A method for treating allergies and enhancing allergen-specific immunotherapy by administering IL-4R antagonists.

Abstract

This invention provides a method for enhancing the efficacy, safety, and / or tolerance of grass allergen-specific subcutaneous immunotherapy (SCIT) regimens in subjects with grass allergies. [Solution] A method is provided which includes administering a therapeutic composition containing an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or its antigen-binding fragment, to a subject in need.

Description

Technical Field

[0001] Cross - reference to Related Applications This application was filed on August 5, 2020, as a PCT international patent application, and claims the priority of U.S. Provisional Patent Application No. 62 / 882,992 filed on August 5, 2019 and European Patent Application No. 20315351.5 filed on July 16, 2020. The content of each of these documents is incorporated herein by reference.

[0002] The present disclosure relates to the use of interleukin - 4 receptor (IL - 4R) antagonists for treating or reducing the symptoms of allergy and for improving the efficacy and / or tolerance of allergen - specific immunotherapy regimens.

Background Art

[0003] Allergy and allergic diseases are serious medical conditions, the consequences of which range from responses that do not threaten life and resolve over time to life - threatening effects such as anaphylaxis. Allergic reactions can be caused by contact or exposure to various products such as certain foodstuffs, insect venoms, plants or plant - derived substances (such as pollen), chemicals, drugs / medications, and animal dander.

[0004] Subcutaneous immunotherapy (SCIT) is a disease-modifying treatment option for subjects with allergic rhinitis caused by airborne allergens (such as pollen, animal dander, or dust). SCIT is recommended when pharmacological therapies are not sufficient for symptom control. In SCIT, increasing doses of the inducing allergen are administered, followed by maintenance doses over several years. The goal is to induce immunological changes associated with symptom relief during therapy and sustained desensitization (immune tolerance) after completion of SCIT. SCIT can provide long-term protection from allergic diseases, but there is also a risk of adverse reactions, efficacy varies among subjects, and it may take at least 3 years to induce immune tolerance (Non-Patent Document 1; Non-Patent Document 2; and Non-Patent Document 3). Typically, patients receive increasing-dose allergen injections at weekly intervals for several weeks to several months under strictly monitored medical supervision at the start of SCIT. The gradual dose escalation allows tolerance to the therapy and reduces the risk of severe allergic reactions related to allergen administration. However, side effects ranging from mild reactions (such as swelling, injection-site reactions, de novo allergic responses, and urticaria formation) to life-threatening reactions (such as asthma exacerbation and anaphylaxis) occur in 40 - 50% of patients (Non-Patent Document 4). Therefore, there is an unmet need for more effective treatment of allergic diseases and improvement in the tolerance, safety, and / or efficacy of immunotherapy treatment strategies.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

[0006] This specification provides methods for enhancing the efficacy, tolerability, and / or safety of allergen-specific immunotherapy in patients with allergies. [Means for solving the problem]

[0007] In one embodiment, a method is provided for inhibiting the increase of allergen-specific IgE in a patient undergoing allergen-specific immunotherapy. In some embodiments, the method includes administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to the patient in combination with allergen-specific immunotherapy. In some embodiments, the method includes administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to the patient before or concurrently with allergen-specific immunotherapy. In some embodiments, at least one dose of an IL-4R antagonist is administered before the initiation of allergen-specific immunotherapy. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment that specifically binds to IL-4R.

[0008] In another embodiment, a method is provided for increasing the ratio of serum allergen-specific IgG4 to serum allergen-specific IgE in a patient undergoing allergen-specific immunotherapy. In some embodiments, the method includes administering one or more doses of an IL-4R antagonist to the patient in combination with allergen-specific immunotherapy. In some embodiments, the method includes administering one or more doses of an IL-4R antagonist to the patient before or concurrently with allergen-specific immunotherapy. In some embodiments, at least one dose of an IL-4R antagonist is administered before the initiation of allergen-specific immunotherapy. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment that specifically binds to IL-4R.

[0009] In another embodiment, a method is provided for facilitating the administration of maintenance doses (complete escalation) of allergen-specific immunotherapy in a patient. In some embodiments, the method includes the step of administering one or more doses of an IL-4R antagonist to the patient in combination with allergen-specific immunotherapy. In some embodiments, the method includes the step of administering one or more doses of an IL-4R antagonist to the patient before or concurrently with allergen-specific immunotherapy. In some embodiments, at least one dose of an IL-4R antagonist is administered before the initiation of allergen-specific immunotherapy. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment that specifically binds to IL-4R.

[0010] In another embodiment, methods are provided for reducing or eliminating the use of epinephrine and / or oral steroids to treat systemic reactions in patients undergoing allergen-specific immunotherapy. In some embodiments, the method includes administering one or more doses of an IL-4R antagonist to the patient in combination with allergen-specific immunotherapy. In some embodiments, the method includes administering one or more doses of an IL-4R antagonist to the patient before or concurrently with allergen-specific immunotherapy. In some embodiments, at least one dose of an IL-4R antagonist is administered before the initiation of allergen-specific immunotherapy. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment that specifically binds to IL-4R.

[0011] In another embodiment, a method is provided for enhancing the efficacy, tolerability, and / or safety of grass allergen-specific subcutaneous immunotherapy (SCIT) regimens in subjects with grass allergy. In some embodiments, the method includes administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to a target in combination with a SCIT regimen, wherein at least one dose of the IL-4R antagonist is administered before the initiation of the SCIT regimen. In some embodiments, the method includes administering one or more doses of an IL-4R antagonist to a target before or simultaneously with a SCIT regimen, wherein at least one dose of the IL-4R antagonist is administered before the initiation of the SCIT regimen.

[0012] In some embodiments, the SCIT regimen includes subcutaneous administration of a herb extract derived from a grass selected from the group consisting of Timothy grass, Bahia, Bermuda, Johnson's sorghum, Kentucky bluegrass, Orchard, Redtop, Rye, Sweet Vernal, Meadow Fescue, and combinations thereof. In some embodiments, the herb extract is derived from Timothy grass.

[0013] In some embodiments, the SCIT regimen includes a cluster SCIT regimen. In some embodiments, the cluster SCIT regimen includes an escalation regimen followed by a maintenance regimen, the escalation regimen comprising administering increasing doses of herb extract over a period of 4 to 12 weeks (e.g., over periods of 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, e.g., over periods of 4 to 10 weeks, 4 to 8 weeks, 6 to 12 weeks, 6 to 10 weeks, 6 to 8 weeks, 8 to 12 weeks, or 8 to 10 weeks), and the maintenance regimen comprising administering one or more maintenance doses of the highest doses of herb extract administered during the escalation regimen. In some embodiments, the escalation regimen comprises administering increasing doses of herb extract over a period of 8 weeks. In some embodiments, the maintenance regimen comprises administering maintenance doses every 1 to 4 weeks over a period of at least 8 weeks (e.g., over a period of at least 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, or longer). In some embodiments, the escalation regimen includes an escalation from a dose of 1 bioequivalent allergy unit (BAU) to a dose of at least about 4,000 BAUs (for example, over 4, 5, 6, 7, 8, 9, 10, 11, or more weeks), and the maintenance regimen includes administering one or more maintenance doses of at least about 4,000 BAUs.

[0014] In some embodiments, the IL-4R antagonist is administered in doses ranging from approximately 75 mg to approximately 600 mg (for example, doses of approximately 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg). In some embodiments, the IL-4R antagonist is administered in an initial dose, followed by one or more secondary doses, each secondary dose administered 1 to 4 weeks after the immediately preceding dose. In some embodiments, the initial dose of the IL-4R antagonist is administered 1 to 7 days before the initiation of the SCIT regimen. In some embodiments, the initial dose comprises 600 mg of the IL-4R antagonist, and each secondary dose comprises 300 mg of the IL-4R antagonist.

[0015] In some embodiments, the IL-4R antagonist and SCIT are not administered to the subjects on the same day.

[0016] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment that specifically binds to IL-4R. In some embodiments, the anti-IL-4R antagonist The antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1, and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab or its bioequivalent.

[0017] In some embodiments, enhancing the efficacy of the SCIT regimen includes reducing the symptoms of the target allergic rhinitis. In some embodiments, the reduction of allergic rhinitis symptoms is measured by the Total Nasal Symptom Score (TNSS) after nasal allergen loading with herbal extracts and includes an improvement in one or more scores of (i) congestion, (ii) itching, (iii) runny nose, or (iv) sneezing compared to the baseline score of the target. In some embodiments, enhancing the efficacy of the SCIT regimen includes reducing the area under the curve (AUC) of the TNSS over the first hour after the peak TNSS is achieved (0–1 hour post-peak TNSS) compared to the baseline AUC of the target.

[0018] In some embodiments, enhancing the efficacy of the SCIT regimen is (a) Compared to SCIT monotherapy, increase the amount of target serum grass allergen-specific IgG4 (sIgG4); (b) Compared to SCIT monotherapy, reducing the amount of target serum grass allergen-specific IgE (sIgE); and / or (c) Compared to SCIT monotherapy, increase the ratio of sIgG4 to sIgE in the subjects. Includes.

[0019] In some embodiments, IL-4R antagonist administration in combination with a SCIT regimen (e.g., prior to or concurrently) reduces or inhibits sIgE induction during the SCIT escalation regimen and / or SCIT maintenance regimen.

[0020] In some embodiments, enhancing the efficacy of the SCIT regimen includes reducing the symptoms of allergic conjunctivitis in the subject. In some embodiments, the reduction of allergic conjunctivitis symptoms is measured by the Total Ocular Symptom Score (TOSS) after nasal allergen loading with herbal extracts and includes improvement in one or more of the following scores compared to the subject's baseline score: (i) itching of the eyes, (ii) redness of the eyes, (iii) ocular tearing, and (iv) swelling / edema of the eyes.

[0021] In some embodiments, IL-4R antagonist administration in combination with a SCIT regimen (e.g., prior to or concurrently) increases the tolerability of the SCIT regimen. In some embodiments, IL-4R antagonist administration in combination with a SCIT regimen (e.g., prior to or concurrently) increases the maximum tolerable SCIT dose for the subject compared to SCIT alone. In some embodiments, IL-4R antagonist administration in combination with a SCIT regimen (e.g., prior to or concurrently) increases the number of tolerable SCIT doses or the duration of SCIT treatment (e.g., days) for the subject compared to SCIT alone.

[0022] In some embodiments, IL-4R antagonist administration in combination with the SCIT regimen (e.g., before or concurrently) reduces the need for rescue medication. In some embodiments, IL-4R antagonist administration in combination with the SCIT regimen (e.g., before or concurrently) reduces the need for epinephrine or oral steroids as rescue medication. Reduce.

[0023] In some embodiments, the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen-type delivery device, and an auto-injector. In some embodiments, the IL-4R antagonist is contained in a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose pre-filled syringe. In some embodiments, the IL-4R antagonist is contained in an auto-injector. In some embodiments, the IL-4R antagonist is contained in a pen-type delivery device.

[0024] Other embodiments will become apparent upon consideration of the detailed description below. [Modes for carrying out the invention]

[0025] Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, as such methods and conditions can vary. It should also be understood that the scope of the present invention is limited only by the appended claims, and that the terms used herein are merely for describing specific embodiments and are not intended to be limiting.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains.

[0027] As used herein, the term “about” means that, when used in reference to a particular numerical value, that value may vary by no more than 1% from the stated value. For example, as used herein, the expression “about 100” includes 99 and 101, as well as all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0028] As used herein, terms such as “to treat” or “to treat” mean to alleviate symptoms, to eliminate the cause of symptoms, whether temporary or permanent, or to prevent or delay the onset of symptoms of a specified disorder or condition.

[0029] When used in relation to an allergic reaction or allergic condition, terms such as “prevent” or “prevent” mean preventing the onset of an allergy, an allergic reaction, or an allergic condition. Also, as used herein, this term includes reducing or eliminating allergen sensitization in order to prevent an allergic reaction. In some embodiments, this term means that, upon administration of an IL-4R antagonist as provided by the methods of this disclosure, serum allergen-specific IgE levels are reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to baseline.

[0030] As used herein, the term “subject requiring it” means a human or non-human animal that (i) exhibits one or more symptoms or signs of allergy, (ii) has been diagnosed with an allergy to the allergen, and / or (iii) is at high risk of developing an allergy or allergic response to the allergen. In certain embodiments, this term includes subjects that exhibit allergen sensitization to one or more allergens (e.g., one or more grass allergens). In certain embodiments, the methods of the present disclosure can be used to treat subjects exhibiting elevated levels of one or more serum biomarkers, including, but not limited to, total IgE, allergen-specific IgE, thymic and activating modulated chemokines (TARCs), lung and activating modulated chemokines (PARCs), lactate dehydrogenase (LDH), and periostin. For example, in some embodiments, the method of the present disclosure includes the step of administering an IL-4R antagonist to a patient having elevated levels of allergen-specific IgE. The terms “subject” and “patient” are used synonymously herein.

[0031] As used herein, terms such as “allergic response,” “allergic reaction,” and “allergic symptoms” include one or more signs or symptoms selected from the group consisting of urticaria formation (e.g., hives), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinusitis, watery eyes, wheezing, bronchospasm, decreased maximum expiratory flow (PEF), gastrointestinal disturbances, flushing, lip swelling, tongue swelling, hypotension, anaphylaxis, and organ dysfunction / failure. Also, “allergic response,” “allergic reaction,” and “allergic symptoms” include immunological responses and reactions, such as increased IgE production and / or increased allergen-specific immunoglobulin production.

[0032] The term "allergen" refers to a substance, chemical, particle, or composition that can stimulate an allergic response in a susceptible individual. Allergens may be found in or derived from food products such as dairy products (e.g., milk), eggs, celery, sesame, wheat, soy, fish, shellfish, sugars (e.g., alpha-galactose, a sugar found in meat), peanuts, other legumes (e.g., beans, peas, soybeans, etc.), and tree nuts. Instead, allergens may be contained in or derived from non-food items such as dust (e.g., including house dust mites), pollen, insect toxins (e.g., toxins from bees, wasps, mosquitoes, fire ants, etc.), mold, animal fur, animal dander, wool, latex, metals (e.g., nickel), household cleaning agents, detergents, medicines, cosmetics (e.g., perfumes, etc.), drugs (e.g., penicillin, sulfonamides, salicylates, etc.), therapeutic monoclonal antibodies (e.g., cetuximab), ragweed, grass, and birch. In some embodiments, allergens are contained in or derived from grass. In some embodiments, allergens are contained in or derived from grass selected from the group consisting of timothy grass, bahia, Bermuda grass, sorghum, Kentucky bluegrass, orchard grass, rhubarb, rye, sweet vernal grass, broadleaf sedge, and combinations thereof. The terms “allergen” and “antigen” are used synonymously throughout this disclosure.

[0033] Any methods and materials similar to or equivalent to those described herein may be used in carrying out the present invention, but typical methods and materials are described herein. All publications referenced herein are incorporated herein in their entirety by reference.

[0034] Introduction This specification provides a method for enhancing the efficacy, tolerability, and / or safety of allergen-specific immunotherapy in patients with allergies, comprising the step of administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist before or concurrently with allergen-specific immunotherapy. As disclosed herein, administration of the IL-4R antagonist dupilumab as an adjuvant to immunotherapy has been found to improve immunotherapy tolerability, as measured by the percentage of patients who completed the immunotherapy regimen, the maximum tolerable dose of immunotherapy, and the number of patients who achieved complete escalation (maintenance dose) of immunotherapy. Furthermore, administration of the IL-4R antagonist resulted in a reduction in the use of epinephrine or oral steroids as rescue agents to treat systemic reactions in patients undergoing allergen-specific immunotherapy.

[0035] treatment method In one embodiment, a method is provided for enhancing the efficacy and / or tolerance of grass allergen-specific subcutaneous immunotherapy (SCIT) regimens. In some embodiments, the method involves grass allergen The procedure includes administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to a subject having ghee prior to or concurrently with a SCIT regimen.

[0036] As used herein, “subcutaneous immunotherapy” or “SCIT” refers to the repeated subcutaneous administration of an allergen to a subject over time as a means of treating or preventing allergies and allergic reactions, or as a means of reducing or eliminating allergic responses. Typically, SCIT involves subcutaneous administration of gradually increasing amounts of the allergen to a subject until a dose effective in inducing immune tolerance to the allergen is reached. In some embodiments, SCIT comprises an escalation regimen followed by a maintenance regimen. Generally, an escalation regimen involves administering increasing doses of the allergen over a period of time until an effective and safe dose is achieved, and a maintenance regimen involves administering one or more doses of the allergen at the highest dose administered during the escalation regimen.

[0037] The SCIT regimen may be a “conventional” SCIT regimen or an “accelerated” SCIT regimen. In some embodiments, the IL-4R antagonist is administered before or concurrently with the conventional SCIT regimen. Typically, in conventional SCIT, increasing doses of the allergen are administered to the patient at weekly intervals over a period of several weeks to several months (e.g., over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or longer) under tightly monitored medical supervision. In some embodiments, the IL-4R antagonist is administered before or concurrently with the accelerated SCIT regimen. Accelerated SCIT regimens accelerate the SCIT escalation schedule compared to conventional SCIT, and accelerated SCIT regimens include “rush SCIT” and “cluster SCIT.” Typically, in rush SCIT, increasing doses of the allergen are administered once daily over several consecutive days (e.g., over 2, 3, 4, 5, 6 days, or over a week) until the maximum tolerable dose is reached. In cluster SCIT, typically, several (e.g., two or three) increasing doses of allergens are administered on a single day, usually over four to eight weeks, over a discontinuous number of days until the maximum tolerable dose is reached. In some embodiments, the IL-4R antagonist is administered before or concurrently with the conventional SCIT regimen. In some embodiments, the IL-4R antagonist is administered before or concurrently with the cluster SCIT regimen. In some embodiments, the IL-4R antagonist is administered before or concurrently with the rush SCIT regimen.

[0038] In some embodiments, the SCIT regimen (e.g., conventional SCIT, rush SCIT, or cluster SCIT regimen) involves subcutaneous administration of a herb extract. In some embodiments, the herb extract is derived from a herb selected from the group consisting of timothy grass, bahia, Bermuda grass, sorghum, Kentucky bluegrass, orchard grass, rhubarb, rye, sweet vernal grass, broadleaf bellflower, and combinations thereof. In some embodiments, the herb extract includes timothy grass extract. Herb extracts are known in the art and are commercially available (e.g., Greer Laboratories, Inc., Renoir, North Carolina).

[0039] In some embodiments, the efficacy, tolerability, and / or safety of the SCIT regimen are “enhanced” if one or more of the following outcomes or phenomena are observed or achieved in the subject: (1) a reduction in the duration of the dose escalation phase without impairment of efficacy or safety; (2) a reduction in the duration of the maintenance phase without impairment of efficacy or safety; (3) a reduction in the number of doses of allergen administered during the dose escalation or maintenance phase without impairment of efficacy or safety; (4) a reduction in the frequency of allergens administered during the dose escalation or maintenance phase without impairment of efficacy or safety; (5) a reduction in the dose of allergens administered during the dose escalation or maintenance phase without impairment of efficacy or safety; (6) an allergic reaction caused by the SCIT regimen. (7) The frequency of allergic responses or adverse side effects is reduced or eliminated; (8) The use or need for conventional allergy agents (e.g., steroids, antihistamines, decongestants, anti-IgE agents, etc.) is reduced or eliminated during the dose-escalation and / or maintenance phases; (9) Total IgE expression levels are reduced; (10) Allergen-specific IgG4 expression levels are increased; (11) The frequency of anaphylactic reactions is reduced or eliminated; or (12) The need for rescue agents (e.g., epinephrine or oral steroids) is reduced or eliminated. In some embodiments, the efficacy of the SCIT regimen is "enhanced" if the subject experiences fewer and / or less severe allergic reactions after SCIT therapy in combination with IL-4R blockade than with SCIT therapy alone. In some embodiments, the efficacy of the SCIT regimen is "enhanced" if the maximum tolerable SCIT dose for the subject increases when an IL-4R antagonist is administered compared to SCIT therapy alone. In some embodiments, the efficacy of the SCIT regimen is "enhanced" when the administration of an IL-4R antagonist reduces the need for rescue medications (e.g., epinephrine or oral steroids) to treat systemic reactions compared to SCIT therapy alone.

[0040] In another embodiment, a method is provided for treating, preventing, or reducing the severity of allergic reactions or allergic symptoms in subjects with grass allergies by administering an IL-4R antagonist. In some embodiments, the IL-4R antagonist is administered before or concurrently with a subcutaneous immunotherapy regimen (e.g., cluster SCIT).

[0041] In some embodiments, treatment with an IL-4R antagonist concurrently with the SCIT regimen reduces the symptoms of the target allergic rhinitis. In some embodiments, the treatment reduces induced allergic rhinitis symptoms after nasal allergen loading (NAC) with an allergen (e.g., herb extract). As used herein, “reducing allergic rhinitis symptoms” includes, but is not limited to, reducing the severity or duration of one or more symptoms of the target allergic rhinitis, such as sneezing, itching (of the nose, eyes, ears, or palate), runny nose, postnasal drip, congestion, anosmia, headache, earache, lacrimation, red eyes, eye swelling, and fatigue. In some embodiments, induced allergic rhinitis symptoms after NAC are measured in the “early stage” (within the first 60 minutes after NAC) and / or “late stage” (about 6 hours after NAC). In some embodiments, treatment with an IL-4R antagonist reduces early-stage induced allergic rhinitis symptoms after NAC. In some embodiments, treatment with an IL-4R antagonist reduces late-stage induced allergic rhinitis symptoms after NAC.

[0042] In some embodiments, the reduction of allergic rhinitis symptoms is measured by the Total Nasal Symptom Score (TNSS). The TNSS is a patient-reported composite symptom assessment of congestion, itching, runny nose, and sneezing, in which the patient-reported symptom score at a given time point is assigned to each category using a 4-point scale (0-3), where 0 indicates no symptoms, a score of 1 indicates mild symptoms that are easily tolerable, a score of 2 indicates bothersome but tolerable symptoms, and a score of 3 indicates severe symptoms that are difficult to tolerate and interfere with daily life. The TNSS is calculated on a maximum of 12 points by adding up the scores for each symptom. In some embodiments, the TNSS score is measured after NAC with the allergen. In some embodiments, the baseline TNSS score of the subject is measured (e.g., during a pre-treatment screening visit).

[0043] In some embodiments, the enhanced efficacy and / or safety of the SCIT regimen and / or reduction of allergic rhinitis symptoms are measured by determining the area under the curve (AUC) of TNSS over the first hour after peak TNSS is achieved following nasal allergen loading ("0-1 hour post-peak TNSS").

[0044] In some embodiments, treatment with an IL-4R antagonist concurrently with the SCIT regimen is performed. This reduces the symptoms of the target allergic conjunctivitis (e.g., reducing allergic rhinitis conjunctivitis after NAC with an allergen (e.g., herb extract)). As used herein, “reducing allergic conjunctivitis symptoms” includes, but is not limited to, reducing or eliminating the severity or duration of one or more symptoms of the target allergic conjunctivitis, such as itching, redness, tearing, or swelling of the eye. In some embodiments, the reduction of allergic conjunctivitis symptoms is measured by the Total Ocular Symptom Score (TOSS). TOSS is a patient-reported composite symptom assessment of itching, redness, tearing or watery eyes, and swelling or puffiness of the eye, in which a patient-reported symptom score is assigned to each category at a given time using a 4-point scale (0-3), where 3 is the most severe symptom. TOSS is calculated by adding up the scores for each symptom to a maximum of 12 points. In some embodiments, the TOSS score is measured after NAC with an allergen. In some embodiments, the baseline TOSS score of the subject is measured (for example, during a pre-treatment screening visit).

[0045] In some embodiments, the enhancement of efficacy and / or safety of the SCIT regimen and / or reduction of allergic rhinitis symptoms is measured by determining the area under the curve (AUC) of TOSS over the first hour after the peak total nasal symptom score (TNSS) is achieved following nasal allergen loading. In some embodiments, the method of the present disclosure reduces the AUC of TOSS over the first hour of loading by at least 10%, 20%, 30%, 40%, 50%, or more compared to the baseline AUC of TOSS after the NAC in question.

[0046] In some embodiments, treatment with an IL-4R antagonist concurrently with the SCIT regimen improves the efficacy and / or safety of the SCIT regimen and / or reduces allergic rhinitis symptoms, as measured by improvements in one or more biomarkers, such as biomarkers related to type 2 immunoactivity and / or allergen-specific biomarkers. In some embodiments, the biomarkers are serum biomarkers. In some embodiments, the biomarkers are total IgE, allergen-specific IgG4, or thymic and activating modulated chemokines (TARCs).

[0047] In some embodiments, the biomarker is a biomarker of type 2 immunoactivity, such as serum TARC or serum total IgE, but is not limited to these. In some embodiments, the biomarker is an allergen-specific biomarker, such as a grass-specific biomarker, such as grass-specific IgE (e.g., serum timothy grass sIgE) or grass-specific IgG4 (e.g., serum timothy grass sIgG4), but is not limited to these. In some embodiments, the method of the present disclosure reduces the level of type 2 biomarkers or inhibits the induction of type 2 biomarkers by SCIT. In some embodiments, administration of an IL-4R antagonist reduces or inhibits the increase in sIgE induced during SCIT (e.g., during the SCIT escalation phase and / or maintenance phase).

[0048] In some embodiments, the biomarker is grass-specific IgG4 (e.g., serum timothy grass sIgG4). While not bound by any particular theory, it is hypothesized that the induction of allergen-specific antibodies, particularly IgG4 isotypes, has a protective effect against IgE-mediated allergic symptoms because IgG4 competes with IgE, blocks IgE-mediated effector cell activation, suppresses histamine release, and inhibits antigen presentation of IgE-allergen complexes by dendritic cells and B cells. In some embodiments, the method of this disclosure increases the level of an allergen-specific biomarker (e.g., serum grass allergen-specific IgG4) compared to a baseline or control level.

[0049] In some embodiments, total IgE biomarkers and allergen-specific IgG4 biomarkers are used. Both markers are measured, and the ratio of the allergen-specific IgG4 marker to the total IgE marker (e.g., the ratio of grass allergen-specific IgE or IgG4 to total IgE) is calculated. In some embodiments, treatment with an IL-4R antagonist concurrently with the SCIT regimen increases the ratio of allergen-specific IgG4 to total IgE in a sample derived from the subject, for example, compared to the baseline value of the subject or to a control value (e.g., of a subject treated with SCIT alone). In some embodiments, the method of the present disclosure increases the ratio of allergen-specific IgG4 to total IgE compared to the baseline value of the subject or to a control value.

[0050] As those skilled in the art will understand, an increase or decrease in serum biomarkers can be determined by (i) comparing the level of the biomarker measured in the subject at a specified time after administration of the IL-4R antagonist with (ii) the level of the biomarker measured in the patient before the initiation of treatment with the IL-4R antagonist (i.e., the "baseline measurement"). The specified time points at which the biomarker is measured may be, for example, approximately 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, 35 days, 40 days, 50 days, 55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, 100 days, 150 days after the initiation of treatment with the IL-4R antagonist, or later.

[0051] Methods for detecting and / or quantifying serum biomarkers such as allergen-specific IgE, total IgE, or TARC are known in the art. Kits for measuring such biomarkers are available from various commercial suppliers, and similarly, various commercial diagnostic testing companies offer services that provide the measurement of such biomarkers.

[0052] For example, Phadiatop® is a commercially available version of a serum-specific or antigen-specific IgE assay test introduced for screening allergy sensitization (Merrett et al., 1987, Allergy Vol. 17: pp. 409-416). This test provides simultaneous testing of serum-specific IgE against a mixture of related allergens that cause common inhalation allergies. The test yields either a positive or negative qualitative result depending on the fluorescence response obtained. A positive result is indicated when a patient sample shows a fluorescence response higher than or equal to the reference. A patient sample with a lower fluorescence response indicates a negative result.

[0053] As another example, an exemplary assay system for measuring levels of the biomarker TARC is the TARC Quantitative ELISA Kit, available from R&D Systems, Minneapolis, Minnesota, under catalog number DDN00.

[0054] Treatment group The methods disclosed herein include the step of administering an IL-4R antagonist or a pharmaceutical composition comprising an IL-4R antagonist to a subject requiring such treatment. In some embodiments, the subject requiring treatment by the methods disclosed herein is a subject who exhibits one or more symptoms or signs of grass allergy (e.g., allergy to one or more of timothy grass, bahia, Bermuda grass, sorghum, Kentucky bluegrass, orchard grass, sedge, rye, sweet vernal grass, or broadleaf vine), has been diagnosed with an allergy to grass allergens, and / or is at high risk of developing a grass allergy or an allergic response to grass allergens. In some embodiments, the subject is an adult.

[0055] In some embodiments, the subject being treated meets one or more of the following criteria: (a) Grass allergy is confirmed by a positive skin prick test (SPT) with a grass (e.g., timothy grass) extract (e.g., mean wheal diameter is at least ≥5 mm larger than that of the negative control); (b) Grass allergy is confirmed by a positive serum grass allergen (e.g., timothy grass)-specific IgE test (e.g., ≥0.35 KU / L); and (c) NAC is positive with a grass (e.g., timothy grass) extract and the peak TNSS score is ≥7 out of 12.

[0056] Interleukin-4 receptor antagonist In some embodiments, the methods of the present disclosure include administering an interleukin-4 receptor (IL-4R) antagonist or a pharmaceutical composition comprising an IL-4R antagonist to a subject in need thereof (e.g., a subject with a grass allergy). As used herein, an "IL-4R antagonist" (also referred herein as an "IL-4R inhibitor," "IL-4R blocker," or "IL-4Rα antagonist") is any agonist that binds to or interacts with IL-4Rα or an IL-4R ligand to inhibit or attenuate the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. The type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and a γc chain. The type 2 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptors interact with and are stimulated by IL-4, while type 2 IL-4 receptors interact with and are stimulated by both IL-4 and IL-13. Therefore, IL-4R antagonists that can be used in the methods of this disclosure can function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4-mediated and IL-13-mediated signaling. Thus, IL-4R antagonists of this disclosure can prevent interaction between IL-4 and / or IL-13 and type 1 or type 2 receptors.

[0057] Non-limiting examples of the IL-4R antagonist category include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor-bodies" (e.g., genetically modified molecules containing ligand-binding domains of IL-4R components), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R antagonists may also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0058] Anti-IL-4Rα antibodies and antigen-binding fragments thereof In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. As used herein, the term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains interconnected by disulfide bonds, two heavy (H) chains and two light (L) chains, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H and a heavy chain constant region. The heavy chain constant region comprises three domains, C H 1, C H 2, and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L and a light chain constant region. The light chain constant region comprises one domain (C L 1). The V H and V L regions can be further subdivided into hypervariable regions named complementarity determining regions (CDRs) interspersed among more conserved regions named framework regions (FRs). Each V H and V L consists of three CDRs and four FRs arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4, from the amino terminus towards the carboxy terminus. In some embodiments, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences. In some embodiments, one or more of the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) are modified, either naturally or artificially.

[0059] Furthermore, the term “antibody,” as used herein, includes the antigen-binding fragment of a full-length antibody molecule. Terms such as “antigen-binding moiety” and “antigen-binding fragment” of an antibody, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from full-length antibody molecules using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques, including manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated, for example, by chemical or molecular biological techniques, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine ​​residues, or modify, add, or delete amino acids.

[0060] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv(scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as the CDR3 peptide), or restrictive FR3-CDR3-FR4 peptides. Domain-specific antibodies, single-domain antibodies, domain deletion antibodies, chimeric antibodies, CDR-transplant antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other genetically modified molecules such as shark variable IgNAR domains are also included in the term “antigen-binding fragment” as used herein.

[0061] The antigen-binding fragment of an antibody will typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and generally contains at least one CDR adjacent to or in-frame one or more framework sequences. H Domain is V L In antigen-binding fragments associated with the domain, V H and V L The domains may be located relative to one another in any preferred arrangement. For example, the variable region may be a dimer, V H -V H , V H -V L , or V L -V L It may contain dimers. Alternatively, the antigen-binding fragment of the antibody may be monomer V. H or V L It may include a domain name.

[0062] In certain embodiments, the antigen-binding fragment of the antibody may include at least one variable domain covalently linked to at least one constant domain. Non-limiting and exemplary configurations of variable and constant domains that can be found within the antigen-binding fragment of the antibody of this disclosure include: (i)V H -C H 1;(ii)V H -C H 2; (iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)V L -CH 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv)V L -C L In any configuration of variable and steady domains, including any of the exemplary configurations listed above, the variable and steady domains may be directly linked to each other or linked by a complete or partial hinge or linker region. The hinge region is a single polypeptide The molecule may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that result in flexible or semi-flexible linkages between adjacent variable domains and / or constant domains within the molecule. Furthermore, the antigen-binding fragments of the antibodies of this disclosure may be linked to each other and / or one or more monomers V H Or V L The domain may include a homodimer or heterodimer (or other polymer) of any of the variable and constant domain configurations listed above, which is non-covalently associated with the domain (e.g., by a disulfide bond).

[0063] The constant region of an antibody is crucial for its ability to immobilize complement and mediate cell-dependent cytotoxicity. Therefore, in some embodiments, the antibody isotype can be selected based on whether or not it is desirable for the antibody to mediate cytotoxicity.

[0064] Furthermore, the term “antibody,” as used herein, includes multispecific (e.g., bispecific) antibodies. A multispecific antibody or antigen-binding fragment of an antibody typically comprises at least two distinct variable domains, each variable domain capable of specifically binding to a different antigen or a different epitope of the same antigen. Any multispecific antibody format can be configured for use in the context of the antibodies or antigen-binding fragments of antibodies of this disclosure using routine techniques available in the art. For example, in some embodiments, the methods of this disclosure involve the use of a bispecific antibody in which one arm of immunoglobulin is specific to IL-4Rα or a fragment thereof, and the other arm of immunoglobulin is specific to a second therapeutic target or conjugated to a therapeutic portion. Exemplary bispecificity formats that can be used in the context of this disclosure include, but are not limited to, scFv-based or diabody bispecificity formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadromas, knobs-into-holes, common light chains (e.g., light chains common with knobs-into-holes), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1 / IgG2, dual-acting Fab(DAF)-IgG, and Mab 2 One example is the bispecific format (for a review of the above format, see, for example, Klein et al., 2012, mAbs Vol. 4: No. 6, pp. 1-11, and the references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugations. For example, site-specific antibody-oligonucleotide conjugates are generated using non-natural amino acids with orthogonal chemical reactivity. These conjugates then self-assemble to form a multimeric complex with a specified composition, valency, and shape. (See, for example, Kazane et al., J.Am.Chem.Soc. [Epub: December 4, 2012]).

[0065] In some embodiments, the antibodies used in the methods of the present disclosure are human antibodies. The term “human antibody,” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of the present disclosure may include, for example, amino acid residues in the CDR, particularly in CDR3, that are not encoded by the human germline immunoglobulin sequence (e.g., mutations introduced by random mutagenesis or site-directed mutagenesis in vitro or somatic mutagenesis in vivo). However, the term “human antibody,” as used herein, is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, has been transplanted into a human framework sequence.

[0066] The antibodies used in the methods of this disclosure may be recombinant human antibodies. The term "recombinant human antibody," as used herein, includes antibodies expressed using a recombinant expression vector (further described below) transfected into host cells, antibodies isolated from a recombinant combinatorial human antibody library (further described below), and This document is intended to include all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies isolated from animals (e.g., mice) into which human immunoglobulin genes have been transfected (see, e.g., Taylor et al., (1992) Nucl. Acids Res. Vol. 20: pp. 6287-6295), or antibodies prepared, expressed, produced, or isolated by any other means including splicing human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if animals into which human Ig sequences have been transfected, in vivo somatic mutagenesis), and therefore the V of the recombinant antibody H Region and V LThe amino acid sequence of the region is human germline V H Array and V L Although it is derived from and related to the sequence, it is a sequence that cannot naturally exist within the human germline repertoire in vivo.

[0067] "Isolated antibodies" refer to antibodies that have been identified, separated, and / or recovered from at least one component of their natural environment. For example, antibodies that have been separated or extracted from at least one component of an organism, or from tissues or cells in which antibodies are naturally present or naturally produced, are "isolated antibodies." Isolated antibodies also include in situ antibodies within recombinant cells. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. According to certain embodiments, isolated antibodies may not substantially contain other cellular material and / or chemical substances.

[0068] According to certain embodiments, the antibody used in the method of this disclosure specifically binds to IL-4Rα. The term "specifically binds," as used herein, means that the antibody or its antigen-binding fragment forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art, and include, for example, equilibrium dialysis and surface plasmon resonance. In some embodiments, antibodies that "specifically bind" to IL-4Rα are measured by surface plasmon resonance assay (e.g., Biacore®, GE Healthcare, Piscataway, New Jersey, Biacore Life Sciences Division) with equilibrium dissociation constants (K) of less than approximately 1000 nM, less than approximately 500 nM, less than approximately 300 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 90 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, less than approximately 50 nM, less than approximately 40 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 1 nM, less than approximately 0.5 nM, less than approximately 0.25 nM, less than approximately 0.1 nM, or less than approximately 0.05 nM. D) binds to IL-4Rα or a portion thereof. In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) may also specifically bind to another antigen, such as an ortholog of the target antigen. For example, in some embodiments, an isolated antibody that specifically binds to human IL-4Rα may cross-react to other antigens, such as IL-4Rα molecules from other (non-human) species.

[0069] In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) containing any of the amino acid sequences of the anti-IL-4R antibody as described in U.S. Patent No. 7,608,693. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment comprising a heavy chain complementarity-determining region (HCDR) of the heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of the light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LDCRs (LCDR1, LDCR2, and LDCR3). HCDR1 contains the amino acid sequence of SEQ ID NO: 3; HCDR2 contains the amino acid sequence of SEQ ID NO: 4; HCDR3 contains the amino acid sequence of SEQ ID NO: 5; LCDR1 contains the amino acid sequence of SEQ ID NO: 6; LCDR2 contains the amino acid sequence of SEQ ID NO: 7; and LCDR3 contains the amino acid sequence of SEQ ID NO: 8.

[0070] In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LDCR1, LDCR2, and LDCR3 of SEQ ID NOs. 3, 4, 5, 6, 7, and 8, respectively, and further comprises an HCVR having at least 85% sequence identity with the amino acid sequence of SEQ ID NO. 1 (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity), and an LCVR having at least 85% sequence identity with the amino acid sequence of SEQ ID NO. 2 (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity). In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises an HCVR containing SEQ ID NO. 1 and an LCVR containing SEQ ID NO. 2.

[0071] In some embodiments, the anti-IL-4R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 10.

[0072] An exemplary antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10 is a fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present disclosure involve the use of dupilumab or its bioequivalent. The term “bioequivalent,” as used herein in relation to dupilumab, refers to an anti-IL-4R antibody or IL-4R-binding protein or fragment thereof that does not show a significant difference in the rate and / or degree of absorption compared to that of dupilumab when administered at the same molar dose under similar experimental conditions, whether single or multiple doses. In some embodiments, the term refers to an antigen-binding protein that binds to IL-4R and does not show a clinically meaningful difference in their safety, purity, and / or potency compared to dupilumab.

[0073] Other anti-IL-4Rα antibodies that can be used in the context of the methods of this disclosure include, for example, the antibody known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., vol. 181 (no. 8): pp. 788-796) or MEDI9314, or any of the anti-IL-4Rα antibodies described in U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, or U.S. Patent No. 8,877,189.

[0074] In some embodiments, the anti-IL-4Rα antibody used in the methods disclosed herein may have pH-dependent binding characteristics. For example, the anti-IL-4Rα antibody for use as disclosed herein may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, the anti-IL-4Rα antibody for use as disclosed herein may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The term “acidic pH” includes pH values ​​less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or lower. As used herein, the term “neutral pH” means a pH of about 7.0 to about 7.4. The term "neutral pH" refers to pH values ​​of approximately 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4. include.

[0075] In certain cases, "binding to IL-4Rα is reduced at acidic pH compared to neutral pH" refers to the K of antibodies that bind to IL-4Rα at acidic pH. D The value of the antibody K that binds to IL-4Rα at neutral pH. DIt is expressed as a ratio to (or vice versa) a value. For example, an antibody or its antigen-binding fragment has an acidic / neutral K of approximately 3.0 or greater. D When a ratio is observed, the antibody or its antigen-binding fragment can be considered to exhibit "reduced binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K of the antibody or antigen-binding fragment of this disclosure D The ratio may be approximately 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or greater.

[0076] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening a population of antibodies for which binding to a specific antigen is reduced (or enhanced) at acidic pH compared to neutral pH. In addition, antibodies with pH-dependent characteristics can be produced by modifying the antigen-binding domain at the amino acid level. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues, an antibody can be obtained in which antigen-binding is reduced at acidic pH compared to neutral pH.

[0077] Preparation of human antibodies Methods for generating human antibodies in transgenic mice are known in the art. In the circumstances of this disclosure, human antibodies that specifically bind to human IL-4R can be produced using such known methods.

[0078] First, a high-affinity chimeric antibody against IL-4R having a human variable region and a mouse constant region is isolated using VELOCIMMUNE® technology (see, for example, U.S. Patent No. 6,596,541, Regeneron Pharmaceuticals, Inc.) or any other known method for generating monoclonal antibodies. VELOCIMMUNE® technology involves generating a transgenic mouse having a genome containing human heavy and light chain variable regions, operably ligated to an endogenous mouse constant region locus, so that the mouse produces an antibody containing the human variable region and the mouse constant region in response to antigen stimulation. The DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably ligated to the DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing a fully human antibody.

[0079] Generally, VELOCIMMUNE® mice are loaded with the target antigen, and lymphocytes (such as B cells) are collected from mice that express antibodies. These lymphocytes are fused with myeloma cell lines to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the target antigen. DNA encoding the variable regions of the heavy and light chains may be isolated and ligated to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells such as CHO cells. Alternatively, antigen-specific chimeric antibodies or DNA encoding the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes.

[0080] First, we isolate high-affinity chimeric antibodies that possess both a human variable region and a mouse constant region. Antibodies are characterized and selected for desirable features, including affinity, selectivity, and epitopes, using standard procedures known to the manufacturer. The mouse constant region is replaced with a desired human constant region to generate the fully human antibodies of this disclosure, e.g., wild-type or modified IgG1 or IgG4. The selected constant region may vary depending on the specific use, but high affinity antigen-binding features and target specificity features reside in the variable region.

[0081] Generally, antibodies that can be used in the methods of this disclosure exhibit the high affinity described above when measured for binding to antigens, whether immobilized on a solid phase or in a liquid phase. A fully human antibody of this disclosure is generated by replacing the mouse constant region with a desired human constant region. The selected constant region may vary depending on the specific use, but the high affinity antigen-binding and target-specific characteristics reside in the variable region.

[0082] In one embodiment, a human antibody or its antigen-binding fragment that specifically binds to IL-4R and can be used in the manner disclosed herein comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1, and three light chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the designated HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia methods. For example, Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Maryland (1991); Al-Lazikani et al., J.Mol.Biol.273:927-948 (1997); and Martin et al., Proc.Natl.Acad.Sci.USA Please refer to Volume 86: pp. 9268-9272 (1989). Public databases for identifying CDR sequences within antibodies are also available.

[0083] Pharmaceutical composition In one embodiment, the present disclosure provides a method comprising the step of administering an IL-4R antagonist to a target, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained within a pharmaceutical composition comprising one or more pharmaceutically acceptable vehicles, carriers, and / or excipients. Various pharmaceutically acceptable carriers and excipients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.

[0084] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, for example, by infusion or bolus injection, by absorption via the epithelium or mucocutaneous lining (e.g., oral mucosa, rectal and intestinal mucosa), and can be administered together with other biological activators. In some embodiments, the pharmaceutical composition as disclosed herein is administered intravenously. In some embodiments, the pharmaceutical composition as disclosed herein is administered subcutaneously.

[0085] In some embodiments, the pharmaceutical composition is administered by intravenous, subcutaneous, intradermal, and intramuscular injection, or by drip infusion. This includes injectable preparations such as dosage forms for injection. Such injectable preparations can be prepared by known methods. For example, an injectable preparation can be prepared by dissolving, suspending, or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injection. Examples of aqueous media for injection include physiological saline, isotonic solutions containing glucose and other adjuvants, which can be used in combination with appropriate solubilizers such as alcohol (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. Examples of oily media include sesame oil and soybean oil, which can be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. The injectable preparations thus prepared can be filled into appropriate ampoules.

[0086] The dose of antibody administered to a subject according to the method of this disclosure may vary depending on the subject's age and size, symptoms, condition, and route of administration. The dose is typically calculated based on body weight or body surface area. The frequency and duration of treatment can be adjusted according to the severity of the condition. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be determined empirically. For example, the progression of the subject can be monitored by periodic assessments, and the dose can be adjusted accordingly. Furthermore, interspecies scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. Vol. 8: p. 1351). Specific exemplary doses of anti-IL-4R antibodies and administration regimens containing them that can be used in the context of this disclosure are disclosed elsewhere herein.

[0087] In some embodiments, the pharmaceutical composition of this disclosure is contained in a container. In other embodiments, a container containing the pharmaceutical composition as disclosed herein is provided. For example, in some embodiments, the pharmaceutical composition is contained in a container selected from the group consisting of glass vials, syringes, pen-type delivery devices, and auto-injectors.

[0088] In some embodiments, the pharmaceutical compositions of the Disclosure are delivered subcutaneously or intravenously, for example, using a standard needle and syringe. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, the pharmaceutical compositions of the Disclosure are delivered using a pen-type delivery device or an auto-injector (for example, in the case of subcutaneous delivery). The pen-type delivery device may be reusable or disposable. Typically, a reusable pen-type delivery device uses a replaceable cartridge containing the pharmaceutical composition. Once the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen-type delivery device can then be reused. Disposable pen-type delivery devices do not have replaceable cartridges. Rather, disposable pen-type delivery devices are provided pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir of pharmaceutical composition is empty, the entire device is discarded.

[0089] Examples of suitable pen-type delivery devices and auto-injector delivery devices include, but are not limited to, AUTOPEN® (Owen Mumford, Inc., Woodstock, UK), DISETRONIC® pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25® pen, HUMALOG® pen, HUMALIN 70 / 30® pen (Eli Lilly and Co., Indianapolis, Indiana), NOVOPEN® I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR® (No Examples include Nordisk (Copenhagen, Denmark), BD Pen (Becton Dickinson, Franklin Lakes, New Jersey), OPTIPEN (trademark), OPTIPEN PRO (trademark), OPTIPEN STARLET (trademark), and OPTICLIK (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen-type delivery devices that have applications for subcutaneous delivery of the pharmaceutical compositions of this disclosure include, but are not limited to, SOLOSTAR® pen (sanofi-aventis), FLEXPEN® (Novo Nordisk), and KWIKPEN® (Eli Lilly), SURECLICK® auto-injector (Amgen, Thousand Oaks, California), PENLET® (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA® pen (Abbott Labs, Abbott Park, Illinois).

[0090] In some embodiments, the pharmaceutical composition is delivered using a controlled-release system. In one embodiment, a pump may be used (Langer, ibid.; Sefton, 1987, CRC). (See Crit.Ref.Biomed.Eng. Vol. 14: p. 201). In another embodiment, polymer materials may be used: Medical Applications of See Controlled Release, Langer and Wise (eds.), 1974, CRC Press, Boca Raton, Florida. In yet another embodiment, the controlled-release system can be positioned near the target of the composition and therefore require only a fraction of the systemic dose (see, e.g., Goodson, 1984, Medical Applications of Controlled Release, ibid., Vol. 2, pp. 115-138). Other controlled-release systems are discussed in the review by Langer, 1990, Science Vol. 249: pp. 1527-1533. Other delivery systems, e.g., liposomes, microparticles, microcapsule encapsulation, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis are known and can be used to deliver pharmaceutical compositions (see, e.g., Wu et al., 1987, J. Biol. Chem. Vol. 262: pp. 4429-4432).

[0091] In some embodiments, the pharmaceutical composition is supplied in a container as disclosed herein (e.g., a glass vial, syringe, pen-type delivery device, or autoinjector) in a volume of about 0.5 mL to about 2.5 mL, for example, about 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.15 mL, 1.2 mL, 1.25 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.75 mL, 1.8 mL, 1.9 mL, 2.0 mL, 2.1 mL, 2.2 mL, 2.25 mL, 2.3 mL, 2.4 mL, or 2.5 mL. In some embodiments, the pharmaceutical composition is contained in a volume of about 0.7 mL. In some embodiments, the pharmaceutical composition is contained in a volume of about 1.15 mL. In some embodiments, the pharmaceutical composition is contained in a volume of about 2.25 mL.

[0092] In some embodiments, the pharmaceutical compositions for use as described herein are prepared in unit dose dosage forms suitable for adapting to the dose of the active ingredient. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), and suppositories.

[0093] Exemplary pharmaceutical compositions containing an anti-IL-4R antibody that can be used in the context of this disclosure are disclosed, for example, in U.S. Patent No. 8,945,559.

[0094] Dosage Generally, IL-4R antagonists (e.g., anti-IL-4R antibodies) are administered to subjects in a therapeutically effective dose according to the methods described herein. Where used herein in reference to IL-4R antagonists, the term “therapeutic dose” means that one or more of the following IL-4R antagonists result in... -4R antagonist amounts mean: (a) treatment of allergic reactions or reduction of their severity or duration; (b) reduction of one or more symptoms or signs of an allergic reaction; (c) an increase in the ratio of serum allergen-specific IgG4 to serum allergen-specific IgE; (d) a reduction in the level of one or more markers of type 2 immune activity (e.g., serum TARC or total IgE); (e) a reduction in the frequency of allergic responses to allergen-specific immunotherapy; and (f) a reduction in induced allergic rhinitis symptoms after nasal allergen loading.

[0095] In the case of anti-IL-4R antibodies, the therapeutically effective dose is approximately 0.05 mg to 600 mg, for example, approximately 0.05 mg, 0.1 mg, 1.0 mg, 1.5 mg, 2.0 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg The anti-IL-4R antibody may be approximately 75 mg to 600 mg. In certain embodiments, 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg of anti-IL-4R antibody is administered to the target.

[0096] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in each dose can be expressed in milligrams of antibody per kilogram of body weight (i.e., mg / kg). For example, an IL-4R antagonist can be administered to a subject in doses ranging from approximately 0.0001 to approximately 10 mg / kg of body weight, such as approximately 1 mg / kg to approximately 10 mg / kg, or approximately 1 mg / kg, approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, or approximately 10 mg / kg.

[0097] In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered to a subject in a dose that results in a serum antagonist concentration level of at least about 70 mg / L (e.g., at least about 75 mg / L, at least about 80 mg / L, at least about 85 mg / L, or greater) when measured after 4 weeks of treatment.

[0098] In the case of SCIT, the dosage of the allergen administered (e.g., grass extract) increases during the escalation regimen. In some embodiments, SCIT is administered at a starting dose of 1 bioequivalent allergy unit (BAU) and is increased during the escalation regimen to a target dose of approximately 1,000–4,000 BAU (for forage grasses, e.g., timothy grass, sorghum, Kentucky bluegrass, orchard grass, rye, sweet vernal grass, or broadleaf grass) or a target dose of approximately 300–1,500 BAU (for Bermuda grass). In some embodiments, SCIT is administered starting at 1 BAU and increasing in doses to approximately 1,000, approximately 1,500, approximately 2,000, approximately 2,500, approximately 3,000, approximately 3,500, or approximately 4,000 BAU. In some embodiments, after an escalation regimen, SCIT is administered at a maintenance dose equal to the target dose (e.g., a target dose of approximately 1,000–4,000 BAU for pasture grass, or approximately 300–1,500 BAU for Bermuda grass). Exemplary dosing regimens for SCIT are shown in Table 1 below.

[0099] Administration regimen In some embodiments, the methods disclosed herein include administering an IL-4R antagonist to a subject at a dosing frequency of approximately four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently as long as a therapeutic response is achieved. In some embodiments, the anti-IL-4R antibody is administered once a week or once every two weeks in an amount of approximately 75 mg, 150 mg, 200 mg, or 300 mg.

[0100] In some embodiments, multiple doses of an IL-4R antagonist are administered to a subject over a specified time period. In some embodiments, the method of the present disclosure includes the step of sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, “sequential administration” means that each dose of the IL-4R antagonist is administered to the subject at different times, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the method of the present disclosure includes the step of sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of an IL-4R antagonist, and optionally followed by one or more tertiary doses of an IL-4R antagonist.

[0101] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the chronological order of administration of the IL-4R antagonist. Thus, the “initial dose” is the dose administered at the beginning of the treatment regimen (also called the “loading dose”); the “secondary dose” is the dose administered after the initial dose; and the “tertiary dose” is the dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but may generally differ from one another in terms of administration frequency. However, in certain embodiments, the amounts of IL-4R antagonist contained in the initial, secondary, and / or tertiary doses may differ from one another over the course of treatment (e.g., adjusted upward or downward as needed). In certain embodiments, one or more doses (e.g., 1, 2, 3, 4, or 5) may be administered at the beginning of the treatment regimen as a “loading dose,” followed by subsequent doses (e.g., “maintenance doses”) administered at a lower frequency. For example, an IL-4R antagonist may be administered to a subject in an initial dose or loading dose of about 400 mg or about 600 mg, followed by one or more secondary doses or maintenance doses of about 75 mg to about 300 mg. In one embodiment, the initial dose and one or more secondary doses each comprise 50 mg to 600 mg of an IL-4R antagonist, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg of an IL-4R antagonist. In some embodiments, the initial dose and one or more secondary doses each comprise the same amount of IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of IL-4R antagonist, and one or more secondary doses each comprise a second amount of IL-4R antagonist. For example, the first dose of the IL-4R antagonist may be 1.5×, 2×, 2.5×, 3×, 3.5×, 4×, or 5×, or more, than the second dose of the IL-4R antagonist. In one exemplary embodiment, the IL-4R antagonist is administered to the subject in a loading dose of about 600 mg, followed by one or more maintenance doses of about 300 mg.In another exemplary embodiment, the IL-4R antagonist may be administered to the subject in a loading dose of approximately 400 mg, followed by one or more maintenance doses of approximately 200 mg. In some embodiments, no loading dose is administered.

[0102] In some embodiments, each secondary and / or tertiary dose is administered 1 to 14 weeks after the preceding dose (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or longer). The term “preceding dose,” as used herein, refers to the sequence of doses immediately following the preceding dose. This refers to the dose of the IL-4R antagonist administered to the patient without an intervening dose before the next dose.

[0103] The methods of the present disclosure may include the step of administering to a patient any number of secondary and / or tertiary doses of an IL-4R antagonist. For example, in one particular embodiment, only a single secondary dose is administered to the patient. In another embodiment, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in one particular embodiment, only a single tertiary dose is administered to the patient. In another embodiment, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0104] In some embodiments involving multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the preceding dose. Similarly, in some embodiments involving multiple tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the preceding dose. Alternatively, the frequency at which secondary and / or tertiary doses are administered to the patient can be varied over the course of the treatment regimen. The frequency of administration may also be adjusted by the physician during the course of treatment according to the individual patient's needs after clinical examinations.

[0105] In some embodiments, SCIT is administered to a subject as a cluster SCIT regimen, which includes an escalating regimen of approximately 4–12 weeks (e.g., 4–10 weeks, 4–8 weeks, 6–12 weeks, 6–10 weeks, 6–8 weeks, 8–12 weeks, or 8–10 weeks), followed by a maintenance regimen of 4, 6, 8, 10, 12 weeks, or longer. In some embodiments, SCIT is administered in increasing doses of an escalating regimen of approximately 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, followed by a maintenance dose for at least 8 weeks. In some embodiments, SCIT is administered in increasing doses of an 8-week escalating regimen, followed by a maintenance dose for 8 weeks or longer.

[0106] In some embodiments, at least one dose of the IL-4R antagonist is administered one day or earlier before the start of the SCIT regimen. In some embodiments, at least one dose of the IL-4R antagonist is administered at least one, two, three, four, five, six, seven, eight, nine, or ten days before the start of the SCIT regimen, or earlier. In some embodiments, the first dose of the IL-4R antagonist is administered one to seven days before the start of the SCIT regimen. In some embodiments, the first dose of the IL-4R antagonist is administered up to one week before the start of the SCIT regimen.

[0107] In some embodiments, the initial dose of the IL-4R antagonist is administered before the initiation of the SCIT regimen, and subsequent doses of the IL-4R antagonist are administered after the initiation of the SCIT regimen. For example, in some embodiments, the initial (loading) dose of the IL-4R antagonist is administered 1–14, 1–10, or 1–7 days before the initiation of the SCIT regimen, and the first secondary (maintenance) dose of the IL-4R antagonist is not administered until at least 1 day after the initiation of the SCIT regimen.

[0108] In some embodiments, a dose greater than one of the IL-4R antagonists is administered before the initiation of the SCIT regimen. For example, in some embodiments, an initial (loading) dose of an IL-4R antagonist and at least one secondary (maintenance) dose of an IL-4R antagonist are administered before the initiation of the SCIT regimen.

[0109] In some embodiments, the IL-4R antagonist and SCIT are not administered to the subjects on the same day.

[0110] Combination therapy In some embodiments, the methods of the present disclosure include the step of administering an IL-4R antagonist or an IL-4R antagonist and SCIT regimen in combination with one or more additional therapeutic agents. As used herein, the expression "in combination with" means that one or more additional therapeutic agents are administered before, simultaneously with, or after the IL-4R antagonist or the IL-4R antagonist and SCIT regimen.

[0111] For example, when administered "before" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 72 hours, 60 hours, 48 ​​hours, 36 hours, 24 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes before the administration of the pharmaceutical composition containing the IL-4R antagonist. When administered "after" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, or 72 hours after the administration of the pharmaceutical composition containing the IL-4R antagonist. "Contemporarily" or together with a pharmaceutical composition containing an IL-4R antagonist means that the additional therapeutic agent is administered in a different dosage form less than 5 minutes (before, after, or simultaneously) with the administration of the pharmaceutical composition containing the IL-4R antagonist, or that the additional therapeutic agent and the IL-4R antagonist are administered to the subject as a single combination drug formulation.

[0112] In some embodiments, the additional therapeutic agent is a steroid, an antihistamine, a decongestant, or an anti-IgE agent. In some embodiments, the additional therapeutic agent is a steroid (e.g., a corticosteroid such as an inhaled corticosteroid (ICS)). In some embodiments, the additional therapeutic agent is an antihistamine (e.g., loratadine, fexofenadine, cetirizine, diphenhydramine, promethazine, carbinoxamine, desloratadine, hydroxyzine, levocetirizine, triprolizine, brompheniramine, or chlorpheniramine). In some embodiments, the additional therapeutic agent is a decongestant (e.g., pseudoephedrine or phenylephrine). In some embodiments, the additional therapeutic agent is an anti-IgE agent (e.g., omalizumab). [Examples]

[0113] The following examples are provided to give a complete disclosure and explanation of methods for preparing and using the methods and compositions of this disclosure to those skilled in the art, and are not intended to limit the scope of what the inventors consider to be their own invention. While efforts have been made to ensure accuracy with respect to the numerical values ​​used (e.g., quantity, temperature, etc.), some experimental errors and deviations should be taken into account. Unless otherwise indicated, parts are parts by weight, molecular weight is the average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric pressure or near atmospheric pressure. [Examples]

[0114] Clinical trial to investigate the efficacy of dupilumab as an adjunct to subcutaneous herbal immunotherapy. Research Design and Objectives This was a phase 2a, multicenter, randomized, double-blind, parallel-group, four-group study of dupilumab as an adjunct to grass SCIT in adults with a history of allergic rhinitis, conducted outside of the timothy grass allergy season. Dupilumab contains a heavy chain with the amino acid sequence of SEQ ID NO: 9 and a light chain with the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair with SEQ ID NO: 1 / 2; and heavy and light chain CDR sequences with SEQ ID NO: 3-8. It contains a fully human anti-IL-4R antibody.

[0115] Eligible patients with a history of allergic rhinitis to grass pollen and who successfully completed the screening procedure were randomized in a 1:1:1:1 ratio to the following four treatment groups: (1) SCIT is gradually increased as described up to a maintenance dose of 4,000 BAU + dupilumab (SC 300 mg Q2W, after a 600 mg loading dose). (2) SCIT is gradually increased as described up to a maintenance dose of 4,000 BAU + placebo of dupilumab. (3) SCIT with placebo + dupilumab (SC 300mg Q2W, after 600mg loading dose) (4) SCIT placebo + dupilumab placebo

[0116] Dupilumab was administered as follows: on day 1, a loading dose of 600 mg of dupilumab subcutaneously (SC) or placebo was administered, followed by 300 mg Q2W SC two weeks later, and the 300 mg Q2W SC was continued for a total of 16 weeks.

[0117] SCIT was administered as follows: On the day following dupilumab administration (up to 7 days after the dupilumab loading dose), subjects were initiated with a modified cluster regimen of timothy grass SCIT, starting at 1 bioequivalent allergy unit (BAU) and increasing up to 4,000 BAU over 8 weeks, followed by maintenance at 4,000 BAU for the remaining 8 weeks. If a subject developed adverse reactions during the SCIT dose escalation phase, the principal investigator (PI), in consultation with the medical supervisor, may decide to reduce the planned maintenance dose of SCIT from 4,000 BAU to 4000 BAU, but not below 400 BAU. Placebo-matched SCIT was prepared using the same formulation (SCIT diluent) without the addition of timothy grass extract. All SCIT visits were supervised at a clinical research facility with a trained research physician. Subjects were observed for at least 30 minutes after SCIT injection. The research physician's regular prescriptions will be provided to all clinical researchers to immediately initiate treatment of reactions, including but not limited to intramuscular administration of epinephrine, based on their own clinical judgment. At all SCIT visits, subjects were pre-administered an H1 antihistamine (oral loratadine 10 mg) 1–6 hours prior to each injection visit, as recommended by clinical guidelines to reduce local and systemic reactions in cluster SCIT.

[0118] screening After obtaining informed consent, the eligibility of subjects was assessed during the following three-part screening period. At the first screening visit, subjects with a history of allergic rhinitis to grass pollen underwent a medical history review, physical examination, timothy grass SPT (Surface Test), and blood sampling for timothy grass-specific IgE. Subjects who met the criteria for timothy grass SPT positivity and timothy grass-specific IgE, according to the inclusion / exclusion criteria, were invited to a second screening visit. At the second screening visit, subjects underwent a pregnancy test if applicable, spirometry, electrocardiogram (ECG), serological testing for chronic viral infections (human immunodeficiency virus infection [HIV] and hepatitis B and C), hematology, chemistry, and urinalysis to be evaluated against the study eligibility criteria, and underwent a baseline nasal brushing. Baseline nasal brushing must be performed between TNSS ≤ 2 and at least 28 days prior to the third screening / registration visit to allow the nasal mucosa to re-epithelialize and return to a resting state before NAC. At the third screening / registration visit (-1 day), subjects must not have taken antihistamines for at least 5 days. If a subject reports taking antihistamines within 5 days of the third screening visit, the schedule for the third screening visit may be changed. At the third screening / registration visit, subjects will be observed for approximately 10 minutes, and a resting / baseline TNSS ≤ 2 must be achieved. This means that the subject does not exhibit active nasal symptoms (for viral infections, sinusitis, allergies, etc.) during the rest period before NAC. If the subject's TNSS is >2, which means they have active nasal symptoms during the rest period, the schedule for the third screening visit can be changed. The TNSS (measured on a scale of 0-12) is a composite symptom assessment of congestion, itching, rhinorrhea (each graded on a scale of 0-3, with 3 being severe), and sneezing (2 is 3-4 sneezes, 3 is >5 sneezes).

[0119] If the subject had a resting / baseline TNSS ≤ 2 and therefore did not exhibit any recognizable nasal symptoms at rest, skin examinations of NAC and early and late reactions were performed as follows. • Perform NAC using increasing doses of timothy grass extract every 10 minutes until a maximum of 1 hour (incremental phase) or TNSS ≥ 7 is reached. • Record peak TNSS. • Record the concentration of timothy grass extract used to achieve TNSS ≥ 7. The subject is then observed for one hour, and the TNSS is recorded every hour at 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, and then up to 6 hours. At baseline, in addition to TNSS, the following parameters are measured approximately every 10 minutes during the escalation phase, and then every hour for the following hour after peak TNSS is achieved (at 5 minutes, 15 minutes, 30 minutes, 45 minutes, and 1 hour), and every hour up to 6 hours: o PNIF; (Measurement of nasal patency, L / min) o Total number of sneezes o TOSS

[0120] Grass allergy subjects were deemed eligible for registration if they had a TNSS ≤ 2 before screening NAC (time 0) and a peak TNSS ≥ 7 within the first hour of the dose escalation phase. In addition, to be eligible, subjects had to either experience a >20% decrease in PNIF between the initial non-zero dose and approximately 10 minutes after the peak dose, or have > / = 3 sneezes counted.

[0121] Patient Selection The target population included adults with a history of grass pollen-induced seasonal allergic rhinitis. Participants were randomized to North American facilities in areas where timothy grass is an associated grass species.

[0122] Selection Criteria: To be eligible to participate in the study, patients had to meet the following criteria: (1) be male or female between 18 and 55 years of age; (2) have a history of grass pollen-induced seasonal allergic rhinitis; (3) have grass pollen allergy confirmed by both (a) positive SPT with timothy grass extract (mean wheal diameter at least ≥5 mm larger than the negative control) and (b) positive serum timothy grass-specific IgE (≥0.35 KU / L); (4) have undergone NAC screening with timothy grass extract. (5) The participant must be at times positive and have a peak TNSS score of ≥7 out of 12; (6) Between the first non-zero dose and approximately 10 minutes after the highest dose of NAC, the participant must either experience a >20% decrease in PNIF or have ≥3 sneezes counted; (7) A signed informed consent form must be provided by the study participant; (8) The participant must be able to understand and complete study-related questionnaires; and (9) The participant must be willing and able to visit the research facility and comply with study-related procedures.

[0123] Exclusion Criteria: The exclusion criteria for the study were as follows: (1) Outside of the grass pollen season, or based (1) Having severe rhinitis (causing TNSS > 2) or sinusitis due to daily contact with other allergens that are expected to cause symptoms consistent with the final NAC assessment as evaluated by the line of care or the principal investigator; (2) having baseline or as evaluated by the principal investigator (3) The subject is expected to experience a significant change in allergen exposure in the home or workplace environment, which is expected to be consistent with the final NAC assessment to be evaluated; (4) At the time of screening NAC, the subject is currently experiencing or being treated for symptoms of an upper respiratory tract infection, acute sinusitis, acute otitis media, or other related infectious process; serous otitis media is not an exclusion criterion [the participant's eligibility can be reassessed after symptoms have resolved]; (5) Any contraindications to SCIT (i.e., severe cardiovascular disease, malignant tumor, autoimmune disease, use of beta-blockers, asthma severe enough to require chronic medication, acute infection); (6) Clinically significant / active underlying hepatobiliary disease, or alanine aminotransferase (ALT) >3 upper limit of normal (ULN); and abnormal laboratory values ​​at screening: creatine phosphokinase (CPK) >10 ULN, or <100,000 cells / mm³ 3 Platelets, or >1500 cells / mm³ 3(6) The patient has any laboratory findings indicating evidence of organ dysfunction or a clinically significant deviation from the normal range, including eosinophils, as determined by the principal investigator at the time of screening; (6) Any concomitant medication, including antihistamines (5 days), leukotriene inhibitors (7 days), mast cell inhibitors (7 days), intranasal corticosteroids and / or inhaled corticosteroids (14 days), oral or topical decongestants (5 days), topical calcineurin inhibitors (4 weeks), beta-blockers (5 days), and any screening (1) The medication was used within each period prior to the visit or optional screening NAC visit (third visit) [Participant eligibility can be reassessed after the period of taking such concomitant medications has elapsed]; (2) Systemic corticosteroid use within 4 weeks of the screening visit or optional NAC visit; (3) Abnormal lung function as judged by the principal investigator, with FEV1 <80% of the predicted value; (4) History of asthma requiring chronic medication use, such as regular inhaled corticosteroids for >4 weeks per year; (5) Entering the previous year (11) A history of asthma with two or more asthma exacerbations requiring hospitalization or systemic corticosteroids; (12) A history of emergency hospitalization or admission for asthma in the past 12 months; (13) A history of severe recurrent sinusitis defined as three episodes per year in the past 2 years, all of which required antibiotic treatment; (14) The presence of two or more symptoms, one of which is ± facial pain / pressure; ± decreased or lost sense of smell; ≥ 12 weeks of nasal congestion / obstruction / congestion or runny nose (prenasal drip / postnasal drip). (14) A history of chronic sinusitis (with or without nasal polyps) as defined as either (rhinorrhea) or (15) a history of any macroscopic mechanical nasal obstruction or nasal or sinus surgery that the principal investigator considers to be precluding the administration of NAC; (16) a history of smoking (ANY) within the past year; (17) a history of any grade 4 anaphylaxis of any cause as defined in the Common Terminology Criteria for Adverse Events of Immunotherapy (CTCAE) assessment criteria; (18) a history of chronic obstructive pulmonary disease;(18) Having a history of other chronic diseases requiring therapy (other than asthma, atopic dermatitis, or allergic rhinitis) (e.g., heart disease, diabetes, or hypertension) that the principal investigator considers to be a risk to the health or safety of the subjects in this study or to the subjects' ability to adhere to the study protocol; (19) Having a history of allergic immunotherapy (SCIT, sublingual immunotherapy, or oral immunotherapy) in the past five years; (20) Any exposure to dupilumab; (21) Having been treated with the study drug within two months prior to screening or within five half-lives (if known), whichever is longer; (22) Being a member of the clinical site research team or a close relative thereof; (23) Having an infectious disease, as determined by the principal investigator. Despite the resolution of the condition, immunosuppression is known or suspected, including a history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis), or otherwise unusually frequent recurrent infections, or long-term infections suggestive of an immunocompromised state; (24) a history of patient-reported alcohol or drug abuse within six months prior to screening; (25) a history of bleeding disorders or treatment with anticoagulant therapy; (26) being subject to testing positive for HIV antibody, hepatitis B surface antigen, or hepatitis C antibody; (27) having used anti-IgE therapy within six months prior to screening; (28) within three months prior to screening and study; (29) Having received treatment with a live (attenuated) vaccine; having had an active chronic or acute infection requiring systemic treatment with antibiotics, antivirals, antiparasitic drugs, antiprotozoal drugs, or antifungal drugs within two weeks prior to the screening visit [Note: The subject may be rescreened after the infection has resolved]; (30) Having a history of malignancy within five years prior to the screening visit, excluding completely treated intraepithelial carcinoma of the cervix, completely treated and resolved non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin; (31) Primary immunosuppressant (32) Having a confirmed diagnosis of any of the following conditions (e.g., severe combined immunodeficiency, Wiscott-Aldrich syndrome, DiGeorge syndrome, X-linked agammaglobulinemia, unclassified immunodeficiency) or secondary immunodeficiency, such as HIV; (33) Being a woman who is pregnant or breastfeeding, or planning to become pregnant or breastfeed during the study; (34) Not being sexually abstinent and not wishing to use highly effective contraception before the initial dose / before the start of the first treatment, during the study, and for at least 120 days after the final dose, and who may give birth. * Being female [ *Postmenopausal women must be abstinent for at least 12 months to avoid being considered fertile. Pregnancy testing and contraception are not required for women who have had a hysterectomy or tubal ligation. Highly effective methods of contraception include (a) the steady use of mixed (estrogen and progestogen-containing) hormonal contraceptives (oral, vaginal, or transdermal) or progestogen-only hormonal contraceptives (oral, injectable, or implantable) associated with ovulation inhibition, initiated two or more menstrual cycles prior to screening; (b) intrauterine devices (IUDs); intrauterine hormone-releasing systems (IUSs); (c) bilateral tubal ligation; (d) vasectomy partners; and / or (e) sexual abstinence†,‡[†Sexual abstinence is considered a highly effective method only if it is defined as refraining from heterosexual intercourse throughout the entire risk period associated with the study treatment. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the subject's preferred normal lifestyle. ‡Cyclic abstinence (calendar method, symptomothermal method, post-ovulation method), withdrawal (ejaculation outside the vagina), spermicides alone, and lactational amenorrhea (LAM) are not acceptable methods of contraception. Female and male condoms should not be used in combination. ]; (34) If the subject is unable to understand and comply with the clinical protocol (35) The use of any prohibited drugs and procedures is planned or anticipated during the study treatment; and (36) The person is an adult who is unable to consent to the study.

[0124] research treatment Dupilumab: Patients received a loading dose of 600 mg dupilumab SC or placebo, followed by 300 mg Q2W SC for a total of 16 weeks.

[0125] Oriental timothy grass SCIT: Oriental timothy grass SCIT was administered for 8 weeks using a cluster dose escalation regimen, followed by maintenance therapy as described below. SCIT was initiated 1 day after the dupilumab loading dose and within 1 week after the dupilumab loading dose. Dupilumab was not administered on the same day or at the same site as SCIT.

[0126] The grass SCIT protocol involves 1 to 3 SC injections per weekly visit of the allergen following the escalation regimen described below over 8 weeks, as shown in Table 1 below, followed by maintenance SC injections for the next 8 weeks. The recommended target maintenance dose of SCIT is 4,000 bioequivalent allergy units (BAU), which is equivalent to approximately 20 mcg of Frem-Pratens 5 (the major timothy grass allergen) (Cox, 2011) (Frew, 2006b). During weeks 1 to 3 of the escalation phase, three doses of SCIT were administered per visit. The first dose (the lowest dose at that visit) was administered, and the subject was monitored for 30 minutes. If the dose was well tolerated, the next higher planned dose was administered at that visit. The subject was then monitored for the next 30 minutes, and if the dose was well tolerated, the next higher planned dose was administered at that visit. The dose was administered. During weeks 4-5 of the dose escalation phase, two doses of SCIT were administered. The first dose (the lowest dose at that visit) was administered, the subject was monitored for 30 minutes, and if the dose was well tolerated, the next higher planned dose was administered at that visit. During weeks 6-8 of the dose escalation phase, one dose of SCIT was administered. In the maintenance phase, one dose per visit was administered as shown in Table 1. Placebo SCIT was administered in the same manner and according to the same protocol as grass SCIT, but a diluent was administered instead of the activator. The first dose (the lowest dose at that visit) was administered, the subject was monitored for 30 minutes, and if the dose was well tolerated, the next higher planned dose was administered at that visit. On the day of SCIT or placebo-SCIT administration, subjects received pre-administered H1 antihistamine (oral loratadine 10 mg) 1–6 hours prior to each injection visit, as recommended by clinical guidelines to reduce local and systemic reactions during cluster SCIT.

[0127] [Table 1]

[0128] Dupilumab / placebo and SCIT / placebo timing As shown in Table 2, dupilumab administration was initiated before SCIT administration. Dupilumab / placebo should never be administered on the same day as SCIT / placebo.

[0129] [Table 2]

[0130] Rescue treatment If necessary, subjects experiencing an allergic reaction were treated with rescue therapy, including but not limited to epinephrine IM or SC, as determined by trained research staff. Subjects may also take oral antihistamines for allergic rhinitis symptoms as needed during the course of the study, but must not use oral antihistamines within 5 days prior to or during NAC or skin examination visits. If you use oral antihistamines within 5 days prior to or during your appointment for testing, your appointment schedule must be changed.

[0131] Procedure and evaluation To evaluate the efficacy / effectiveness of dupilumab monotherapy, SCIT monotherapy, dupilumab + SCIT, and placebo, various parameters were collected during the study. These parameters included NAC and NAC assessments (TNSS, TOSS, PNIF, and total sneezing), as well as biomarker analysis in serum or plasma (TARC, total IgE, timothy grass-specific IgE, timothy grass-specific IgG4).

[0132] NAC and NAC assessment (TNSS, TOSS, PNIF, and total sneezing) TNSS: The TNSS assessment was performed as follows: At the end of therapeutic NAC (week 17), subjects were observed for approximately 10 minutes, and a rest / baseline TNSS ≤ 2 had to be achieved, meaning that the subject did not have active nasal symptoms (due to viral infection, sinusitis, allergies, etc.) during the rest period prior to NAC. The TNSS (measured on a scale of 0-12) is a composite symptom assessment of congestion, itching, rhinorrhea (each graded on a scale of 0-3, with 3 being severe), and sneezing (2 is 3-4 sneezes, 3 is >5 sneezes). If a subject had a rest / baseline TNSS ≤ 2 and therefore did not have any recognizable nasal symptoms during the rest period, NAC would be performed. NAC will be performed using increasing doses of timothy grass extract every 10 minutes, and the TNSS score will be recorded approximately every 10 minutes until the concentration of timothy grass extract used to achieve a total nasal symptom score (TNSS) ≥ 7 at the baseline NAC visit is reached (escalating symptom score). This TNSS score will be recorded. After recording the TNSS achieved using the concentration of timothy grass extract used to achieve a total nasal symptom score (TNSS) ≥ 7 at the baseline NAC visit, the subjects will be observed for the following hour, and the TNSS will be recorded every hour at 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, and then every hour up to 6 hours.

[0133] TOSS: TOSS (measured on a scale of 0-3, with 3 being severe) is a composite symptom assessment of ocular symptoms (itching, redness, lacrimation [watery eyes], and swelling [eye swelling]) as evaluated as follows. The TOSS score will be recorded during the NAC assessment. The TOSS score will be recorded approximately every 10 minutes (gradual increase in symptom score) until the concentration of timothy grass extract used to achieve TNSS ≥ 7 at the baseline NAC visit is reached. This TOSS score will be recorded. The subject will then be observed for the following hour, and the TOSS score will be recorded. You will record A every hour at intervals of 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, and up to 6 hours.

[0134] PNIF: The PNIF assessment was performed as follows: Peak nasal inspiratory flow rate (measured with nasal patency, L / min) was measured and recorded approximately every 10 minutes during the NAC escalation phase, and then every hour for the following hour after peak TNSS was achieved (at 5 minutes, 15 minutes, 30 minutes, 45 minutes, and 1 hour), and up to 6 hours.

[0135] Total sneezing: Total sneezing was counted and recorded during the escalation phase and in the hour following the achievement of the peak TNSS.

[0136] In addition, skin prick tests (SPT) with serial allergen titration were performed to evaluate the initial response from 0 to 60 minutes. Intradermal allergen injections were administered to evaluate the late response from 6 to 24 hours. Nasal fluid was collected during two NAC study visits to determine the levels of cytokines and chemokines produced in response to NAC. The safety of dupilumab in this population was assessed based on adverse events, detailed medical history, thorough physical examination, vital signs, electrocardiogram (ECG), Evaluation was performed by assessing vital capacity, maximal expiratory flow rate, and clinical laboratory tests. Concomitant medications and procedures were collected from the time of informed consent to the end of the study. Blood samples for drug concentrations and anti-dupilumab antibody levels were collected at predetermined points in time. Study samples and samples for exploratory biomarker analysis were collected.

[0137] Pharmacokinetic and biomarker procedures Biomarkers: Biomarker samples were collected at specified time points. Biomarker measurements (TARC, total IgE, timothy grass-specific IgE, timothy grass-specific IgG4) were performed in serum or plasma to assess the impact of relevant physiological and pathogenic processes on biomarkers.

[0138] Pharmacokinetics: Concentration data was determined for each sampling time.

[0139] statistical analysis Primary efficacy endpoints and sequential secondary efficacy endpoints were analyzed using an analysis of covariance (ANCOVA) model and multiple imputation (MI) with last observation carry-forward (LOCF). For MI, missing data was imputed 40 times using the System of Statistical Analysis (SAS) procedure MI to generate 40 complete datasets. Each of the 40 complete datasets was analyzed using the ANCOVA model. Treatment group was the principal factor, and baseline values ​​were used as covariates. Valid statistical inferences were generated using the SAS MIANALYZE procedure by combining the results of the 40 analyses using the Rubin formula. All observational data were used in the analysis.

[0140] Biomarker-related serial endpoints were analyzed using a rank-based ANCOVA model with treatment and relevant baseline as covariates. Missing data were imputed using the LOCF method.

[0141] result Patient baseline characteristics 103 patients were randomized to either placebo (n=25) or one of three treatment groups: dupilumab (n=26), SCIT (n=26), or dupilumab + SCIT (n=26). Baseline demographics and clinical characteristics were relatively well-balanced across the treatment groups (Table 3).

[0142] [Table 3]

[0143] safety In the 16-week SCIT regimen, significantly more patients discontinued treatment due to clinically significant SCIT-related allergic reactions compared to the group treated with SCIT alone. In the SCIT treatment group, 8 out of 26 patients (31%) discontinued treatment during the 16-week SCIT phase (7 out of 8 due to clinically significant SCIT-related allergic reactions), whereas in the dupilumab + SCIT treatment group, only 1 out of 26 patients (4%) discontinued SCIT treatment. This patient's discontinuation was not related to a SCIT reaction.

[0144] Table 4 shows that treatment with dupilumab in combination with SCIT reduced the need for epinephrine and oral steroids to treat systemic reactions compared to the SCIT group. In the SCIT group, 19.2% of subjects required epinephrine (compared to 7.7% in the dupilumab + SCIT group), and 19.2% of subjects required oral steroids (compared to 7.7% in the dupilumab + SCIT group). A greater number of systemic allergic reactions were observed in the dupilumab + SCIT group after SCIT injection (11 in the dupilumab group compared to 10 in the SCIT group, 1 in the dupilumab group, and 1 in the placebo group; of the 11 reactions, 2 were grade 1 and 9 were grade 2; there were no grade 3 reactions in the dupilumab + SCIT group, in contrast to the SCIT group which had 2 grade 3 systemic allergic reactions). Adverse events and serious adverse events were similar between the treatment groups. There were two serious adverse events in the dupilumab + SCIT group, and one each in the SCIT group, the dupilumab group, and the placebo group.

[0145] [Table 4]

[0146] efficacy LOCF analysis of the primary endpoint, measured as the percentage change in TNSS AUC after NAC (hours 0-1), suggested that administering dupilumab as an adjunct to SCIT was beneficial. In the LOCF analysis, patients who discontinued treatment in the treatment group were considered "non-responders" and assigned a total nasal symptom score (TNSS) of "no change from baseline" after allergen loading. As shown in Table 5, treatment with SCIT alone resulted in a placebo-adjusted TNSS reduction of -16.3% (p=0.1871), while dupilumab + SCIT resulted in a placebo-adjusted TNSS reduction of -24.6% (p=0.0474).

[0147] [Table 5]

[0148] biomarkers The results of the biomarker analysis are shown in Table 6. SCIT significantly increased serum timothy grass sIgE levels from baseline (a 98% increase at week 17). Individuals with a dramatic increase in IgE were also observed to be at higher risk of treatment discontinuation. Adding dupilumab to SCIT inhibited the increase in grass-specific IgE (a 56.4% reduction). Dupilumab inhibited the increase in sIgE very early during the SCIT dose escalation phase and continued to inhibit sIgE during the SCIT maintenance phase. Both SCIT and dupilumab + SCIT increased serum timothy grass sIgG4 to a similar extent with similar kinetics (1896% with dupilumab + SCIT, compared to 1812% with SCIT). Treatment with dupilumab in combination with SCIT increased the sIgG4 / sIgE [log] ratio at week 17 compared to treatment with SCIT alone (1.7 vs. 0.87, p<0.0001). Both SCIT and dupilumab + SCIT also increased specific total IgG over 16 weeks. Patients treated with dupilumab alone, or dupilumab in combination with SCIT, showed a reduction in systemic TARC levels at week 17 compared to the placebo and SCIT groups.

[0149] In participants who completed the study (non-responders were not adjusted), skin prick tests by serial allergen titration showed similar results for SCIT and dupilumab combined with SCIT (the change in wheal size was -45.2% with SCIT compared to -47.1% with dupilumab + SCIT). Skin prick tests induced by intradermal allergen injection showed a greater reduction with SCIT compared to dupilumab combined with SCIT (-42.4% vs. -10.7%).

[0150] [Table 6]

[0151] Pharmacokinetics Functional dupilumab concentrations were similar regardless of whether or not SCIT treatment was performed. Mean, median, and variability of functional dupilumab concentrations were consistent between the dupilumab + SCIT group and the dupilumab group. トラフ Since the measured values ​​were considered consistent in both groups from week 5 to week 17, it is thought that the functional dupilumab concentration reached a steady state by week 5. After the end of treatment (week 17), the mean functional dupilumab concentration decreased from approximately 79 mg / L to 16 mg / L in both groups by week 24.

[0152] Tolerability Tolerability parameter data (percentage of subjects who achieved 4000 BAU of SCIT by week 8 or 16, and the maximum tolerated dose by week 8 or 16) are shown in Table 7. Treatment with dupilumab in combination with SCIT increased the number of subjects who successfully completed 16 weeks of SCIT compared to the SCIT group (92% vs. 69%). %). In addition, treatment with dupilumab in combination with SCIT increased the number of subjects who achieved a maintenance dose of 4000 BAU (complete escalation) (62% vs. 46%). After 16 weeks, the dupilumab + SCIT group achieved a higher mean SCIT dose than the SCIT group (3071 BAU vs. 2683 BAU).

[0153] [Table 7]

[0154] conclusion In this Phase 2a clinical trial, administering dupilumab as an adjunct to SCIT resulted in significant improvements in safety and tolerability compared to SCIT alone. Dupilumab treatment improved the tolerability of SCIT, as measured by the percentage of patients who completed 16 weeks of SCIT, the percentage of patients who achieved the full maintenance dose, the mean SCIT dose achieved over 16 weeks, and the reduced need for epinephrine and oral steroids as rescue medications.

[0155] The present invention should not be limited in scope by the specific embodiments described herein. In fact, those skilled in the art will see from the above description and the accompanying drawings that there are various modifications to the present invention beyond those described herein. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A method for enhancing the efficacy and / or tolerance of a grass allergen-specific subcutaneous immunotherapy (SCIT) regimen in a subject with grass allergy, comprising the step of administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist in combination with the SCIT regimen, wherein at least one dose of the IL-4R antagonist is administered before the initiation of the SCIT regimen, and the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

2. The method according to claim 1, wherein the SCIT regimen comprises subcutaneous administration of a herb extract derived from a grass selected from the group consisting of timothy grass, bahia, Bermuda grass, sorghum, Kentucky bluegrass, orchard grass, sedge, rye, sweet vernal grass, broadleaf moss, and combinations thereof.

3. The method according to claim 2, wherein the herb extract is derived from timothy grass.

4. The method according to any one of claims 1 to 3, wherein the SCIT regimen includes a cluster SCIT regimen.

5. The method according to claim 4, wherein the cluster SCIT regimen comprises an escalation regimen followed by a maintenance regimen, the escalation regimen comprising administering increasing doses of herb extract over a period of 4 to 12 weeks, and the maintenance regimen comprising administering one or more maintenance doses of the highest doses of the herb extract administered during the escalation regimen.

6. The method according to claim 5, wherein the escalation regimen comprises administering increasing doses of herbal extract over a period of eight weeks.

7. The method according to claim 5 or 6, wherein the maintenance regimen comprises administering a maintenance dose every one to four weeks for at least eight weeks.

8. The method according to any one of claims 5 to 7, wherein the escalation regimen comprises escalating from a dose of 1 bioequivalent allergy unit (BAU) to a dose of 4,000 BAU, and the maintenance regimen comprises administering one or more maintenance doses of 4,000 BAU.

9. The method according to any one of claims 1 to 8, wherein the IL-4R antagonist is administered in a dose of approximately 75 mg to approximately 600 mg.

10. The method according to any one of claims 1 to 9, wherein an IL-4R antagonist is administered in an initial dose, followed by one or more secondary doses, each secondary dose being administered 1 to 4 weeks after the immediately preceding dose.

11. The method according to claim 10, wherein the initial dose of the IL-4R antagonist is administered 1 to 7 days before the start of the SCIT regimen.

12. The method according to claim 10 or 11, wherein the initial dose comprises 600 mg of IL-4R antagonist, and each secondary dose comprises 300 mg of IL-4R antagonist.

13. The method according to any one of claims 10 to 12, wherein each secondary dose is administered two weeks after the immediately preceding dose.

14. The method according to any one of claims 1 to 13, wherein the IL-4R antagonist and SCIT are not administered to the subject on the same day.

15. The method according to any one of claims 1 to 14, wherein the enhancement of the efficacy and / or tolerability of the SCIT regimen includes reducing the symptoms of the target allergic rhinitis.

16. Enhanced efficacy and / or tolerability of the SCIT regimen (a) Compared to SCIT monotherapy, increase the amount of target serum grass allergen-specific IgG4 (sIgG4); (b) reducing the amount of serum grass allergen-specific IgE (sIgE) in the subject compared to SCIT monotherapy; and / or (c) Compared to SCIT monotherapy, increasing the ratio of sIgG4 to sIgE in the subject. The method according to any one of claims 1 to 15, including the method described in any one of claims 1 to 15.

17. The method according to any one of claims 1 to 16, wherein administration of an IL-4R antagonist in combination with a SCIT regimen reduces or inhibits sIgE induction during a SCIT escalation regimen and / or a SCIT maintenance regimen.

18. The method according to any one of claims 1 to 17, wherein administration of an IL-4R antagonist in combination with a SCIT regimen increases the maximum tolerable SCIT dose for the subject.

19. The method according to any one of claims 1 to 18, wherein administration of an IL-4R antagonist in combination with the SCIT regimen reduces the use of epinephrine or oral steroids as rescue medication.

20. The method according to any one of claims 1 to 19, wherein the anti-IL-4R antibody or its antigen-binding fragment comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

21. The method according to any one of claims 1 to 20, wherein the anti-IL-4R antibody or its antigen-binding fragment comprises an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO:

2.

22. The method according to any one of claims 1 to 21, wherein the anti-IL-4R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

23. The method according to any one of claims 1 to 22, wherein the IL-4R antagonist is dupilumab or its bioequivalent.

24. The method according to any one of claims 1 to 23, wherein the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen-type delivery device, and an auto-injector.

25. The method according to claim 24, wherein the IL-4R antagonist is contained in a pre-filled syringe.

26. The method according to claim 25, wherein the pre-filled syringe is a single-dose pre-filled syringe.

27. The method according to claim 24, wherein the IL-4R antagonist is included in the autoinjector.

28. The method according to claim 24, wherein the IL-4R antagonist is included in a pen-type delivery device.

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