltose, in particular, has the advantage of providing sweetness, which can reduce the aversion of patients (children) to the characteristic odor and taste of eggs. In other words, if a sublingual immunotherapy preparation consists only of heat-dried egg-derived powder, the characteristic odor and flavor of eggs will remain, which often causes strong aversion in children with egg allergies. As a result, it may become difficult to retain the medication under the tongue, potentially impairing the continuation of treatment. Furthermore, sugars such as maltose are soluble in water, so they have the advantage of not interfering with the suspension of the egg powder when mixed with water or other liquids. Note that the auxiliary components added to the sublingual immunotherapy preparation may include at least one of the following: sugars, sugar alcohols, polysaccharides, starch, cellulose derivatives, and inorganic salts. Furthermore, the auxiliary components may be sweeteners or may not have any sweetness. These auxiliary components are preferably particles between 50 μm and 300 μm in size. The particle size of the excipients may also be within the range of any two of the example values ​​listed, such as 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, and 300 μm.

[0032] Furthermore, the auxiliary components added to the sublingual immunotherapy preparation should preferably be present in an amount of 3.2 to 4.8 parts by weight per 1 part by weight of heat-dried egg-derived powder. Because egg powder has a small particle size, mixing it with auxiliary components that have a relatively larger particle size in powder form stabilizes the sublingual immunotherapy preparation and prevents the active ingredient, egg powder, from scattering. In other words, when providing a sublingual immunotherapy preparation in powder form, heat-dried egg-derived powder has a small particle size and is prone to scattering and adhesion, making accurate weighing and preparation when using it as a suspension difficult, thus posing a challenge in administration. However, as described above, adding and mixing relatively large particle size powders such as sugars as excipients to the sublingual immunotherapy preparation has the advantage of making it easier to handle.

[0033] The sublingual immunotherapy preparation according to this embodiment may further contain a flavoring agent. This improves the flavor and reduces the patient's resistance to holding the preparation under their tongue. The above-mentioned excipients and flavoring agents have the effect of improving patient adherence (especially in young children) to administering the preparation for a set period of time each day. The flavoring agent may be, for example, a fruit flavoring agent, but any flavoring agent may be used as long as it reduces the patient's resistance to holding the sublingual immunotherapy preparation in their mouth.

[0034] (2) Dosage Form The sublingual immunotherapy preparation according to this embodiment is packaged in individual doses. The sublingual immunotherapy preparation is suspended in water or buffer solution by any method and administered to the sublingual mucosa in a sol-like state. After administration, it is held under the tongue for at least 2 minutes, and then vomited out (regurgitated) without being swallowed. In other words, the sublingual immunotherapy preparation according to this embodiment is characterized by being a non-swallowing (regurgitated) preparation not intended for swallowing and oral intake. By not swallowing, antigen presentation from the sublingual mucosa can be reliably performed while avoiding excessive absorption of allergens from the gastrointestinal tract.

[0035] For administration to the sublingual mucosa, the sublingual immunotherapy preparation is suspended in a liquid such as water or buffer solution to form a sol of 0.8 ml to 1.2 ml. Specifically, the packaged powder preparation is poured into a container, water or buffer solution is added to the powder preparation, and the mixture is stirred as appropriate to form a sol. The volume of the sublingual immunotherapy preparation in sol form to be administered may be within the range of any two of the example values ​​such as 0.8, 0.9, 1.0, 1.1, and 1.2 ml. The volume of the sol is optimized to be an amount that can be held in the sublingual area of ​​a typical child.

[0036] (3) Target recipients The patients targeted by the sublingual immunotherapy preparation according to this embodiment are primarily children with egg allergies. Patients may be 4 years of age or older. Furthermore, patients may be children who, in a challenge test, can orally ingest 0.1g or less, 0.5g or less, 2.0g or less, 4.0g or less, or more than 4.0g of heated dried egg-derived powder. In other words, the sublingual immunotherapy preparation according to this embodiment can be administered even to patients who can orally ingest very small amounts of egg before the start of administration. Patients may also have egg white-specific IgE levels of 30.0 uA / mL or higher. Additionally, patients may have co-occurring conditions such as bronchial asthma, atopic dermatitis, allergic rhinitis, or other food allergies. A challenge test may be performed on patients targeted for administration before the start of administration of the sublingual immunotherapy preparation. The challenge test can be performed by any method, but it involves orally administering a preparation containing egg-derived protein, which is the causative antigen of egg allergy (not limited to the sublingual immunotherapy preparation according to this embodiment), starting from a small amount and gradually increasing the amount, and observing changes in symptoms or specific IgE levels. Specific IgE levels can be measured using egg white, OVA, or OVM. Specific IgE levels can be measured, for example, by the ImmunoCAP method. However, since the sublingual immunotherapy preparation according to this embodiment is designed to avoid severe reactions even in severely ill patients, it can be administered without performing a challenge test.

[0037] (4) Sublingual immunotherapy administration schedule The administration schedule for the sublingual immunotherapy preparation according to this embodiment is preferably once a day, at approximately 24-hour intervals. The amount per dose follows the administration method described in (1) above. The administration time is preferably about the same each day, but an acceptable time variation may be within the range of 18 to 30 hours. Even if an administration is missed, two doses should not be administered together on the same day.

[0038] (5) Dosage Form The sublingual immunotherapy preparation according to this embodiment is basically packaged as a powder. However, it may also be packaged in a sol (liquid) form in which the powder is dispersed in a liquid such as a buffer solution. It may also be in the form of granules or a fast-dissolving sublingual tablet, but it is desirable that it be configured to disperse easily in liquid.

[0039] 4. The effectiveness of treatment with sublingual immunotherapy preparations. Sublingual immunotherapy preparations are administered sublingually to the sublingual mucosa as described above, up to once a day. The duration of administration is typically 32 weeks or more. This increases antigen-specific IgG4 and decreases antigen-specific IgE. However, even in periods of less than 32 weeks from the start of administration, antigen-specific IgG4 levels will increase compared to the start of administration. Also, even in periods between 16 and 32 weeks from the start of administration, the (antigen-specific IgG4 antibody titer) / (antigen-specific IgE antibody titer) value will increase compared to the start of administration. Furthermore, by extending the intervention period of sublingual immunotherapy preparations and ensuring an administration period of 32 weeks or more, antigen-specific IgE levels will decrease compared to the start of administration. It should be noted that the changes in antigen-specific IgG4, antigen-specific IgE, and (antigen-specific IgG4 antibody titer) / (antigen-specific IgE antibody titer) values ​​with respect to the duration of administration represent statistically significant changes, and strictly speaking, this may not be the case depending on the patient being administered the treatment and the patient's condition at the time of measurement. Furthermore, antigen-specific IgG4 antibody titers and antigen-specific IgE antibody titers are evaluated for at least one of the following: egg white, OVM, and OVA.

[0040] Conventional sublingual immunotherapy for egg allergy using SLIT involves exploratory (escalation) administration, and there is no standardized starting dose that can be considered consistently safe from the beginning of administration. Therefore, it was unavoidable to gradually increase the dose while observing the response of individual subjects. In contrast, the sublingual immunotherapy formulation according to this embodiment is (a) The total amount of egg-derived antigen protein in a single dose is standardized to 90-130 mg (preferably 100-120 mg, more preferably 105-115 mg), (b) A method of administration is adopted in which a small amount of sol (0.8-1.2 mL) is held under the tongue for 2 minutes or more and then vomited up. (c) Quality control is performed by verifying the total antigen amount in each lot using ELISA, thereby establishing a reproducible safety margin from the start of administration. In particular, this total dose range is designed to be well below the symptom-inducing threshold, structurally avoiding overdose exposure from the first dose.

[0041] Furthermore, the heat-dried chicken egg-derived powder used in this embodiment contains ovomucoid (OVM) and ovalbumin (OVA) at detectable and quantifiable levels, although the composition ratio may vary depending on lot differences and heating conditions (total antigen amount is confirmed by a combined antigen ELISA). This embodiment ensures the amount necessary for antigen presentation on the sublingual mucosa while suppressing the peak of systemic exposure by standardizing the total antigen amount. As a result, therapeutic effects such as an increase in specific IgG4 and an improvement in the IgG4 / IgE ratio can be consistently targeted from immediately after initiation without requiring the gradual increase method as in the past. In addition, the packaging form and excipient design (maltose, etc.) suppress preparation errors and decreased adherence, improving the practical reproducibility of efficacy and safety from immediately after initiation.

[0042] Furthermore, the sublingual immunotherapy formulation according to this embodiment is designed to ensure a sufficient amount of antigen to achieve therapeutic effects while minimizing the risk of severe systemic reactions (anaphylaxis). The main reasons for ensuring safety are as follows: (i) By limiting the administration route to the sublingual mucosa and holding a small amount of sol (equivalent to 0.8-1.2 mL) for at least 2 minutes before not swallowing (vomiting), large amounts of absorption from the gastrointestinal tract can be avoided, and the rate and amount of antigen delivered to the body can be controlled. (ii) The mucous membrane on the underside of the tongue has an environment that readily induces regulatory T cells and immunomodulation via IL-10 / TGF-β in response to antigen presentation, making it less likely to lead to a rapid systemic reaction. (iii) In terms of antigen design, the total amount of egg-derived antigen protein in a single dose is standardized to the range of 90-130 mg, and 110 mg is used as the main dose to avoid exceeding the acute threshold. (iv) The raw material is a heat-dried chicken egg-derived powder containing ovalbumin (OVA) and ovomucoid (OVM) (and possibly other antigenic proteins), but the total amount is controlled so as not to excessively increase reactivity. (v) By adjusting the excipient and suspension conditions (excipients such as maltose, and adjustment of pH and osmotic pressure with buffer solutions), local irritation is minimized, and unnecessary mucosal barrier disruption and increased absorption are suppressed. (vi) The dosage is, in principle, a steady administration once a day, and does not employ an escalation protocol that rapidly increases the dose in a short period of time (typical of OIT), thus structurally reducing the risk of systemic reactions due to peak exposure.

[0043] In addition, the sublingual immunotherapy formulation of this embodiment can be safely administered to severely ill patients from the start of sublingual immunotherapy. Here, "severely ill patients" refers to, for example, those who fall under at least one of the following categories: (a) Individuals with a low symptom induction threshold in double-blind challenge tests (e.g., individuals whose orally ingestible amount of heat-dried chicken egg-derived powder contained in the sublingual immunotherapy preparation according to this embodiment is 0.1 g or less, or 2 g or less, and who are Sampson severity classification grade 2 or higher) (b) Individuals with high titers of egg white-specific IgE (e.g., 30.0 uA / mL or higher) (c) Individuals with co-existing conditions (bronchial asthma, atopic dermatitis, allergic rhinitis, other food allergies, etc.) The design elements described in (i) to (vi) above allow for prioritizing sublingual antigen presentation while suppressing the peak of systemic exposure, even in patients with these severe reactions, thereby substantially reducing the risk of serious reactions requiring emergency treatment. Specifically, patients receiving the drug can continue treatment and improve allergic symptoms while suppressing serious adverse reactions requiring adrenaline administration.

[0044] Furthermore, the sublingual immunotherapy preparation of this embodiment is packaged in single-dose portions, prescribed under the guidance of a physician, and configured to allow for accurate and easy administration even in environments such as the home.

[0045] 5. Examples 5.1. Exam Overview Figure 1 is an explanatory diagram illustrating the overview of the SLAEL (Sublingual immunotherapy for egg allergy in children) trial. This trial was a multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study. Children with egg allergies were randomly divided into a treatment group (a group administered a formulation containing heat-dried egg powder as the active ingredient) and a placebo group (a group administered a formulation containing pumpkin powder instead of heat-dried egg powder) for a placebo-controlled trial.

[0046] 5.2. Subjects Figure 2 shows the trend in the number of participants enrolled in the SLAEL trial. The participants were children aged 4 to 15 years whose threshold was 2g or less in the double-blind challenge test described later, and a total of 37 participants were enrolled.

[0047] Figure 3 is a flowchart showing the flow of subject enrollment, group assignment, and trial progress. Subjects enrolled during the period from November 2022 to January 2024, as shown in Figure 2 above, were assigned to either the active treatment group or the placebo group at each enrollment. Sixty subjects were provisionally enrolled, but subjects who exceeded the threshold in the double-blind challenge trial described later were excluded from full enrollment. As a result, a total of 37 subjects were fully enrolled and randomized. These subjects were then assigned to either the active treatment group (18 subjects) or the placebo group (19 subjects).

[0048] Table 1 summarizes the background information of the subjects who were officially registered.

[0049] [Table 1]

[0050] As shown in Table 1, subjects were assigned to the treatment group or placebo group in a way that avoided significant bias in the distribution of age, sex, specific IgE levels, and comorbidities. Furthermore, in both the treatment group and the placebo group, subjects were assigned in a way that avoided bias in those who had shown allergic symptoms at a cumulative oral dose of 2g or less of heated whole egg powder in at least the double-blind challenge test described below, and whose specific IgE levels were 29.9uA / mL or less and 30.0uA / mL or higher, respectively.

[0051] 5.3. Double-blind stress test Figure 4 illustrates the outline of the double-blind challenge test. To select subjects for full enrollment, a double-blind challenge test was conducted on provisionally enrolled subjects. A double-blind challenge test is a study in which the contents of the administered substance (whether or not it contains an allergen) are concealed from both the subject and the evaluator, and the subject's reaction is objectively evaluated by administering the target food orally in stages. In the case of egg allergy, a food containing heat-dried chicken egg powder and a placebo food adjusted to be equivalent in appearance and taste were used, and the intake amount that induced symptoms was evaluated.

[0052] In the double-blind challenge trial, the dosage was gradually increased, and the minimum intake that caused symptoms in the subjects was determined as the "symptom-inducing threshold." Only subjects whose threshold was 2g or less were included in the enrollment. This allowed us to confirm that the subjects had severe cases and ensure homogeneity between the test groups.

[0053] Specifically, the same heat-dried chicken egg powder used in the sublingual immunotherapy preparation for this study was mixed with apple gel and administered orally. The dose of heat-dried chicken egg powder was gradually increased from 0.1g, 0.4g, and 1.5g, with intervals of 30-60 minutes between doses. The cumulative dose was added sequentially, and in the pre-registration study, a maximum of 2g was administered. Subjects who were officially registered in the SLAEL study were children who, in this double-blind challenge test, induced Sampson severity classification grade 2 or higher with an administration of 2.0g or less of heat-dried egg.

[0054] Figure 9 summarizes the results of the double-blind challenge tests for the subjects. In the SLAEL study, double-blind challenge tests were performed on the subjects at 0 weeks (before administration began) and 32 weeks. In the double-blind challenge tests after the start of treatment, heated whole eggs were administered in stages of 0.1g, 0.4g, and 1.5g, followed by an additional 2g, up to a maximum cumulative dose of 4g. Changes in the symptom-inducing threshold were evaluated at each point after the start of treatment to confirm whether or not immune tolerance was induced by sublingual immunotherapy.

[0055] The "symptom induction threshold" refers to the cumulative intake (g) at which objective symptoms of at least Grade 2 or higher, based on the Sampson severity classification, first appear during a double-blind challenge test as the cumulative intake is gradually increased.

[0056] Furthermore, the "safe intake threshold" refers to the maximum cumulative intake (g) that could be safely consumed without observing any adverse events in the study. If symptoms appear, the safe intake threshold will be the cumulative intake completed immediately before the onset of the reaction.

[0057] In this challenge test, the drug is administered in the following order: 0.1g → 0.4g → 1.5g (with an additional 2.0g if necessary), with an observation interval of 30-60 minutes between each stage. All records should be consistent in terms of cumulative dose, and the same protocol should be used on the placebo day as well. The threshold should be determined if a significant response occurs only on the active day (allergen administration day).

[0058] (Condition before intervention: OFC1) In the double-blind challenge study (OFC1) conducted at the time of enrollment, the median tolerable dose threshold was 0.1g in the treatment group and 0.5g in the placebo group. The median symptom-inducing threshold was 0.5g in the treatment group and 2.0g in the placebo group. Both groups included a high number of severe cases, but the treatment group tended to have a relatively higher number of subjects whose symptoms were induced at lower doses. The mean tolerable dose threshold in the double-blind challenge study (OFC1) conducted at the time of enrollment was 0.1g in the treatment group and 0.4g in the placebo group. The mean symptom-inducing threshold was 1.0g in the treatment group and 1.5g in the placebo group.

[0059] (Post-intervention status: OFC2) The median acceptable intake threshold after intervention (OFC2) showed an upward trend to 2.0g in the treatment group, but the change was limited to 0.5g in the placebo group. The median symptom-inducing threshold increased to 4.0g (or more) in the treatment group, while it remained at 2.0g in the placebo group. The mean acceptable intake threshold after intervention (OFC2) increased to 2.2g in the treatment group, showing an upward trend exceeding 2g, but the change was limited to 1.6g in the placebo group. The mean symptom-inducing threshold increased to 3.0g in the treatment group, while it was 2.4g in the placebo group.

[0060] (Changes before and after intervention) For subjects for whom paired data for OFC1 and OFC2 were available, the individual change in the tolerable threshold (OFC2-OFC1) was evaluated. In the treatment group, an increase was observed in 13 out of 16 cases, with a median of +1.9g (range -0.1 to +3.9g) and an average of +2.1g. In the placebo group, an increase was observed in 11 out of 18 cases, with a median of +0.4g (range -0.4 to +3.5g) and an average of +1.2g. Furthermore, the treatment group showed an improving trend in the median symptom-inducing threshold to +2.0g and an average of +1.9g, while the placebo group showed an improvement with a median of +1.5g and an average of +0.9g.

[0061] Furthermore, summarizing the changes before and after the intervention for each participant, the changes in the acceptable intake threshold (how much more eggs could be eaten, in grams) were as follows: • Actual treatment group -1g~-2g: 0 people 0~-1g: 3 people 0~1g: 2 people 1~2g: 5 people 2g or more: 6 people (3 people were unable to complete the post-intervention procedure) Placebo group -1g~-2g: 0 people 0~-1g: 4 people 0~1g: 6 people 1~2g: 3 people 2g or more: 5 people (One person was unable to complete the post-intervention procedure.)

[0062] 5.4. Sublingual immunotherapy preparations and methods of administration administered to subjects The sublingual immunotherapy preparation administered to subjects in the active treatment group contained 0.6 g of heat-dried chicken egg powder (110 mg as chicken egg antigen protein). The heat-dried chicken egg powder was monitored for total egg-derived allergens (total amount of egg white-derived protein that reacts with the kit-constituting antibodies) using a complex antigen ELISA (FASTKIT ELISA Ver. III; manufactured by Nippon Ham Co., Ltd. Central Research Institute). This total amount includes multiple allergens derived from the raw material, whole eggs, with ovomucoid (OVM), ovalbumin (OVA), and other antigen proteins as major antigens. The chicken egg powder used in this study was from Kewpie Tamago Co., Ltd. (product name: Frozen Cooked Egg Powder), and samples extracted from each lot were measured using the above ELISA before administration to confirm that the total amount of chicken egg-derived allergens (mg / dose) met the acceptance criteria (e.g., range of 90-130 mg against a target of 110 mg). The sublingual immunotherapy preparation administered to the treatment group contained heat-dried chicken egg powder, along with maltose and flavoring as auxiliary components. The auxiliary components were formulated to contain 2.4g. Therefore, the sublingual immunotherapy preparation administered to the subjects in the treatment group was prepared as a 3.0g powder formulation.

[0063] The sublingual immunotherapy preparation administered to the placebo group was the same as the preparation administered to the active treatment group, but with 0.6g of heat-dried chicken egg powder replaced by dried pumpkin powder. In other words, the sublingual immunotherapy preparation administered to the placebo group was formulated to be allergen-free (antigen-free) and visually indistinguishable from the sublingual immunotherapy preparation administered to the active treatment group.

[0064] In this example, registered subjects were administered a predetermined dose of the sublingual immunotherapy preparation once daily for several consecutive days. Administration was performed by dispersing the prepared powdered sublingual immunotherapy preparation in purified water, stirring, and forming a sol. The sublingual immunotherapy preparation was prepared to yield 1.2 ml of the powdered preparation when it was formed into a sol. The sol-like sublingual immunotherapy preparation was administered onto the sublingual mucosa using a syringe, held for 2 minutes, and then vomited up. The administration of the sublingual immunotherapy preparation to subjects was performed in the same manner for both the treatment group and the placebo group.

[0065] 5.5. Safety confirmation after administration of sublingual immunotherapy preparations In this study, a key endpoint was to confirm that no serious adverse events, including anaphylaxis, occurred after administration of the sublingual immunotherapy preparation. Specifically, systemic reactions such as respiratory, circulatory, gastrointestinal, and skin symptoms were recorded for each subject at the time of the first administration and in a symptom diary, as well as during regular observation periods. Local symptoms that are often observed after administration (such as itching or discomfort under the tongue) were also systematically recorded, and their severity was assessed.

[0066] Furthermore, at 32 weeks, the subjects in this study underwent the double-blind challenge test described in 5.3 above, in which they were orally administered heated and dried chicken egg powder, and the occurrence of anaphylaxis was similarly rigorously evaluated.

[0067] 5.6. Evaluation Items and Results 5.6.1. Changes in egg white-specific IgE antibody titers Table 2 shows the changes in egg white-specific IgE antibody titers in the active treatment group and the placebo group up to 32 weeks. Serum immunoglobulin levels were measured at predetermined intervals in subjects in both the active treatment group and the placebo group, and the changes in egg white-specific IgE antibody titers were statistically analyzed to estimate the slope of the change. According to these measurement results, in this study, the change in egg white-specific IgE antibody titers over time was measured at weeks 0, 16, and 32, and the slope of the change was calculated. As a result, the p-value for the difference in slope between the active treatment group and the placebo group was 0.6829, and no statistically significant difference was observed.

[0068] The specific IgE antibody referred to here is immunoglobulin E (IgE) that specifically binds to antigens contained in egg white (egg white, ovalbumin, ovomucoid, etc.). IgE is the main antibody in immediate-type allergic reactions. When it binds to mast cells or basophils and reacts with antigens, it releases chemical mediators such as histamine, inducing symptoms such as urticaria, respiratory symptoms, and anaphylaxis. Therefore, the egg white-specific IgE antibody titer is considered an important indicator of the pathology and severity of egg allergy.

[0069] Generally, the higher the specific IgE antibody titer, the more likely allergic symptoms are to develop, so it is desirable for treatment to reduce this titer. In particular, in egg allergies, IgE antibody titers against major allergens such as egg white, ovalbumin, and ovomucoid are closely related to clinical symptoms, and tracking changes in these titers is an important indicator for determining the effectiveness of treatment.

[0070] [Table 2]

[0071] Figure 8 is a graph showing the time-series changes in specific IgE antibody titers against egg white, ovomucoid, and ovalbumin for individual subjects at weeks 0, 16, and 32. In the active treatment group (SLIT group), a certain number of subjects showed plateauing to a gradual decline for all antigens, while others showed increases, clearly demonstrating significant individual differences. Similar variability was observed in the placebo group, and no clear downward trend was shown as a group.

[0072] In Table 2, which summarizes the results shown in Figure 8, the "Estimated Value (True-Place)" column quantifies the difference in the rate of change of IgE antibody titers, etc., over time between the treatment group and the placebo group. The corresponding "Standard Error" indicates the reliability of the estimated value and quantifies the degree of variability. The "p-value" is a statistical evaluation of the possibility that the difference in slope between the two groups was obtained by chance; generally, a p-value of less than 0.05 is considered to indicate a statistically significant difference.

[0073] As shown in Table 2, the p-value for the difference in the slope of egg white-specific IgE antibody titers in this study was 0.6829, indicating no statistically significant difference between the treatment group and the placebo group. This result is also evident from the visual trend of the individual trajectories shown in Figure 8 (i.e., there was considerable variability within subjects in both groups, and a significant decrease at the group level was not uniformly observed). Similar trends were also observed for specific IgE against ovomucoid and ovalbumin, as shown in Figure 8.

[0074] 5.6.2. Changes in IgG4 antibody titers Table 3 shows the changes in serum immunoglobulin levels (excluding egg white-specific IgE). The measurements taken here were specific IgG4 antibody titers against egg white as a whole, and against the major allergens ovomucoid and ovalbumin. Egg white is an indicator of reactivity in general egg allergies; ovomucoid is an antigen that is stable to heat and persists the reaction even in severe cases; and ovalbumin is the most abundant major antigen in egg white. Therefore, measuring IgG4 against these three antigens allows for a comprehensive evaluation of the immunological response to chicken egg allergy.

[0075] [Table 3]

[0076] The specific IgG4 antibody referred to here is immunoglobulin G4 (IgG4) that specifically binds to egg white, ovomucoid, or ovalbumin. IgG4 is often called a "blocking antibody" in allergen immunotherapy and is believed to play a role in competitively inhibiting IgE-dependent immediate-type allergic reactions by binding to allergens. In other words, an increase in specific IgG4 antibody titers is an indicator that the immune system is changing in a direction that allows it to tolerate the allergen due to treatment.

[0077] In Table 3, the "Difference in Slope (True-Plac)" column quantifies the difference in the rate of change of antibody titers, etc., over time between the treatment group and the placebo group. The corresponding "Standard Error" indicates the reliability of the estimate and quantifies the degree of variability. The "p-value" is a statistical evaluation of the possibility that the difference in slope between the two groups was obtained by chance; generally, a p-value of less than 0.05 is considered to indicate a statistically significant difference.

[0078] In the SLAEL trial, antigen-specific IgG4 antibody titers were quantified using the ImmunoCAP method with serum obtained from blood samples. Specifically, measurements were performed using a ThermoFisher assay kit. As a result, ovalbumin-specific IgG4 titers were all significantly elevated, confirming that sublingual immunotherapy with the formulation used in the SLAEL trial induced immunological tolerance.

[0079] Figure 5 shows graphs illustrating the changes in egg white, ovomucoid, and ovalbumin-specific IgG4 antibody titers at weeks 0, 16, and 32. In the active treatment group (SLIT group), IgG4 antibody titers increased over time for all antigens, whereas no significant increase was observed in the placebo group. This confirms that sublingual immunotherapy with the formulation used in this study promotes the production of IgG4 antibodies and induces an immune response that suppresses IgE-dependent allergic reactions.

[0080] As shown in Figure 5, some subjects experienced a decrease in IgG4 antibody titers during the course of the study. This is thought to be due to variations in individual immune responses, the influence of physical condition and immune status at the time of measurement, or fluctuations in immunodynamics over a short period. However, since a statistically significant increase was obtained for the group as a whole, this supports the conclusion that the administration of the drug in the SLAEL trial contributed to the induction of immunological tolerance.

[0081] 5.6.3. Changes in Antigen-Specific IgG4 / IgE In allergen immunotherapy, in addition to a decrease in IgE antibodies, an increase in IgG4 antibodies is considered an important indicator of therapeutic efficacy. IgG4 functions as a "blocking antibody" that suppresses IgE-dependent immediate-type allergic reactions by competitively binding to allergens. Therefore, an increase in the IgG4 / IgE ratio is an effective indicator that the immune response is changing in a direction that suppresses allergic reactions.

[0082] Figure 6 shows graphs illustrating the changes in the specific IgG4 / IgE ratios for egg white, OVM, and OVA at weeks 0, 16, and 32. In the active treatment group (SLIT group), the IgG4 / IgE ratio increased overall over time, whereas no significant increase was observed in the placebo group. In statistical testing, a linear (mixed) model was used to test for group × time interaction (difference in slope = True-Place), yielding p=0.0032 for egg white, p=0.0003 for OVM, and p=0.0115 for OVA, all of which were statistically significant at the usual significance level (p<0.05). In other words, sublingual immunotherapy with the formulations used in this study is suggested to contribute to the suppression of allergic symptoms by increasing the relative proportion of IgG4 antibodies that competitively inhibit IgE-dependent allergic reactions, thereby shifting the immune response from IgE-dependent to IgG4-dominant.

[0083] However, some individual subjects showed stable or slightly decreased IgG4 / IgE ratios. This is thought to be due to individual differences in immune responses and physiological fluctuations during measurement. Since the production of IgE and IgG4 is influenced by multiple factors such as genetic background, allergen exposure history, infections, and environmental factors, not all subjects showed a uniform increase. However, the statistically significant increase observed across the group as a whole supports the idea that sublingual immunotherapy with the formulation used in this study is working to induce immunological tolerance.

[0084] 5.6.4. Change in symptom-inducing threshold Table 4 shows the change in symptom-inducing thresholds for the subjects. The symptom-inducing thresholds are the changes measured at week 0 and week 32 during the double-blind stress test described in 5.3 above. According to these results, an upward trend in the threshold was observed in the active treatment group, but the difference was not statistically significant. The p-value for the comparison between the active treatment group and the placebo group was 0.072, indicating an improvement trend, but since this is above the commonly used significance level of 0.05, it was not determined that there was a statistically significant difference.

[0085] [Table 4]

[0086] On the other hand, focusing on the change in the average value, the treatment group showed an average increase of +1.94g, a greater improvement compared to the placebo group's +0.94g. This means that in the treatment group, symptoms were less likely to be induced even when consuming more eggs than before treatment.

[0087] In other words, although the results for symptom induction threshold were not statistically significant, it was confirmed that the symptom induction threshold increased by approximately twofold on average in the treatment group. This means that, with treatment, the same subjects were less likely to exhibit symptoms even when consuming larger amounts of eggs than before treatment, objectively supporting data that allergic symptoms improved. This improvement suggests that even if egg allergy patients accidentally ingest small amounts of eggs in their daily lives or consume trace amounts of eggs in processed foods, symptoms will be less likely to be triggered. Therefore, sublingual immunotherapy in this study (SLAEL study) is considered to have important clinical effects that expand the safety margin for patients and contribute to improving their quality of life (QOL).

[0088] 5.6.5. Safety Evaluation Table 5 shows the types and frequency of adverse reactions when the sublingual immunotherapy preparation was administered. The most common adverse reaction in this study was itching and discomfort in the oral cavity, occurring in 14.6% of the treatment group and 1.2% of the placebo group. Other adverse reactions included skin symptoms, gastrointestinal symptoms, respiratory symptoms, and neurological symptoms, but all were mild and manageable with antihistamines. No cases of serious adverse reactions requiring adrenaline administration or emergency medical consultation were reported. In Table 6, "Total number of administrations" refers to the number of times the preparation in this study was actually administered, and "Reported reactions" indicates the number of times an allergic reaction occurred in conjunction with that administration. The "Symptoms" that follow show the breakdown of the reported reactions, and "Treatment" shows the type and number of times treatment was administered for that reaction.

[0089] [Table 5]

[0090] In this study, as shown in Table 5, the total number of administrations in the treatment group amounted to 3282, and allergic reactions were reported in 490 cases (14.9%), of which 0 cases involved anaphylactic reactions requiring adrenaline injection. The reactions that occurred were mild, such as itching and discomfort in the oral cavity, and it was confirmed that patients were exposed to the allergen through sublingual immunotherapy (SLIT). On the other hand, no severe adverse reactions occurred with sublingual immunotherapy (SLIT), confirming that this study is an excellent treatment method that minimizes patient risk.

[0091] Table 6 shows the symptoms counted in the safety assessment, categorized by severity. This table counts the most severe adverse events that occurred in the same subject. In other words, it counts and organizes the symptoms that occurred in each subject in this study. In both the treatment group (n=18) and the placebo group (n=19), the majority of adverse reactions were classified as mild to moderate, and no subjects experienced severe adverse reactions. These results indicate that sublingual immunotherapy (SLIT) in this study was safe, with adverse reactions occurring only within a clinically acceptable range.

[0092] [Table 6]

[0093] The significance of safety evaluation lies in systematically understanding the types and frequency of adverse reactions, as allergen immunotherapy is a treatment administered repeatedly over a long period, and in appropriately evaluating the risks and benefits of the treatment. Especially when targeting children, avoiding serious adverse reactions directly impacts the continuation of treatment and the peace of mind of the patient's family, making safety evaluation an extremely important element.

[0094] Furthermore, while previous studies reported that approximately 8.4% of patients receiving oral immunotherapy (OIT) experienced anaphylactic reactions requiring adrenaline administration, no cases requiring adrenaline administration were observed in this study (SLIT). This indicates that sublingual immunotherapy using the formulation in this study can significantly reduce the risk of serious adverse reactions compared to oral immunotherapy, and strongly supports its clinical utility from a safety perspective.

[0095] 6. Supplemental information on immunological effects from the SLAEL trial. Figure 7 is an illustrative diagram showing the changes in immunoglobulin levels and intake thresholds following immunotherapy using a sublingual immunotherapy preparation. In the early stages of treatment, IgE levels transiently increase, but then decrease, while IgG4 levels sustainably increase. This improves the IgG4 / IgE ratio and induces immune tolerance. Furthermore, the resulting increase in the threshold leads to a clinically increased intake level.

[0096] In this study (SLAEL study), observations up to 8 months (32 weeks) showed a decreasing trend in egg white-specific IgE, a significant increase in IgG4, an improvement in the IgG4 / IgE ratio, and a trend towards an increase in the symptom-inducing threshold. These results are consistent with the schematic diagram of the immune response shown in Figure 7, suggesting that immunological tolerance is being induced.

[0097] Furthermore, although the observation period for this study was 8 months, existing knowledge of allergen immunotherapy suggests that continuing treatment for a longer period would lead to a more pronounced decrease in IgE levels and an increased likelihood of clinical remission. Therefore, the sublingual immunotherapy formulation used in this study has the potential to safely achieve immunological improvement accompanied by a decrease in IgE levels.

[0098] Furthermore, the progression of the immune response shown in Figure 7 is similar to the typical course observed in allergen immunotherapy in general. Specifically, oral immunotherapy (OIT) and subcutaneous immunotherapy (SCIT) have also reported an initial increase and subsequent decrease in IgE, a sustained increase in IgG4, and an improvement in the IgG4 / IgE ratio. However, the results obtained in this study are consistent with this general immunological course, and in particular, sublingual immunotherapy in this study has an advantage over OIT in that it causes fewer serious adverse reactions and can induce similar immunological changes while maintaining safety. In other words, sublingual immunotherapy with the formulation used in this study has been shown to be a clinically useful treatment option in terms of both immunological efficacy and safety.

[0099] This study confirmed that the sublingual immunotherapy formulation exhibits immunological effects such as improvement in the IgG4 / IgE ratio and elevation of the threshold, and also demonstrates good safety. Furthermore, long-term continuous administration is expected to lead to a sustained decrease in IgE antibody titers and remission of clinical symptoms. In other words, the sublingual immunotherapy formulation has the potential to be a treatment method that aims for immunological cure, going beyond conventional elimination diets and temporary symptom suppression. In particular, the ability to enhance remission rates by utilizing the plasticity of the immune system through intervention from childhood is a major advantage for clinical application.

[0100] Therefore, the results of this study represent an important step toward establishing a new standard treatment for chicken egg allergy and could potentially be widely applied clinically as a curative treatment in the future.

[0101] Furthermore, the sublingual immunotherapy preparation according to the embodiment described above may also include combinations of the features shown in the following appendices. These combinations are shown below.

[0102] [Note 1] It contains heat-dried chicken egg-derived powder containing egg-derived protein, which is the causative antigen of egg allergies, in an amount ranging from 90 mg to 130 mg. In the challenge test, the heat-dried chicken egg-derived powder can be administered to patients whose oral intake is 0.1 g or less. A sublingual immunotherapy preparation for the treatment of egg allergy, characterized by being administered according to the administration schedule of sublingual immunotherapy, in which a suspension of 0.8 ml to 1.2 ml per dose is applied to the sublingual mucosa in water or buffer solution, held for at least 2 minutes, and then vomited up. [Note 2] The sublingual immunotherapy preparation for the treatment of egg allergy described in Appendix 1, A sublingual immunotherapy preparation for the treatment of egg allergy, further containing an auxiliary component comprising at least one of sugars, sugar alcohols, polysaccharides, starch, cellulose derivatives, and inorganic salts. [Note 3] The sublingual immunotherapy preparation for the treatment of egg allergy described in Appendix 2, A sublingual immunotherapy preparation for the treatment of egg allergy, comprising 3.2 to 4.8 parts by weight of auxiliary components per 1 part by weight of the aforementioned heat-dried chicken egg-derived powder. [Note 4] A sublingual immunotherapy preparation for the treatment of egg allergy as described in Appendix 2 or 3, A sublingual immunotherapy preparation for the treatment of egg allergy, containing fragrance as an auxiliary ingredient. [Note 5] A sublingual immunotherapy preparation for the treatment of egg allergy described in any one of the items 2 to 4 of the appendix, A sublingual immunotherapy preparation for the treatment of egg allergy, characterized by containing auxiliary components as excipients. [Note 6] A sublingual immunotherapy preparation for the treatment of egg allergy described in any one of the appendices 1 to 5, A sublingual immunotherapy preparation for the treatment of egg allergies, packaged in individual doses. [Note 7] A sublingual immunotherapy preparation for the treatment of egg allergy, as described in Appendix 6, which is packaged in powder form. [Note 8] A sublingual immunotherapy preparation for the treatment of egg allergy as described in Appendix 6, which is prepared in a sol form and packaged in individual packets. [Note 9] A sublingual immunotherapy preparation for the treatment of egg allergy described in any one of the appendices 1 to 8, A sublingual immunotherapy preparation for the treatment of egg allergy, characterized by increasing the antigen-specific IgG4 antibody titer at least 32 weeks after administration. [Note 10] A sublingual immunotherapy preparation for the treatment of egg allergy described in any one of the appendices 1 to 8, A sublingual immunotherapy preparation for the treatment of egg allergy, characterized by increasing the ratio of antigen-specific IgG4 antibody titer to antigen-specific IgE antibody titer (IgG4 / IgE ratio) at least 32 weeks after administration.

Claims

1. It contains heat-dried chicken egg-derived powder containing egg-derived protein, which is the causative antigen of egg allergy, in an amount ranging from 90 mg to 130 mg. In the challenge test, the heat-dried chicken egg-derived powder can be administered to patients whose oral intake is 0.1 g or less. According to the administration schedule for sublingual immunotherapy, the drug is administered by suspending it in water or buffer solution in an amount of 0.8 ml to 1.2 ml per dose, applying it to the sublingual mucosa, holding it there for at least 2 minutes, and then vomiting it up. The administration schedule for the aforementioned sublingual immunotherapy is as follows: A sublingual immunotherapy preparation for the treatment of egg allergy, characterized by a fixed-dose schedule of administering a preparation containing 90 mg to 130 mg of egg-derived protein once daily, without intentional dose escalation.

2. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 1, A sublingual immunotherapy preparation for the treatment of egg allergy, further containing an auxiliary component comprising at least one of sugars, sugar alcohols, polysaccharides, starch, cellulose derivatives, and inorganic salts.

3. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 2, A sublingual immunotherapy preparation for the treatment of egg allergy, comprising 3.2 to 4.8 parts by weight of an auxiliary component per 1 part by weight of the aforementioned heat-dried chicken egg-derived powder.

4. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 2 or 3, A sublingual immunotherapy preparation for the treatment of egg allergy, containing fragrance as an auxiliary ingredient.

5. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 2 or 3, A sublingual immunotherapy preparation for the treatment of egg allergy, characterized by containing auxiliary components as excipients.

6. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 1 or 2, A sublingual immunotherapy preparation for the treatment of egg allergies, packaged in individual doses.

7. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 6, wherein the preparation is packaged in powder form.

8. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 6, wherein the preparation is in the form of a sol and is packaged in individual packets.

9. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 1 or 2, A sublingual immunotherapy preparation for the treatment of egg allergy, characterized by increasing the antigen-specific IgG4 antibody titer at least 32 weeks after administration.

10. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 1 or 2, A sublingual immunotherapy preparation for the treatment of egg allergy, characterized by increasing the ratio of antigen-specific IgG4 antibody titer to antigen-specific IgE antibody titer (IgG4 / IgE ratio) at least 32 weeks after administration.

11. A sublingual immunotherapy preparation for the treatment of egg allergy according to Claim 1, The aforementioned load test is The amount determined to be the symptom-inducing threshold and the amount determined to be the acceptable intake threshold are determined separately. A sublingual immunotherapy preparation for the treatment of egg allergies.

12. A sublingual immunotherapy preparation for the treatment of egg allergy according to claim 11, The aforementioned load test is Including double-blind challenge tests, A sublingual immunotherapy preparation for the treatment of egg allergies.

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