Methods for treating allergy and enhancing allergen-specific immunotherapy by administering il-4r inhibitor

Abstract

To provide: methods for treating, preventing or reducing the severity of allergic reactions; and methods for enhancing the efficacy and / or safety of an allergen-specific immunotherapy (SIT) regimen.SOLUTION: The methods of the present invention comprise administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4Rα) antagonist such as an anti-IL-4Rα antibody.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the use of interleukin-4 receptor inhibitors for treating or preventing allergic reactions and for improving the efficacy and / or safety of allergen-specific immunotherapeutic regimens. [Background technology]

[0002] Allergies and allergic diseases are serious medical conditions with consequences ranging from non-fatal responses that resolve over time to fatal effects such as anaphylaxis. Allergic reactions can occur as a result of contact or exposure to a variety of products, such as certain foods, insect venoms, plant-derived substances (e.g., pollen), chemicals, drugs / medicines, and animal dander. Current treatment options for allergies include avoidance, pharmacological symptom treatment, and prevention using allergen-specific immunotherapy (SIT). Unfortunately, these current treatment strategies are often insufficient, expensive, difficult to implement, or involve significant risks. For example, avoidance of allergens is not always possible and can adversely affect the quality of life of patients and caregivers. On the other hand, immunotherapy approaches involve the planned administration of allergens to susceptible individuals, which is inherently risky and can result in undesirable severe allergic reactions or anaphylaxis. Thus, there is an unmet need in the art for new therapeutic approaches to prevent or treat allergic responses, as well as to improve the safety and / or efficacy of immunotherapeutic treatment strategies. Summary of the Invention [Means for solving the problem]

[0003] According to one embodiment of the present invention, a method for treating, preventing, or reducing the severity of an allergic reaction in a subject is provided. The method according to this embodiment of the present invention comprises administering a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist to a subject in need thereof. The pharmaceutical composition comprising an IL-4R antagonist can be administered to the subject before, during, or after allergen exposure or allergic symptom manifestation.

[0004] According to another aspect of the present invention, a method for improving the efficacy and / or safety of an allergen-specific immunotherapy (SIT) regimen is provided. The method according to this aspect of the present invention comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an IL-4R antagonist in combination with a SIT regimen. According to certain embodiments of this aspect of the present invention, the pharmaceutical composition comprising an IL-4R antagonist is administered before the start of the SIT regimen or during the course of the SIT regimen. For example, the pharmaceutical composition comprising an IL-4R antagonist can be administered during the escalation phase of the SIT regimen and / or during the maintenance phase of the SIT regimen.

[0005] According to another aspect of the present invention, there is provided a method of reducing total serum IgE levels in a subject exposed to an allergen, the method according to this aspect of the present invention comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist in an amount sufficient to reduce or inhibit IgE production or reduce or eliminate serum IgE levels in the subject.

[0006] In various embodiments, a pharmaceutical composition comprising an IL-4R antagonist is administered orally, subcutaneously, epicutaneously or intravenously to a subject in need thereof.

[0007] Exemplary IL-4R antagonists that can be used in conjunction with the methods of the present invention include, for example, small molecule chemical inhibitors of IL-4R or its ligands (IL-4 and / or IL-13), or biological agents that target IL-4R or its ligands. According to certain embodiments, the IL-4R antagonist is an antigen-binding protein that binds the IL-4Rα chain and blocks signaling by IL-4, IL-13, or both IL-4 and IL-13. One such type of antigen-binding protein that can be used in conjunction with the methods of the present invention is an anti-IL-4Rα antibody, such as dupilumab.

[0008] Other embodiments of the invention will become apparent from review of the subsequent detailed description. [Brief description of the drawings]

[0009] [Figure 1] Panel A depicts the time course of a peanut allergy mouse model in which mice were administered two doses of anti-IL-4Rα antibody. Panel B depicts the extent of anaphylaxis in three groups of experimental mice, as assessed by the fall in core body temperature over time after IV peanut extract challenge. Mice that did not receive antibody are shown as grey circles; mice that received anti-IL-4Rα antibody are shown as black squares; mice that received isotype control antibody are shown as white squares. [Diagram 2] FIG. 2 shows IgE levels in the three groups of mice mentioned in FIG. 1 after challenge with peanut extract. [Diagram 3] Panel A depicts the time course of a peanut allergy mouse model in which mice were administered a single dose of anti-IL-4Rα antibody on day 13. Panel B depicts the extent of anaphylaxis in three groups of experimental mice, as assessed by the drop in central body temperature over time following IV peanut extract challenge. Mice that did not receive antibody are shown as grey circles; mice that received anti-IL-4Rα antibody are shown as black squares; mice that received isotype control antibody are shown as open squares. [Figure 4]Panel A depicts the time course of a peanut allergy mouse model in which mice were administered a single dose of anti-IL-4Rα antibody on day 27. Panel B depicts the extent of anaphylaxis in three groups of experimental mice, as assessed by the fall in core body temperature over time following IV peanut extract challenge. Mice that did not receive antibody are shown as grey circles; mice that received anti-IL-4Rα antibody are shown as black squares; mice that received isotype control antibody are shown as white squares. [Diagram 5] Figure 3 shows total IgE levels at days 12, 26, and 28 of the experimental time course in the three treatment groups (untreated mAb, anti-IL-4Rα, and isotype control treated mice) from Figures 3 and 4. Panel A shows the results of an experiment in which a single dose of antibody was administered on day 13; Panel B shows the results of an experiment in which a single dose of antibody was administered on day 27. [Figure 6] FIG. 1 depicts the time course of the peanut-specific immunotherapy mouse model, including the sensitization phase, SIT dose-escalation phase, and peanut extract challenge. Five antibody injections were administered to mice on the indicated days. [Figure 7] Figure 7 shows the extent of anaphylaxis in three groups of experimental mice subjected to the peanut-specific immunotherapy regimen described in Figure 6, and in a control group without immunotherapy. Results are assessed by the fall in central body temperature over time after challenge with peanut extract. Mice challenged but not receiving immunotherapy ("No IT") are shown with open circles and dashed lines; mice receiving immunotherapy but not antibody ("IT") are shown with closed squares and dashed lines; mice receiving immunotherapy and isotype control antibody ("IT+isotype control") are shown with open squares and dashed lines; mice receiving immunotherapy and anti-IL-4Rα antibody ("IT+anti-IL-4Rα") are shown with closed squares and solid lines. [Figure 8]Figure 8 shows total IgE levels (Figure 8) in three groups of experimental mice subjected to the peanut-specific immunotherapy regimen described in Figure 6, and in a control group without immunotherapy. The various immunoglobulin levels are shown on days 77 and 96. Mice challenged but not receiving immunotherapy ("No IT") are shown as filled circles; mice receiving immunotherapy but no antibody ("IT") are shown as open circles; mice receiving immunotherapy and isotype control antibody ("IT+isotype control") are shown as filled squares; mice receiving immunotherapy and anti-IL-4Rα antibody ("IT+anti-IL-4Rα") are shown as open squares. Each symbol represents the level measured in an individual mouse. [Figure 9] Peanut-specific IgG1 levels (FIG. 9) in three groups of experimental mice subjected to the peanut-specific immunotherapy regimen described in FIG. 6, and in a control group without immunotherapy. The different immunoglobulin levels are shown on days 77 and 96. Mice subjected to challenge but not receiving immunotherapy ("No IT") are shown as filled circles; mice receiving immunotherapy but not antibody ("IT") are shown as open circles; mice receiving immunotherapy and isotype control antibody ("IT+isotype control") are shown as filled squares; mice receiving immunotherapy and anti-IL-4Rα antibody ("IT+anti-IL-4Rα") are shown as open squares. Each symbol represents the measured level in an individual mouse. [Figure 10] Peanut-specific IgG2a levels (FIG. 10) in three groups of experimental mice subjected to the peanut-specific immunotherapy regimen described in FIG. 6, and in a control group without immunotherapy. The various immunoglobulin levels are shown on days 77 and 96. Mice challenged but not receiving immunotherapy ("No IT") are shown as filled circles; mice receiving immunotherapy but no antibody ("IT") are shown as open circles; mice receiving immunotherapy and isotype control antibody ("IT+isotype control") are shown as filled squares; mice receiving immunotherapy and anti-IL-4Rα antibody ("IT+anti-IL-4Rα") are shown as open squares. Each symbol represents the measured level in an individual mouse. [Figure 11]Figure 11 shows hIgG levels (Figure 11) in three groups of experimental mice subjected to the peanut-specific immunotherapy regimen described in Figure 6, and in a control group without immunotherapy. The various immunoglobulin levels are shown on days 77 and 96. Mice subjected to challenge but not receiving immunotherapy ("No IT") are shown as filled circles; mice receiving immunotherapy but not antibody ("IT") are shown as open circles; mice receiving immunotherapy and isotype control antibody ("IT+isotype control") are shown as filled squares; mice receiving immunotherapy and anti-IL-4Rα antibody ("IT+anti-IL-4Rα") are shown as open squares. Each symbol represents the measured level in an individual mouse. [Figure 12] FIG. 7 depicts the time course of a variation of the peanut-specific immunotherapy mouse model of FIG. 6, in which lower doses of peanut extract (8 vs. 12) were administered during the dosing phase as indicated. Five antibody injections were administered to the mice on the days indicated. [Figure 13] Figure 13 shows the extent of anaphylaxis in three groups of experimental mice subjected to the peanut-specific immunotherapy regimen described in Figure 12, and in a control group without immunotherapy. Results are assessed by the decrease in central body temperature over time after challenge with peanut extract. Treatment groups are the same as in Figure 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Before describing the invention, it is to be understood that the invention is not limited to the particular methods and experimental conditions described, since such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the invention is limited only by the appended claims.

[0011] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. As used herein, the term "about" when used in reference to a particular stated value means that the value may vary by 1% or less from the stated value. For example, as used herein, The expression "about 100" includes 99 and 101 and all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0012] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference as if set forth in their entirety.

[0013] Methods for Treating, Preventing, or Reducing the Severity of an Allergic Reaction The present invention includes a method for treating, preventing, or reducing the severity of an allergic reaction in a subject. The method according to this aspect of the present invention includes administering a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist to a subject in need thereof. As used herein, the terms "treat", "treating" and the like refer to alleviating symptoms, temporarily or permanently eliminating the cause of symptoms, or preventing or delaying the onset of symptoms of an allergic reaction. As used herein, the term "subject in need thereof" refers to any human or non-human animal that (a) is susceptible to an allergic reaction or response when exposed to one or more allergens; (b) has previously exhibited an allergic reaction or reaction to one or more allergens; (c) has a known history of allergy; and / or (d) shows signs or symptoms of an allergic response or anaphylaxis.

[0014] The present invention also includes a method of reducing total serum IgE levels in a subject exposed to an allergen. The method according to this aspect of the present invention includes administering to the subject a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist in an amount sufficient to reduce or inhibit IgE production or reduce or eliminate serum IgE levels. As used herein, a reduction in serum IgE levels means that the amount of IgE measured in the serum of a control exposed to an allergen and treated with an IL-4R antagonist is at least 5%, 10%, 20%, 50%, 80% or 90% lower than the serum IgE levels measured in the same or comparable subject not treated with an IL-4 antagonist. In certain embodiments, a reduction in serum IgE levels means that there is no or negligible amount of allergen-specific IgE detected in the serum of the subject.

[0015] As used herein, the phrases "allergic response", "allergic reaction", "allergic symptoms" and the like include one or more signs or symptoms selected from the group consisting of urticaria (e.g., rash), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinusitis, watery eyes, wheezing, bronchospasm, decreased peak expiratory flow (PEF), gastrointestinal disorders, flushing, swollen lips, swollen tongue, decreased blood pressure, anaphylaxis, and organ dysfunction / failure. "Allergic response", "allergic reaction", "allergic symptoms" and the like also include immune responses and reactions, such as, for example, increased IgE production and / or increased allergen-specific immunoglobulin production.

[0016] The term "allergen" as used herein includes any substance, chemical, particle or composition that can stimulate an allergic response in a susceptible individual. Allergens can be contained in or derived from foods, such as dairy products (e.g., milk), eggs, celery, sesame, wheat, soybeans, fish, shellfish, sugars (e.g., sugars present on meat, such as α-galactose), peanuts, other legumes (e.g., beans, peas, soybeans, etc.) and nuts. Alternatively, allergens can be contained in or derived from foods, such as dust (e.g., those containing dust mites), pollen, insect venom (e.g., venom of bees, wasps, mosquitoes, red fire ants, etc.), mold, animal fur, animal dander, wool, latex, metals (e.g., nickel), household cleaners, detergents, medicines, cosmetics (e.g., perfumes, etc.), drugs (e.g., penicillin, sulfonamides, salicylic acid, etc.), and other substances that can cause allergic reactions. They may also be contained or derived from non-food substances, such as thirat, therapeutic monoclonal antibodies (e.g., cetuximab), ragweed, grasses and birch. Exemplary pollen allergens include, for example, tree pollens, such as birch pollen, cedar pollen, oak pollen, alder pollen, hornbeam pollen, horse chestnut pollen, willow pollen, poplar pollen, sycamore pollen, linden pollen, olive pollen, mountain cedar pollen and Alstonia scoralis pollen.

[0017] The method of the present invention includes administering a pharmaceutical composition comprising an IL-4R antagonist to a subject before, after and / or during allergen exposure. For example, the present invention includes a method comprising administering a pharmaceutical composition comprising an IL-4R antagonist to a subject less than 12 hours, less than 10 hours, less than 8 hours, less than 6 hours, less than 4 hours, less than 2 hours, less than 1 hour, or less than 30 minutes before allergen exposure. In certain embodiments, a pharmaceutical composition comprising an IL-4R antagonist is administered to a subject several days to several weeks before allergen exposure (e.g., about 1 day to about 2 weeks before allergen exposure). The present invention also includes a method comprising administering a pharmaceutical composition comprising an IL-4R antagonist to a subject less than 12 hours, less than 10 hours, less than 8 hours, less than 6 hours, less than 4 hours, less than 2 hours, less than 1 hour, or less than 30 minutes after allergen exposure. As used herein, the phrase "allergen exposure" means any occurrence, episode, or occurrence in which a subject ingests, inhales, touches, or otherwise comes into direct or indirect contact with an allergen.

[0018] The present invention also includes a method comprising administering a pharmaceutical composition comprising an IL-4R antagonist to a subject after the onset of one or more allergic symptoms in the subject. For example, the present invention includes a method comprising administering a pharmaceutical composition comprising an IL-4R antagonist to a subject immediately, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours after the first onset of one or more allergic symptoms in the subject.

[0019] The present invention includes the method of treating, preventing, or reducing the severity of the allergic reaction induced by any of the above-mentioned allergens or classes of allergens.For example, the present invention includes the method of treating, preventing, or reducing the severity of the allergic reaction induced by the ingestion or exposure to food (e.g., milk, egg, wheat, soybean, fish, shellfish, peanuts or nuts).The present invention also includes the method of treating, preventing, or reducing the severity of the allergic reaction induced by non-food allergens (e.g., insect venom, dust, mold, animal dander, pollen, latex, medicine, ragweed, grass or birch).

[0020] The present invention includes a method of treating, preventing, or reducing the severity of an allergic reaction, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4R antagonist to a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in multiple doses, e.g., as part of a particular therapeutic dosing regimen. For example, the therapeutic dosing regimen includes administering multiple doses of the pharmaceutical composition to the subject about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, or less frequently.

[0021] The method of the invention according to certain embodiments comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an IL-4R antagonist in combination with a second therapeutic agent. The second therapeutic agent may be, for example, an agent selected from the group consisting of steroids, antihistamines, decongestants, and anti-IgE agents. As used herein, the phrase "in combination with" means that the pharmaceutical composition comprising an IL-4R antagonist is administered to a subject simultaneously with, immediately before, or immediately after administration of the second therapeutic agent. In certain embodiments, the second therapeutic agent is administered to a subject in combination with an IL-4R antagonist. The IL-4R antagonist is administered in a co-formulation with an IL-4R antagonist. In a related embodiment, the invention includes a method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an IL-4R antagonist to a subject undergoing a background anti-allergy therapy regimen. The background anti-allergy therapy regimen may include a series of administrations of, for example, steroids, antihistamines, decongestants, anti-IgE agents, etc. The IL-4R antagonist may be added on top of the background anti-allergy therapy regimen. In some embodiments, the IL-4R antagonist is added as part of a "background step-down" scheme in which the subject is gradually (e.g., stepwise) weaned from the background anti-allergy therapy while the subject is gradually administered a constant or increasing or decreasing dose of IL-4R.

[0022] Methods for improving the efficacy and / or safety of allergen-specific immunotherapy (SIT) The present invention also includes a method for improving the efficacy and / or safety of allergen-specific immunotherapy (SIT). The method according to this aspect of the present invention comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an IL-4R antagonist immediately before or simultaneously with a SIT regimen.

[0023] As used herein, the phrases "allergen-specific immunotherapy", "specific immunotherapy", "SIT", "SIT regimen" and the like refer to the repeated administration of allergens to a subject over time as a means of treating or preventing allergies and allergic reactions or reducing or eliminating allergic responses. In a typical SIT regimen, a small amount of allergen is initially administered to an allergic subject, followed by an increased amount of the allergen. In some cases, the SIT regimen includes at least two consecutive phases: (1) an up-titration phase and (2) a maintenance phase. In the up-titration phase, gradually increasing doses of the allergen are administered until an effective and safe dose is reached. The dose established at the end of the up-titration phase is then administered to the subject throughout the course of the maintenance phase. The duration of the up-titration phase may be several weeks or months. However, in certain embodiments, the up-titration phase is of substantially shorter duration (e.g., less than 1 week, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days). SIT regimens that include an escalation phase of less than 5 days are sometimes referred to as "rapid" immunotherapy or "rapid SIT." The maintenance phase of a SIT regimen may last for weeks, months, years, or indefinitely.

[0024] According to this aspect of the invention, the SIT regimen may include administration of a food allergen derived from foods selected from the group consisting of dairy products, eggs, wheat, soybeans, fish, shellfish, peanuts, and nuts. Alternatively, the SIT regimen may include administration of a non-food allergen selected from the group consisting of insect venom, dust, mold, animal dander, pollen, latex, medicines, ragweed, grass, and birch.

[0025] According to the method of the present invention, the IL-4R antagonist can be administered to the subject throughout the entire course of the SIT regimen or for only a portion of the SIT regimen.For example, the method of the present invention includes administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an IL-4R antagonist about once a week, once every two weeks, once every three weeks, once a month, once every two months, once every four months, once every six months, or less frequently before or during the up-dosing phase.In certain embodiments, the pharmaceutical composition comprising an IL-4R antagonist is administered to the subject about once a week, once every two weeks, once every three weeks, once a month, once every two months, once every four months, once every six months, or less frequently during or after the maintenance phase.

[0026] According to the present invention, the efficacy and / or safety of a SIT regimen is "improved" if one or more of the following outcomes or phenomena are observed or achieved in a subject: (1) the duration of the dose expansion phase is reduced without compromising efficacy or safety; (2) the duration of the dose expansion phase is reduced without compromising efficacy or safety; ) the duration of the maintenance phase is reduced without compromising efficacy or safety; (3) the number of allergen doses administered during the titration phase or maintenance phase is reduced without compromising efficacy or safety; (4) the frequency of allergen administration during the titration phase or maintenance phase is reduced without compromising efficacy or safety; (5) the dose of allergen administered during the titration phase or maintenance phase is increased without compromising efficacy or safety; (6) the frequency of or elimination of allergic responses or adverse side effects induced by the SIT regimen is reduced; (7) the use or need for conventional allergy medications (e.g., steroids, antihistamines, decongestants, anti-IgE agents, etc.) during the titration phase and / or maintenance phase is reduced; (8) the level of allergen-induced IgE expression is reduced; and / or (9) the frequency of or elimination of anaphylactic reactions. The efficacy of a SIT regimen is also considered, according to the present invention, to be "improved" if a subject experiences fewer and / or less severe allergic reactions following SIT therapy in combination with an IL-4R blocker than following SIT therapy alone.

[0027] The present invention also includes a method for weaning a subject from a SIT regimen. The method according to this aspect of the present invention includes administering to the subject one or more doses of a pharmaceutical composition comprising an IL-4R antagonist, and gradually reducing the frequency and / or amount of allergen administered to the subject during the course of the SIT regimen. In certain embodiments, the amount of IL-4R antagonist is increased while the amount of allergen administered as part of the SIT regimen is decreased. Preferably, the administration of the IL-4R antagonist will terminate the SIT regimen while still providing adequate protection from undesired allergic reactions.

[0028] Interleukin-4 receptor antagonist The method of the present invention includes administering a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist to a subject in need thereof. As used herein, an "IL-4R antagonist" (also referred to herein as an "IL-4Rα antagonist", "IL-4R blocker", "IL-4Rα blocker", etc.) is any agent that binds to or interacts with IL-4Rα or an IL-4R ligand and inhibits or attenuates 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. Type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and a γc chain. Type 2 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptor interacts with and is stimulated by IL-4, whereas type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, the IL-4R antagonist that can be used in the method of the present invention can function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4-mediated and IL-13-mediated signaling. Thus, the IL-4R antagonist of the present invention can prevent the interaction of IL-4 and / or IL-13 with type 1 or type 2 receptors.

[0029] Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g., "peptibody" molecules), "receptor-bodies" (e.g., engineered molecules that contain the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind IL-4 and / or IL-13.

[0030] Anti-IL-4Rα antibodies and antigen-binding fragments thereof According to certain exemplary embodiments of the present invention, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. The term "antibody" as used herein includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (referred to herein as HCVR or VVL). H The heavy chain constant region is made up of three domains: H 1. C H 2 and C H Each light chain comprises a light chain variable region (herein LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L The regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions of greater conservedness, termed framework regions (FRs). H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments of the invention, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0031] The term "antibody", as used herein, also includes antigen-binding fragments of complete antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, 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 obtained from complete antibody molecules using any suitable standard technique, such as proteolytic or recombinant genetic engineering techniques, including, for example, the manipulation and expression of DNA encoding the 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 can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to place one or more variable and / or constant domains in a suitable position, or to introduce codons, generate cysteine ​​residues, modify, add or delete amino acids, and the like.

[0032] 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 regions (e.g., isolated complementarity determining regions (CDRs), e.g., CDR3 peptides) or constrained FR3-CDR3-FR4 peptides of an antibody. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs) and shark variable IgNAR domains, are also encompassed by the expression "antigen-binding fragment" as used herein.

[0033] An 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 will generally contain at least one CDR that is contiguous or in frame with one or more framework sequences. L V associated with the domain H Antigen binding domain In the case of the merging fragment, V H and V L The domains can be positioned relative to each other in any suitable configuration. For example, the variable region can be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a monomeric V H or V L It may also contain a domain.

[0034] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary arrangements of variable and constant domains found in an antigen-binding fragment of an antibody of the invention include the following: (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 For any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible link between adjacent variable and / or constant domains within a single polypeptide molecule. Furthermore, antigen-binding fragments of the antibodies of the present invention may be linked to each other and / or to one or more monomeric V H Or V L The variable and constant domains may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain arrangements listed above, in which the variable and constant domains are non-covalently associated (e.g., by disulfide bonds).

[0035] The term "antibody" as used herein also includes multispecific (e.g., bispecific) antibodies. A multispecific antibody, or a multispecific antigen-binding fragment of an antibody, will typically comprise at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in conjunction with the antibody or antigen-binding fragment of an antibody of the present invention using routine techniques available in the art. For example, the present invention includes a method comprising the use of a bispecific antibody, where one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in connection with the present invention include, but are not limited to, for example, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadromas, knobs-into-holes, common light chains (e.g., common light chains with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED) bodies, leucine zippers, duobodies, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab 2 Bispecific formats include (for a review of the aforementioned formats, see, for example, Klein et al., 2012, mAbs 4:6, pp. 1-11, and references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, for example, using unnatural amino acids with orthogonal chemical reactivity to generate site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with defined composition, valency, and geometry. (See, for example, Kazane et al., J. Am. Chem. Soc. [Epub: December 4, 2012]).

[0036] The antibody used in the methods of the invention may be a human antibody. The term "human antibody," as used herein, refers to an antibody having variable and constant amino acids derived from human germline immunoglobulin sequences. The term "human antibody" as used herein is intended to include antibodies having regions. Nevertheless, the human antibodies of the present invention contain amino acid residues (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation) that are not encoded by human germline immunoglobulin sequences, e.g., in the CDRs and particularly in CDR3. However, the term "human antibody" as used herein is not intended to include antibodies in which the CDR sequences are derived from the germline of another mammalian species, such as a mouse, grafted onto human framework sequences.

[0037] The antibody used in the method of the invention may be a recombinant human antibody. The term "recombinant human antibody" as used herein is intended to include all human antibodies prepared, expressed, produced or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:2687-6295), or antibodies prepared, expressed, produced or isolated by any other means, including splicing of human immunoglobulin gene sequences to 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, in the case of using animals transgenic for human Ig sequences, in vivo somatic mutagenesis), thus improving the V H and V L The amino acid sequence of the region is human germline V H and V LThese are sequences that are derived from and related to sequences but do not naturally occur in the human antibody germline repertoire in vivo.

[0038] According to certain embodiments, the antibody used in the method of the present invention specifically binds IL-4Rα. The term "specifically binds" and the like 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, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" IL-4Rα, as used in the context of the present invention, has a K of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or less than about 0.5 nM as measured by a surface plasmon resonance assay. D The term "antibody" includes antibodies that specifically bind IL-4Rα or a portion thereof. However, an isolated antibody that specifically binds human IL-4Rα may have cross-reactivity to other antigens, such as IL-4Rα molecules from other (non-human) species.

[0039] According to certain exemplary embodiments of the present invention, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR) and / or a complementarity determining region (CDR) comprising any of the amino acid sequences of the anti-IL-4R antibodies described in U.S. Pat. No. 7,608,693. In certain exemplary embodiments, an anti-IL-4Rα antibody or antigen-binding fragment thereof that can be used in connection with the methods of the present invention comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity determining region (LCDR) of the light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. According to certain embodiments, an anti-IL-4Rα antibody or antigen-binding fragment thereof 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. wherein 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. In yet other embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO:1 and an LCVR comprising SEQ ID NO:2. According to certain exemplary embodiments, the methods of the invention comprise the use of an anti-IL-4Rα antibody, referred to as dupilumab, known in the art as dupilumab, or a biological equivalent thereof.

[0040] Other anti-IL-4Rα antibodies that can be used in connection with the methods of the invention include, for example, the antibody designated and known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or any of the anti-IL-4Rα antibodies described in U.S. Pat. Nos. 7,186,809, 7,605,237, 7,608,693, or 8,092,804.

[0041] Anti-IL-4Rα antibodies for use in connection with the methods of the invention may have pH-dependent binding properties. For example, anti-IL-4Rα antibodies for use in the methods of the invention may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, anti-IL-4Rα antibodies of the invention may exhibit enhanced binding to their antigen at acidic pH compared to neutral pH. The expression "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. The expression "neutral pH" as used herein means a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0042] In some cases, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" is defined as the K D K value of antibody binding to IL-4Rα at neutral pH D For example, an antibody or antigen-binding fragment thereof may be expressed as a ratio of an acidic / neutral K value of about 3.0 or greater. D When a ratio is given, it is considered for purposes of the present invention to indicate "reduced binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K D The ratio can be about 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 more.

[0043] Antibodies with pH-dependent binding properties can be obtained, for example, by screening antibody populations for reduced (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. In addition, antibodies with pH-dependent properties can be obtained by modifying the antigen-binding domain at the amino acid level. For example, by replacing one or more amino acids in the antigen-binding domain (e.g., in the CDR) with histidine residues, antibodies with reduced antigen-binding properties at acidic pH compared to neutral pH can be obtained. The expression "acidic pH" as used herein means a pH of 6.0 or lower.

[0044] Pharmaceutical Compositions The present invention includes a method comprising administering to a subject an IL-4R antagonist contained in a pharmaceutical composition. The pharmaceutical compositions of the present invention can be formulated with other suitable agents that provide the desired effect. Many suitable formulations can be found in a formulary known to all pharmacists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (e.g., LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci Technol 52:238-311.

[0045] Various delivery systems are known and can be used to administer the pharmaceutical compositions of the present invention, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J.Biol.Chem.262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral routes. The compositions can be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other bioactive agents.

[0046] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, for subcutaneous delivery, a pen delivery device can be easily utilized to deliver the pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and easily replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. A disposable pen delivery device does not have a replaceable cartridge. Rather, a disposable pen delivery device comes pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is empty of the pharmaceutical composition, the entire device is discarded.

[0047] In certain circumstances, pharmaceutical compositions can be delivered in controlled release systems. In one embodiment, pumps can be used. In another embodiment, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed in close proximity to the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0048] The injectable preparations include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc. These injectable preparations can be prepared by known methods. For example, the injectable preparations can be prepared by, for example, adding the above-mentioned antibody or a salt thereof to a sterile aqueous solution that is conventionally used for injection. The injection can be prepared by dissolving, suspending or emulsifying in a solvent or oily solvent. Examples of aqueous solvents for injection include isotonic solutions containing physiological saline, glucose and other auxiliary agents, and the like, which can be used in combination with suitable solubilizers, such as alcohol (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], and the like. Examples of oily solvents include sesame oil, soybean oil, and the like, which can be used in combination with solubilizers, such as benzyl benzoate, benzyl alcohol, and the like. It is preferable to fill the injection thus prepared into a suitable ampoule.

[0049] The above-mentioned oral or parenteral pharmaceutical compositions are advantageously prepared in a dosage form suitable for combining a dosage of the active ingredient, such as tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0050] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in connection with the present invention are disclosed, for example, in US Patent Application Publication No. 2012 / 0097565.

[0051] Dosage The amount of IL-4R antagonist (e.g., anti-IL-4Rα antibody) administered to a subject according to the method of the present invention is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to the amount of IL-4R antagonist that results in one or more of the following: (a) reducing the severity or duration of allergic reaction; (b) alleviating one or more symptoms or signs of allergic reaction; (c) preventing or reducing anaphylaxis; (d) reducing serum IgE levels; (e) reducing the use or need for conventional allergy therapy (e.g., reducing or eliminating the use of antihistamines, decongestants, nasal or inhaled steroids, anti-IgE treatment, epinephrine, etc.); and (f) reducing the frequency of allergic response to allergen-specific immunotherapy (SIT).

[0052] In the case of an anti-IL-4Rα antibody, a therapeutically effective amount is about 0.05 mg to about 600 mg of an anti-IL-4R antibody, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 6 The dose can be about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. In certain embodiments, 300 mg of an anti-IL-4R antibody is administered.

[0053] The amount of IL-4R antagonist contained in an individual dose can be expressed in milligrams of antibody per kg of patient body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to a patient at a dose of about 0.0001 to about 10 mg / kg of patient body weight.

[0054] Working Example The following examples provide a complete disclosure and description of how to make and use the methods and compositions of the present invention. The present invention is presented to provide an understanding and explanation to one of ordinary skill in the art and is not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. EXAMPLES

[0055] IL-4R blockade prevents systemic anaphylaxis in a mouse model of peanut allergy In this example, the effect of IL-4Rα blockers on peanut-induced anaphylaxis in a mouse model was evaluated. The experimental protocol is outlined in FIG. 1A. Briefly, three groups of five C57BL / 6 mice were each sensitized with 100 μg crude peanut extract and alum (2 mg / ml) administered by subcutaneous injection on day 0, followed by a booster injection on day 14. A challenge injection of 50 μg peanut extract was administered intravenously on day 28. The first group of mice received no treatment. The second group of mice received an anti-mouse IL-4Rα antibody ("anti-mIL-4Rα") subcutaneously at a dose of 25 mg / kg on days 13 and 27. The third group of mice received an isotype control antibody on days 13 and 27. The anti-mIL-4Rα antibody used in this and subsequent examples was an antibody comprising a HCVR having the amino acid sequence of SEQ ID NO:9 and a LCVR having the amino acid sequence of SEQ ID NO:10.

[0056] Systemic anaphylaxis in this model was manifested as a drop in central body temperature. Therefore, to assess the extent of anaphylaxis in this experimental system, mouse central body temperatures were measured over a period of 180 min after challenge injection. The results are shown in Figure 1B. Untreated mice and mice receiving an isotype control antibody showed a rapid drop in central body temperature 30 min after challenge, indicative of an anaphylactic reaction. Central body temperature in control mice gradually increased to baseline by 180 min after challenge. In contrast, mice receiving anti-mIL-4Rα treatment showed only a small drop in central body temperature 30 min after challenge and returned to normal temperature by the 60 min time point. The difference in central body temperature change between anti-mIL-4Rα treated mice and controls at 30 min was statistically significant (P<0.0001).

[0057] Final IgE levels were also measured for each experimental group (Figure 2). As shown, IL-4Rα blockade significantly reduced total IgE levels below the limit of detection compared to untreated and isotype control treated animals.

[0058] The previous experiment involved two independent doses of anti-mIL-4Rα antibody (administered on D13 and D27). A second set of experiments was then performed to evaluate the effect of a single dose on either day 13 or day 27 in the same peanut allergy model. The experimental protocol is outlined in Figure 3A (administered on D13) and Figure 4A (administered on D27). The results are shown in Figures 3B and 4B, respectively. Mice receiving a single dose of anti-mIL-4Rα antibody on day 13 showed significantly less anaphylaxis compared to untreated and control-treated animals (see Figure 3B), although this protective effect was not as pronounced as in the two-dose experiment (Figure 1B). The protective effect of anti-IL-4Rα treatment was substantially attenuated in mice receiving a single dose of antibody on day 27 (see Figure 4B).

[0059] In the single dose experiment, IgE levels were measured in samples taken from animals on days 12, 26, and 28. The results are shown in Figure 5A (day 13 dose) and Figure 5B (day 27 dose). Importantly, the effect of anti-mIL-4Rα antibodies on systemic anaphylaxis correlated with the degree of IgE inhibition. The reduction in IgE levels was not immediate after anti-mIL-4Rα treatment, but rather appeared to require approximately 13 days from the time of antibody administration until IgE levels were completely suppressed. Thus, this example supports a role for IL-4R antagonism in preventing allergic responses. EXAMPLES

[0060] Use of IL-4R blockade in a peanut-specific immunotherapy model The purpose of this example was to determine the effect of IL-4Rα blockade when added to an allergen-specific immunotherapy (SIT) regimen. For these experiments, a mouse peanut-specific immunotherapy model was developed based in part on the model of Kulis et al., J. Allergy Clin. Immunol. 127(1):81-88 (2011). Two sets of experiments were performed, as described below.

[0061] The experimental protocol used in the first set of experiments is outlined in FIG. 6. Four groups of mice were used in these experiments. Three of the four groups of mice were subjected to a peanut-specific immunotherapy regimen that included a sensitization phase, a dose-escalation phase, and a challenge dose. The sensitization phase consisted of administration of 0.5 mg peanut extract + 2 mg alum administered intraperitoneally on days 0, 7, and 28. The dose-escalation phase consisted of 12 separate administrations of various doses of peanut extract without alum on days 49, 51, 53, 56, 58, 60, 63, 65, 67, 70, 72, and 74. The challenge dose consisted of administration of 1 mg peanut extract on day 98.

[0062] The various treatment groups for these experiments were as follows: Group A, which received neither immunotherapy nor antibody ("No IT"); Group B, which received only immunotherapy without antibody ("IT"); Group C, which received immunotherapy and an isotype control antibody on days 36, 50, 57, 64 and 71 ("IT+isotype control"); and Group D, which received immunotherapy and an anti-mIL-4Rα antibody (25 mg / kg, subcutaneous) on days 36, 50, 57, 64 and 71 ("IT+anti-IL-4Rα"). The anti-mIL-4Rα antibody used in these experiments was the same antibody used in Example 1 herein.

[0063] To assess the extent of anaphylaxis in this system, mouse central temperatures were measured for 180 min after challenge injection. In addition, serum samples were collected throughout the experiment (days 35, 46, 77, and 98) for immunoglobulin measurements. Anaphylaxis results are shown in Figure 7. Total IgE, IgG1, IgG2a, and IgG levels on days 77 and 96 are shown in Figures 8, 9, 10, and 11, respectively.

[0064] The results of these experiments show that allergen-specific immunotherapy alone protects against peanut-induced systemic anaphylaxis in this model (see FIG. 7). Importantly, administration of anti-IL-4Rα antibodies did not interfere with the observed protective effect of SIT. In addition, a trend towards increased IgE induced by SIT was observed in IT-only and IT+isotype control treated animals. In contrast, IgE production was blocked in anti-IL-4Rα treated animals (see FIG. 8). A trend towards increased peanut-specific IgG1 titers was observed in animals treated with immunotherapy (with or without antibody treatment), although statistical significance was only observed in IT animals at day 77 (see FIG. 9). It was also observed that IL-4Rα blockade produced an increase in peanut-specific IgG2a (see FIG. 10). The results from this first set of experiments experimentally support the use of IL-4R blockade as a potential means of improving the efficacy and safety of allergen-specific immunotherapy.

[0065] A second set of experiments was then performed to determine the effect of IL-4R blockade in a SIT regimen using lower allergen doses in the titration phase. The experimental protocol used in this second set of experiments is outlined in FIG. 12. As before, four groups of mice were used in these experiments. Three of the four groups of mice were subjected to a peanut-specific immunotherapy regimen identical to that used in the first set of experiments, except that lower doses of allergen were administered in the titration phase. Specifically, the titration phase of these experiments consisted of only eight separate administrations (instead of twelve) of various doses of peanut extract without alum on days 51 and 53 (0.1 mg), 58 and 60 (0.25 mg), 65 and 67 (0.5 mg), and 72 and 74 (0.5 mg).

[0066] Again, four treatment groups were used ("No IT", "IT only", "IT + isotype control"; and "IT + anti-IL-4Rα"). Antibodies were administered at the same dose as before (25 mg / kg, SQ), but injections were administered on days 36, 49, 56, 63, and 70 (as opposed to days 36, 50, 57, 64, and 71 in the first set of experiments). The extent of anaphylaxis was determined by measuring mouse central body temperature over a 240-minute period following the challenge injection. The results are shown in FIG. 13.

[0067] In these experiments, less frequent allergen administration during the ramp-up phase provided less protection against anaphylaxis compared to the more frequent dosing regimen used in the first set of experiments (8 doses versus 12). In particular, a substantial drop in central body temperature was observed in IT and IT+isotype control mice during the first 60 minutes after allergen challenge, which was only slightly less severe than that observed in "no IT" mice. In contrast, only a mild anaphylactic response (i.e., a slight drop in central body temperature) was observed in anti-IL-4Rα-treated mice. The ramp-up phase in this model can be considered similar to the maintenance phase in conventional SIT regimens in humans. Thus, the results from this example show that IL-4R blockers can substantially improve the safety of allergen-specific immunotherapy regimens by allowing for reduced maintenance phase dosing. Less frequent allergen administration is also more convenient and results in greater patient compliance in SIT regimens.

[0068] The present invention is not intended to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. 1. A method for treating, preventing, or reducing the severity of an allergic reaction, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist.

2. The method of claim 1, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that binds IL-4Rα and prevents the interaction of IL-4 and / or IL-13 with type 1 or type 2 IL-4 receptors.

3. The method of claim 2, wherein the antibody or antigen-binding fragment thereof prevents interaction of IL-4 and IL-13 with both type 1 and type 2 IL-4 receptors.

4. The method of claim 3, wherein the antibody or antigen-binding fragment thereof comprises 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.

5. The method of claim 4, wherein the antibody or antigen-binding fragment thereof 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.

6. The method of claim 5, wherein the HCVR comprises the amino acid sequence of SEQ ID NO:1 and the LCVR comprises the amino acid sequence of SEQ ID NO:

2.

7. 2. The method of claim 1, wherein the IL-4R antagonist is dupilumab or a biological equivalent thereof.

8. The method of claim 1 , wherein the pharmaceutical composition is administered to the subject prior to allergen exposure.

9. 10. The method of claim 8, wherein the pharmaceutical composition is administered to the subject less than 4 hours prior to allergen exposure.

10. The method of claim 1 , wherein the pharmaceutical composition is administered to the subject during or after allergen exposure.

11. 11. The method of claim 10, wherein the pharmaceutical composition is administered to the subject less than 4 hours after allergen exposure.

12. The method of claim 10, wherein the pharmaceutical composition is administered to the subject following the onset of one or more allergic symptoms in the subject.

13. 13. The method of claim 12, wherein the pharmaceutical composition is administered to the subject less than 4 hours after onset of one or more allergic symptoms of the subject.

14. 13. The method of claim 12, wherein the allergic symptoms are selected from the group consisting of hives, angioedema, rhinitis, asthma, vomiting, difficulty breathing, swollen lips, swollen tongue, and decreased blood pressure.

15. 2. The method of claim 1, wherein the allergic reaction is anaphylaxis.

16. The method of claim 1 , wherein the allergic response is triggered by ingestion of or exposure to a food.

17. 17. The method of claim 16, wherein the food product is selected from the group consisting of dairy, egg, wheat, soy, fish, shellfish, peanuts and nuts.

18. 10. The method of claim 1, wherein the allergic response is induced by exposure to a non-food allergen.

19. 20. The method of claim 18, wherein the non-food allergen is selected from the group consisting of dust, pollen, insect venom, mold, animal fur, animal dander, wool, latex, metals, household cleaners, detergents, drugs, therapeutic monoclonal antibodies, ragweed, grasses and birch.

20. 10. The method of claim 1, wherein the pharmaceutical composition is administered to the subject as part of a therapeutic dosing regimen comprising administration of the pharmaceutical composition once a week, once every two weeks, once every three weeks, or once a month.

21. 10. The method of claim 1, wherein the pharmaceutical composition is administered to the subject in combination with a second therapeutic agent selected from the group consisting of steroids, antihistamines, decongestants, and anti-IgE agents.

22. A method for improving the efficacy and / or safety of an allergen-specific immunotherapy (SIT) regimen, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist immediately prior to or simultaneously with the SIT regimen.

23. The method of claim 22, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that binds IL-4Rα and prevents the interaction of IL-4 and / or IL-13 with type 1 or type 2 IL-4 receptors.

24. The method of claim 23, wherein the antibody or antigen-binding fragment thereof prevents interaction of IL-4 and IL-13 with both type 1 and type 2 IL-4 receptors.

25. 25. The method of claim 24, wherein the antibody or antigen-binding fragment thereof comprises 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.

26. The method of claim 25, wherein the antibody or antigen-binding fragment thereof 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.

27. 27. The method of claim 26, wherein the HCVR comprises the amino acid sequence of SEQ ID NO:1 and the LCVR comprises the amino acid sequence of SEQ ID NO:

2.

28. 23. The method of claim 22, wherein the IL-4R antagonist is dupilumab or a biological equivalent thereof.

29. 23. The method of claim 22, wherein the SIT regimen comprises a boost phase followed by a maintenance phase.

30. 30. The method of claim 29, wherein the SIT regimen is a rapid SIT regimen.

31. 31. The method of claim 30, wherein the pharmaceutical composition is administered to the subject about once a week, once every two weeks, once every three weeks, or once a month prior to or during the boosting phase.

32. 31. The method of claim 30, wherein the pharmaceutical composition is administered to the subject about once weekly, once every two weeks, once every three weeks, or once a month during or after the maintenance phase.

33. 31. The method of claim 30, wherein the pharmaceutical composition is administered to the subject about once a week, once every two weeks, once every three weeks, or once a month throughout the course of the SIT regimen.

34. 23. The method of claim 22, wherein the SIT regimen comprises administration of a food allergen derived from a food selected from the group consisting of dairy, egg, wheat, soy, fish, shellfish, peanuts, and tree nuts.

35. 23. The method of claim 22, wherein the SIT regimen comprises administration of a non-food allergen selected from the group consisting of dust, pollen, insect venom, mold, animal fur, animal dander, wool, latex, metals, household cleaners, detergents, drugs, therapeutic monoclonal antibodies, ragweed, grass and birch.

36. 23. The method of claim 22, wherein the pharmaceutical composition is administered to the subject in combination with a second therapeutic agent selected from the group consisting of steroids, antihistamines, decongestants, and anti-IgE agents.

37. 1. A method for reducing total serum IgE levels in a subject exposed to an allergen, comprising administering to the subject a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist in an amount sufficient to reduce or inhibit IgE production.

38. 38. The method of claim 37, wherein the IL-4R antagonist is an antibody or antigen-binding fragment thereof that binds IL-4Rα and prevents the interaction of IL-4 and / or IL-13 with type 1 or type 2 IL-4 receptors.

39. The method of claim 38, wherein the antibody or antigen-binding fragment thereof prevents interaction of IL-4 and IL-13 with both type 1 and type 2 IL-4 receptors.

40. 40. The method of claim 39, wherein the antibody or antigen-binding fragment thereof comprises 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.

41. The method of claim 40, wherein the antibody or antigen-binding fragment thereof 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.

42. 42. The method of claim 41, wherein the HCVR comprises the amino acid sequence of SEQ ID NO:1 and the LCVR comprises the amino acid sequence of SEQ ID NO:

2.

43. 38. The method of claim 37, wherein the IL-4R antagonist is dupilumab or a biological equivalent thereof.

44. 38. The method of claim 37, wherein the allergen is a food allergen derived from or contained in a food selected from the group consisting of dairy products, eggs, wheat, soybeans, fish, shellfish, peanuts and tree nuts.

45. 38. The method of claim 37, wherein the allergen is a non-food allergen selected from the group consisting of insect venom, dust, mold, animal dander, pollen, latex, ragweed, grass and birch.

46. 38. The method of claim 37, wherein the pharmaceutical composition is administered to the subject in combination with a second therapeutic agent selected from the group consisting of steroids, antihistamines, decongestants, and anti-IgE agents.

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