RU2777328C2 - Methods for preventing or treating allergies by introducing an il-4r antagonist - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: group of inventions relates to the pharmaceutical industry, namely to a method for reducing serum allergen-specific IgE in a patient and to the use of an interleukin-4 receptor antagonist (IL-4R) to reduce serum allergen-specific IgE in a patient with an elevated level of serum allergen-specific IgE. A method for reducing serum allergen-specific IgE in a patient, including: administration to a patient with atopic dermatitis, asthma and/or allergic rhinitis, a therapeutically effective amount of an interleukin-4 receptor antagonist (IL-4R), and before or during treatment, the patient has a serum allergen-specific IgE level of 0.35 kU/ml at determination by immunoassay, and the allergen comes from a source selected from a group consisting of gray alder, black rot, Bermuda grass, silver birch, cat dandruff, cladosporium, cockroach, Dermatophagoides farinae, D. pteronyssinus, dog dandruff, elm, Johnson's grass, white oak, ragweed, timothy, white ash, white candida, Malasezzia furfur, Pityrosporum orbiculare, mold, staphylococcal enterotoxin A and staphylococcal enterotoxin B; moreover, the IL-4R antagonist is an antibody or its antigen-binding fragment that specifically bind IL-4Rα, and contains three complementarity-determining regions of the heavy chain (HCDR1, HCDR2 and HCDR3) and three complementarity-determining regions of the light chain (LCDR1, LCDR2 and LCDR3), where HCDR1 contains the amino acid sequence SEQ ID NO: 3; HCDR2 contains the amino acid sequence SEQ ID NO: 4; HCDR3 contains the amino acid sequence SEQ ID NO: 5; LCDR1 contains the amino acid sequence SEQ ID NO: 6; LCDR2 contains the amino acid sequence SEQ ID NO: 7 and LCDR3 contains the amino acid sequence SEQ ID NO:8, wherein the IL-4R antagonist is administered for at least 16 weeks, wherein the IL-4R antagonist is administered in an initial dose followed by one or more secondary doses, where each secondary dose is administered after 1-4 weeks after the immediately preceding dose, and moreover: i) the initial dose contains 600 mg and each secondary dose contains 300 mg of an IL-4R antagonist, or ii) the initial dose contains 400 mg and each secondary dose contains 200 mg of an IL-4R antagonist. The use of an interleukin-4 receptor antagonist (IL-4R) to reduce serum allergen-specific IgE in a patient with elevated serum allergen-specific IgE. The use of an interleukin-4 receptor antagonist (IL-4R) to obtain a drug to reduce serum allergen-specific IgE in a patient with an elevated level of serum allergen-specific IgE.

EFFECT: above-described method and application make it possible to more effectively reduce serum allergen-specific IgE in a patient with an elevated level of serum allergen-specific IgE.

23 cl, 11 dwg, 3 tbl, 4 ex

Description

[001] This application contains a sequence listing, which is presented in electronic form in ASCII format and, thus, is incorporated herein by reference in its entirety. The specified ASCII copy, created on August 18, 2017, is named SequenceList_28PCT.txt and has a size of 11043 bytes.

FIELD OF THE INVENTION

[002] The present invention relates to the prevention and/or treatment of allergies and allergic conditions. More specifically, the invention relates to the administration of interleukin-4 receptor (IL-4R) antagonists for the prevention or treatment of allergy in a patient.

BACKGROUND OF THE INVENTION

[003] Allergies and allergic diseases are serious medical conditions whose consequences range from non-life-threatening responses that resolve over time to life-threatening effects such as anaphylaxis. Allergic reactions can result from contact with or exposure to various foods, such as certain foods, insect venom, plant material (such as pollen), chemicals, drugs/drugs, and animal dander. The pathophysiology of allergy is influenced by a complex interplay between immunoglobulin E (IgE) mediated sensitization, the immune system, and environmental factors. Current allergy treatment options include contact avoidance, pharmacological treatment of symptoms, and prophylaxis using allergen-specific immunotherapy (SIT). Unfortunately, these current treatment strategies are often insufficient, expensive, impractical, or involve significant risk. For example, avoidance of an allergen is not always possible and may have a negative effect on the quality of life of the patient and caregiver. Immunotherapeutic approaches, on the other hand, involve intentionally administering an allergen to susceptible individuals and are thus inherently risky, with the potential for unwanted severe allergic reactions or anaphylaxis. Thus, there is an unmet need in the art for new therapeutic approaches that prevent or treat allergies or allergic responses and reduce the risk of developing an allergic response.

BRIEF DESCRIPTION OF THE INVENTION

[004] According to some aspects, the present invention relates to methods for preventing or treating allergies in an individual. Also included are methods of reducing the susceptibility to an allergic reaction or reducing an individual's allergen sensitization. In some embodiments, the invention relates to methods for reducing allergen-specific IgE serum levels in an individual. The methods of the present invention include administering to an individual in need thereof a pharmaceutical composition containing a therapeutically effective amount of an interleukin-4 receptor (IL-4R) antagonist. In some embodiments, the pharmaceutical composition is administered subcutaneously at a dose of 75-600 mg.

[005] In some embodiments, the implementation of the present invention relates to methods for preventing or treating allergies, where the prevention or treatment of allergies includes reducing the level of allergen-specific IgE. In some embodiments, the patient experiences at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% reduction in allergen-specific IgE levels upon administration of an IL-4R antagonist. In some embodiments, an individual's allergic reaction or predisposition is triggered by sensitization to an allergen. In some embodiments, the present invention relates to methods for reducing or eliminating allergen sensitization.

[006] In some embodiments, the individual is sensitized to an allergen derived from one or more sources, including, but not limited to, gray alder, black rot, Bermuda grass, warty birch, cat dander, cladosporium, cockroach (redhead), Dermatophagoides farinae (mite), D. pteronyssinus , dog dander, elm, Johnson's grass, white oak, common ragweed, wormwood, timothy grass (Phleum), white ash, white candida, Malasezzia furfur , Pityrosporum orbiculare , mold, staphylococcal enterotoxin A or staphylococcal enterotoxin B. In some embodiments, the individual is sensitized to an allergen derived from a food item selected from the group consisting of dairy product, fish, shellfish, peanut, tree nut, fruit (eg, melon), egg, wheat, and soy.

[007] According to certain embodiments, the present invention relates to methods for treating or preventing allergies or reducing the susceptibility to an allergic reaction in an individual, where the methods include sequentially administering to the individual from about 50 mg to about 600 mg of an IL-4R antagonist as the initial dose, and after this one or more secondary doses. In some embodiments, the initial dose and one or more secondary doses each contain from about 75 mg to about 300 mg of an IL-4R antagonist. In some embodiments, the IL-4R antagonist is administered as an initial dose of 400 mg or 600 mg, and then one or more secondary doses are administered, where each secondary dose contains 200 mg or 300 mg. According to this aspect of the invention, the pharmaceutical composition may be administered to the individual at a dosing frequency such as once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. In one embodiment, the IL-4R antagonist is administered at an initial dose of 400 mg followed by one or more secondary doses where each secondary dose contains 200 mg and is administered once a week.

[008] In some embodiments, the invention relates to methods for treating or preventing allergies or reducing the susceptibility to an allergic reaction in an individual, where the individual has a disease or disorder selected from the group consisting of atopic dermatitis, asthma, allergic rhinitis, eosinophilic esophagitis, and food allergies . In one embodiment, the individual has moderate to severe atopic dermatitis.

[009] Examples of IL-4R antagonists that can be used in the context of 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 to IL-4R or its ligands. In certain embodiments, an IL-4R antagonist is an antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) that binds the IL-4Rα chain and blocks IL-4, IL-13, or both IL-4 and IL signaling. -13. In one embodiment, an antibody or antigen-binding fragment thereof that specifically binds IL-4R comprises complementarity determining regions (CDRs) of heavy chain variable region (HCVR)/heavy chain variable region (LCVR) sequence pairs of SEQ ID NO: 1/2. In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain CDR (HCDR1) having the amino acid sequence of SEQ ID NO: 3, HCDR2 having the amino acid sequence of SEQ ID NO: 4, HCDR3 having the amino acid sequence of SEQ ID NO: 5, a light CDR chain (LCDR1) having the amino acid sequence of SEQ ID NO: 6, LCDR2 having the amino acid sequence of SEQ ID NO: 7, and LCDR3 having the amino acid sequence of SEQ ID NO: 8. One such type of antigen-binding protein that can be used in the context of the methods of of the present invention is an anti-IL-4Rα antibody such as dupilumab.

[010] In some embodiments, the implementation of the pharmaceutical composition is administered to the individual subcutaneously or intravenously.

[011] In some embodiments, the implementation of the pharmaceutical composition is administered to the patient before, after, or simultaneously with the second therapeutic agent. In some embodiments, the second therapeutic agent is selected from the group consisting of another IL-4R inhibitor, an IgE inhibitor, a corticosteroid (e.g., a topical corticosteroid or a systemic corticosteroid), a non-steroidal anti-inflammatory agent (NSAID), an antihistamine, systemic immunotherapy, and IFNγ.

[012] In some embodiments, the present invention relates to the use of an IL-4R antagonist of the invention for the manufacture of a medicament for the treatment or reduction or prevention of allergy or allergen sensitization in a patient.

[013] Other embodiments of the present invention will become clear after considering the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[014] Figure 1 shows the root mean square (LS) mean of percent change in eczema severity and area index (EASI) scores from baseline to week 16 and the study described in Example 1. *P<0.0001 vs. placebo; qw, once a week, SE, standard error.

[015] FIG . 2 shows the LS mean of the percentage change in peak weekly pruritus scores (NRS) from baseline to week 16 in the study described in Example 1. *P<0.01 vs. placebo; LS, rms values.

[016] FIG . 3 shows serum thymus-activated chemokine (TARC) levels from baseline to week 16 in the study described in Example 2. **P<0.001 vs. placebo; DPL, dupilumab; PBO, placebo; qw, once a week; SE, standard error.

[017] Figure 4 shows serum levels of pulmonary activation-regulated chemokine (PARC) from baseline to week 16 in the study described in Example 2. ***P<0.0001 vs. placebo; DPL, dupilumab; PBO, placebo; qw, once a week; SE, standard error.

[018] Figure 5 shows serum periostin levels from baseline to week 16 in the study described in Example 2. *P<0.01 vs. placebo; DPL, dupilumab; PBO, placebo; qw, once a week; SE, standard error.

[019] Figure 6 shows serum total IgE levels from baseline to week 16 in the study described in Example 2. ***P<0.0001 vs. placebo; DPL, dupilumab; PBO, placebo; qw, once a week; SE, standard error.

[020] FIG. 7 shows that dupilumab inhibits a wide variety of allergen-specific IgE in serum after treatment for 16 weeks as described in Example 2.

[021] Figure 8 shows the suppression of IgE specific to a wide variety of allergens in serum after administration for 16 weeks of placebo, dupilumab at a dose of 100 mg every 4 weeks (q4w) or dupilumab at a dose of 300 mg q4w, as described in the example 2. * P <0.05, ** P <0.01, P <0.001, P <0.0001 vs placebo. D. farinae , Dermatophagoides farinae ; D. pteronyssinus , Dermatophagoides pteronyssinus ; M. furfur , Malasezzia furfur ; P. orbiculare ; Pityrosporum orbiculare ; enterotoxin S. A/B, staphylococcal enterotoxin A/B. interquartile range: Q1, lower quartile; Q3, top quartile.

[022] Figure 9 shows the suppression of IgE specific to a wide variety of allergens in serum after treatment for 16 weeks with dupilumab at a dose of 200 mg every 2 weeks (q2w), 300 mg q2w or 300 mg weekly (qw), as described in Example 2. * P < 0.05, ** P < 0.01, P < 0.001, P < 0.0001 vs placebo. D. farinae , Dermatophagoides farinae ; D. pteronyssinus , Dermatophagoides pteronyssinus ; M. furfur , Malasezzia furfur ; P. orbiculare ; Pityrosporum orbiculare ; enterotoxin S. A/B, staphylococcal enterotoxin A/B. interquartile range: Q1, lower quartile; Q3, top quartile.

[023] Figure 10 shows the content of Staphylococcus aureus in the damaged skin of patients with atopic dermatitis in the study according to example 3.

[024] Figure 11 shows the content of S. aureus in the damaged skin of patients with atopic dermatitis in the study according to example 3.

DETAILED DESCRIPTION

[025] 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 may vary. It should also be understood that the terminology used in the present specification is only intended to describe specific embodiments and is not intended to be limiting, as the scope of the present invention is only limited by the appended claims.

[026] Unless otherwise indicated, all technical and scientific terms used in the present description have the same meaning, which usually implies a specialist in the field to which the present invention relates. In the context of the invention, the term "approximately", when used in relation to a specific specified numerical value, means that this value may differ from the specified value by no more than 1%. For example, within the scope of the invention, the expression "about 100" includes 99 and 101, and all values in between (eg, 99.1, 99.2, 99.3, 99.4, etc.).

[027] While any methods and materials similar or equivalent to those described herein may be used to practice the present invention, preferred methods and materials are described herein. All publications mentioned in the present description are incorporated herein by reference in their entirety.

[028] In certain aspects, the present invention includes methods for preventing or treating an allergy in an individual, wherein the methods comprise administering a therapeutically effective amount of an IL-4R antagonist to an individual in need thereof. Within the scope of the invention, the terms "treat", "treatment", etc. means alleviating allergy symptoms, removing the cause of allergy symptoms either temporarily or permanently, or preventing or slowing the onset of allergy symptoms in an individual. Within the scope of the invention, the terms "warn", "warning", etc. relate to preventing the development of an allergy, an allergic reaction, or an allergic condition. This term, within the scope of the invention, also includes the reduction or elimination of allergen sensitization in order to prevent an allergic reaction. In some embodiments, the term refers to a reduction in serum allergen-specific IgE of at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to with baseline upon administration of an IL-4R antagonist provided by the methods of the present invention.

[029] The present invention relates to methods that include administering to a patient a therapeutic composition containing an IL-4R antagonist. In the context of the invention, the expression "patient" means a human or non-human animal that exhibits one or more symptoms or signs of allergy or atopy and/or has been diagnosed with an allergy to an allergen. In some embodiments, the term "patient" includes individuals who are at increased risk of developing an allergy or an allergic response to an allergen. In some embodiments, the term includes individuals who exhibit sensitization to one or more allergens. In some embodiments, the methods of the present invention can be used to treat individuals who have elevated levels of one or more serum biomarkers, including, but not limited to, total IgE, allergen-specific IgE, thymus-regulated and activating chemokine (TARC), pulmonary regulated activation of chemokine (PARC), lactate dehydrogenase (LDH) and periostin. For example, the methods of the present invention include administering an IL-4R antagonist to patients with elevated levels of allergen-specific IgE. The terms "individual" and "patient" are used interchangeably herein.

[030] Within the scope of the invention, the terms "allergic response", "allergic reaction", "allergy symptom", etc. include one or more signs or symptoms selected from the group consisting of rash (eg, urticaria), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinus inflammation, watery eyes, wheezing, bronchospasm, decreased maximum speed exhalation (PEF), gastrointestinal upset, redness, swelling of the lips, swelling of the tongue, lowering of blood pressure, anaphylaxis, and organ dysfunction/failure. "Allergic response", "allergic reaction", "allergy symptom", etc. also include immunological responses and reactions such as, for example, increased production of IgE and/or increased production of allergen-specific immunoglobulins.

[031] The term "allergen", within the scope of the invention, includes any substance, chemical, particle or composition that is capable of stimulating an allergic response in a predisposed individual. Allergens can be contained in or originate from foods such as dairy products (eg cow's milk), eggs, celery, sesame, wheat, soy, fish, shellfish, sugars (eg sugars present in meat such as alpha -galactose), peanuts, other legumes (eg beans, peas, soybeans, etc.), and hazelnuts. Alternatively, the allergen may be present in or not derived from the food, such as dust (e.g. containing house dust mites), pollen, insect venom (e.g. bee, wasp, mosquito, fire ant, etc.), mould, animal hair, animal dander, wool, latex, metals (e.g. nickel), household cleaners, detergents, medicines, cosmetics (e.g. perfumes, etc.), medicines (e.g. penicillin, sulfonamides, salicylate, etc.), therapeutic monoclonal antibodies (eg cetuximab), ragweed, grass and birch. Exemplary pollen allergens include, for example, tree pollen 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, juniper pollen, and pollen. Alstonia scholaris . Other examples of allergens can be found in the present description. The terms "allergen" and "antigen" are used interchangeably herein.

[032] In some aspects, the present invention relates to methods for reducing the susceptibility to an allergic reaction in an individual, the methods comprising administering a therapeutically effective amount of an IL-4R antagonist to an individual in need thereof. In some embodiments, the term "individual in need thereof" includes an individual predisposed to an allergic reaction or having an increased risk of developing an allergic reaction to an allergen. In some embodiments, an individual may be at risk of developing an allergy or an allergic response to an allergen due to sensitization to said allergen. For example, the term includes individuals who exhibit increased levels of serum IgE specific to one or more allergens ("allergen sensitization"). In the context of the present invention, the term "individual in need thereof" also includes individuals who have a disease or disorder selected from the group consisting of atopic dermatitis, asthma, allergic rhinitis, eosinophilic esophagitis, and food allergy. The term "individual" also includes individuals with elevated levels of serum total and allergen-specific IgE, or serum chemokines (eg, CCL17 or CCL27), which may be at increased risk of developing an allergic response. The present invention relates to methods for reducing the risk of developing an allergy or an allergic response in predisposed individuals.

[033] According to some aspects, the present invention provides methods for reducing serum allergen-specific IgE levels in an individual, the methods comprising administering a therapeutically effective amount of an IL-4R antagonist. In some embodiments, serum levels of allergen-specific IgE are reduced by at least 10%, 20%, 30%, 40%, or 50% from baseline after administration of an IL-4R antagonist.

[034] Methods for detecting and/or quantifying a serum biomarker, such as allergen-specific IgE or total IgE, are known in the art; kits to quantify such a biomarker are available from a variety of commercial sources, and various commercial diagnostic laboratories offer services to quantify such biomarkers.

[035] For example, Phadiatop™ is a commercially available serum-specific or antigen-specific IgE test proposed for screening for allergic sensitization (Merrett et al 1987, Allergy 17: 409-416). This test provides simultaneous testing of serum specific IgE to a mixture of relevant allergens that cause general inhalation allergy. This test gives a qualitative result, either positive or negative, depending on the fluorescent response obtained. When a patient sample gives a fluorescent response greater than or equal to that of the reference, a positive test result is given. A patient sample with a lower fluorescent response provides a negative test result. The present invention relates to methods comprising selecting an individual who demonstrates a positive test result and administering to the individual a therapeutically effective amount of an IL-4R antagonist.

[036] The present invention also relates to methods for determining whether an individual is a suitable individual who would benefit from administration of a pharmaceutical composition containing an IL-4R antagonist. For example, if an individual, prior to administration of a pharmaceutical composition containing an IL-4R antagonist, has a serum biomarker level (e.g., allergen-specific IgE) that indicates allergen sensitization, then the individual is thus determined to be an appropriate individual to whom administration of the pharmaceutical composition of the invention (composition containing anti-IL-4R antibody) is useful.

[037] According to some aspects of the invention, methods of preventing or treating allergies are provided, which include: (a) selecting an individual who has an IgE level specific to at least one allergen before or during treatment, which means sensitization to the allergen; and (b) administering to the subject a pharmaceutical composition containing a therapeutically effective amount of an IL-4R antagonist. In some embodiments, the patient is selected by determining whether the level of allergen-specific IgE is elevated. The level of allergen-specific IgE is determined or measured by obtaining a sample from the patient for the analysis of biomarkers known in this field. In some other embodiments, the patient is selected by obtaining information regarding elevated allergen-specific IgE levels from the patient. In some embodiments of this aspect of the invention, the individual is selected based on an elevated level of IgE, or TARC, or periostin.

[038] As one of skill in the art will appreciate, an increase or decrease in a serum biomarker level can be determined by comparing (i) the level of the biomarker measured in an individual at a given time point after administration of the IL-4R antagonist with (ii) the level of the biomarker measured in patient prior to administration of the IL-4R antagonist (i.e., "measurement at baseline"). The target time at which the biomarker is quantified 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 or more after administration of the antagonist IL-4R.

[039] According to some specific embodiments of the present invention, the individual may have a decrease in the level of serum IgE specific to one or more allergens after administration of a pharmaceutical composition containing an IL-4R antagonist (for example, an anti-IL-4R antibody). For example, approximately 8 days, 15 days, 22 days, 25 days, 29 days, 36 days, 43 days, 50 days, 57 days, 64 days, 71 days, 85 days, or 112 days after administration of one or more doses of the pharmaceutical composition containing approximately 75, 150, 200, or 300 mg of an anti-hIL-4R antibody (e.g., dupilumab), an individual according to the present invention may show an allergen-specific IgE reduction of approximately 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or more of baseline (wherein "baseline" is defined as the level of allergen-specific IgE in the individual immediately prior to the first administration).

Receptor antagonists interleukin-4

[040] The methods of the present invention include administering to an individual in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist. Within the meaning of the invention, an "IL-4R antagonist" (also referred to herein as "IL-4R inhibitor", "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 reduces the normal biological signaling function of the type 1 and/or type 2 IL-4 receptor. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. The type 1 IL-4 receptor is a dimeric receptor containing an IL-4Rα chain and a γc chain. The type 2 IL-4 receptor is a dimeric receptor containing 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. Thus, IL-4R antagonists that can be used in the methods of the present invention can function to block IL-4 mediated signaling, IL-13 mediated signaling, or both IL-4 and IL-13 mediated signaling. Thus, the IL-4R antagonists of the present invention can interfere with the interaction of IL-4 and/or IL-13 with a type 1 or type 2 receptor.

[041] Non-limiting examples of IL-4R antagonist categories include small molecule inhibitors of IL-4R, anti-IL-4R aptamers, peptidic IL-4R inhibitors (e.g., "peptide antibody" molecules), "receptor-antibodies" (e.g., engineered molecules containing ligand-binding domain as a component of IL-4R), and antibodies or antigen-binding antibody fragments that specifically bind to human IL-4Rα. Within the scope of the invention, IL-4R antagonists also include antigen-binding proteins that specifically bind IL-4 and/or IL-13.

Anti-IL-4Rα antibodies and their antigen-binding fragments

[042] According to some 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", within the scope of the invention, includes immunoglobulin molecules containing four polypeptide chains: two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, as well as their multimers (for example, IgM). In a typical antibody, each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or V _H ) and a heavy chain constant region. The heavy chain constant region contains three domains: C _H 1, C _H 2 and C _H 3. Each light chain contains a light chain variable region (abbreviated herein as LCVR or V _L ) and a light chain constant region. The light chain constant region contains one domain (C _L 1). The V _H and V _L regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), separated by regions that are more conserved, called framework regions (FRs). Each V _H and V _L contains three CDRs and four FRs in the following order from T-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments, the FR of an anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences, or may be naturally occurring or artificially modified. The amino acid consensus sequence can be determined by analyzing two or more CDRs simultaneously.

[043] The term "antibody", within the scope of the invention, 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 produced, synthetic, or engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody can be generated, for example, from complete antibody molecules using any standard methods such as proteolytic cleavage or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding the variable and optionally constant domains of an antibody. 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. DNA can be sequenced and modified chemically or using molecular biology techniques, for example, to provide one or more variable and/or constant domains with an appropriate configuration, or to introduce codons, form cysteine residues, modify, add or remove amino acids, etc.

[044] 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 molecules (scFv); (vi) dAb fragments; and (vii) minimal recognition elements consisting of amino acid residues that mimic an antibody hypervariable region (eg, a distinguished complementarity determining region (CDR) such as a CDR3 peptide), or a limited FR3-CDR3-FR4 peptide. Also, the expression "antigen-binding fragment", within the scope of the invention, covers other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diantibodies, triantibodies, tetrabodies, minibodies, nanobodies (for example , monovalent nanoantibodies, bivalent nanoantibodies, etc.), small modular immunopharmaceutical proteins (SMIPs), and shark IgNAR variable domains.

[045] An antigen-binding fragment of an antibody typically contains at least one variable domain. The variable domain may be of any size or amino acid composition and typically contains at least one CDR that is adjacent to or in reading frame with one or more framework sequences. In antigen-binding fragments having a V _H domain associated with a V _L domain, the V _H and V _L domains may be positioned relative to each other in any suitable manner. For example, the variable region may be dimeric and may contain V _H -V _H , V _H -V _L or V _L -V _L dimers. Alternatively, an antigen-binding fragment of an antibody may comprise a V _H or V _L monmeric domain.

[046] In some embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting illustrative configurations of variable and constant domains that may be present in an antigen-binding fragment of an antibody of the present invention include: (i) V _{H -CH} 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 the variable and constant domains, including any of the exemplary configurations above, the variable and constant domains may either be directly linked to each other or may be linked through a complete or partial hinge or linker region. A hinge region may be at least 2 (eg, 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations above, non-covalently bonded to each other and/or to one or more V _H or V _L monomeric domains. (for example, via disulfide bond(s)).

[047] The term "antibody", within the scope of the invention, also includes multispecific (eg, bispecific) antibodies. A multispecific antibody or antigen-binding antibody fragment typically contains at least two distinct variable domains, where each variable domain is capable of specifically binding to a different antigen or a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in the context of the antibody or antigen-binding antibody fragment of the present invention using standard techniques available in the art. For example, the present invention relates to methods involving the use of bispecific antibodies, 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 conjugated to a therapeutic moiety. Illustrative bispecific formats that can be used in the context of the present invention include, but are not limited to, for example, scFv or diantibody based bispecific formats, IgG-scFv fusion constructs, Ig double variable domain (DVD), quadroma, constructs like " lumen, common light chain (e.g., common light chain with lugs, etc.), CrossMab, CrossFab, antibody-(primer), leucine zipper, duoantibody, IgG1/IgG2, Fab (DAF) -IgG dual action and Mab ² bispecific formats (See, for example, Klein et al . 2012, mAbs 4:6, 1-11, and references cited therein for an overview of the above formats). Bispecific antibodies can also be constructed using peptide/nucleic acid conjugation, for example, where non-natural amino acids with independently differing reactivity are used to generate site-specific antibody-oligonucleotide conjugates, which then self-assemble into multimeric complexes with specific composition, valency, and geometry (see ., for example, Kazane et al ., J. Am. Chem. Soc . [ Epub : Dec. 4, 2012 ]).

[048] The antibodies used in the methods of the present invention may be human antibodies. The term "human antibody", as used herein, includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. However, human antibodies of the invention may include amino acid residues not encoded by a human germline immunoglobulin sequence (e.g., mutations introduced by in vitro random or site-directed mutagenesis, or in vivo somatic mutation), such as in CDRs and, in particular, CDR3. However, the term "human antibody", within the meaning of the invention, does not include antibodies in which CDR sequences derived from a germline sequence of another mammalian species, such as a mouse, are grafted into human framework sequences.

[049] The antibodies used in the methods of the present invention may be recombinant human antibodies. The term "recombinant human antibody", within the meaning of the invention, includes all human antibodies that are produced, expressed, generated or isolated by recombinant methods, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described in detail below), antibodies isolated from a recombinant combinatorial human antibody library (described in detail below), antibodies isolated from an animal (e.g., mouse) that is transgenic for human immunoglobulin genes (see, e.g., Taylor et al . (1992) Nucl. Acids Res. 20:6287-6295) or antibodies produced, expressed, constructed or isolated by any other means that involve the fusion of 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 some embodiments, such human recombinant antibodies undergo in vitro mutagenesis (or, when an animal transgenic for human Ig sequences, in vivo somatic mutagenesis is used) and thus the amino acid sequences of the V _H and V _L regions of the recombinant antibodies are sequences which, although derived from and related to the human germline V _H and V _L sequences, may not exist naturally in the in vivo human germline antibody repertoire.

[050] In certain embodiments, the antibodies used in the methods of the present invention specifically bind IL-4Rα. The term "specifically binds" and the like. means that the antibody or antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds 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, includes antibodies that bind IL-4Rα, or a portion thereof, with a K _D of less than about 1000 nM, less than about 500 nM, less than about 300 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 1 nM, less than about 0.5 nM, less than about 0.25 nM, less than about 0 .1 nM or less than about 0.05 nM, as measured in an assay using surface plasmon resonance. However, an isolated antibody that specifically binds to human IL-4Rα may be cross-reactive with other antigens, such as IL-4Rα molecules from non-human species.

[051] According to certain exemplary embodiments of the present invention, an IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment containing a heavy chain variable region (HCVR), a light chain variable region (LCVR), and/or complementarity determining regions ( CDR) containing any of the amino acid sequences of anti-IL-4R antibodies as described in US Pat. No. 7,608,693. Heavy chain variable region (HCVR) heavy chain regions (HCDR) containing the amino acid sequence of SEQ ID NO: 1, and light chain variable region complementarity determining regions (LCDR) (LCVR) containing the amino acid sequence of SEQ ID NO: 2. According to certain options Thus, an anti-IL-4Rα antibody or antigen-binding fragment thereof contains three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), where 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 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, an anti-IL-4R antibody or antigen-binding antibody thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2. In certain exemplary embodiments, the methods of the present invention include the use of an anti-IL-4R antibody comprising the amino acid sequences HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 according to SEQ ID NO: 3-4-5-6-7-8 (referred to and known in the art as "dupilumab"), or its bioequivalent. In some embodiments, the methods of the present invention comprise the use of an anti-IL-4R antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: : 10. An exemplary antibody containing 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. In certain illustrative embodiments, the methods of the present invention include the use of dupilumab or a bioequivalent thereof. The term "bioequivalent", within the meaning of the invention, refers to antibodies against IL-4R or IL-4R binding proteins or fragments thereof, which are pharmaceutical equivalents or pharmaceutical alternatives, the rate and/or degree of absorption of which does not show a significant difference from dupilumab when administered in the same molar dose under similar experimental conditions, both in a single dose and in multiple doses. In the context of the invention, the term refers to antigen-binding proteins that bind to IL-4R, which have no clinically significant differences from dupilumab in terms of safety, purity and/or efficacy.

[052] Other anti-IL-4Rα antibodies that can be used in the context of the methods of the present invention include, for example, the antibody referred to and known in the art as AMG317 (Corren et al ., 2010, Am J Respir Crit Care Med., 181 (8):788-796), or MEDI 9314, or any of the anti-IL-4Rα antibodies mentioned in US Pat. No. 7,186,809; US Pat. No. 7,605,237; USA No. 8877189.

[053] Anti-IL-4Rα antibodies used in the context of the methods of the present invention may have pH-dependent binding characteristics. For example, an anti-IL-4Rα antibody for use in the methods of the present invention may exhibit reduced binding to IL-4Rα at acidic pH values compared to neutral pH. Alternatively, an anti-IL-4Rα antibody of the invention may exhibit enhanced binding to its antigen under acidic pH conditions 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 less. In the context of the invention, the expression "neutral pH" means a pH from about 7.0 to about 7.4. The term "neutral pH" includes pH values of approximately 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

[054] In certain cases, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" is expressed in terms of the ratio of the K _D value of binding of an antibody to IL-4Rα at acidic pH values with the K _D value of binding of an antibody to IL- 4Rα at neutral pH values (or vice versa). For example, an antibody or antigen-binding fragment thereof may be considered to exhibit "reduced binding to IL-4Rα at acidic pH values compared to neutral pH values" for the purposes of the present invention if the antibody or antigen-binding fragment thereof exhibits a K _D ratio under acidic/neutral conditions of approximately 3 ,0 or more. In certain exemplary embodiments, the acidic/neutral K _D ratio for an antibody or antigen-binding fragment of the present invention may 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.

[055] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening the antibody population for reduced (or increased) binding to a particular antigen at acidic pH values compared to neutral pH values. In addition, modifications to the antigen-binding domain at the amino acid level can provide antibodies with pH-dependent characteristics. For example, by replacing one or more amino acids in an antigen-binding domain (eg, in a CDR) with a histidine residue, an antibody with reduced antigen binding at acidic pH values relative to neutral pH values can be obtained. Within the scope of the invention, the expression "acidic pH values" means a pH of 6.0 or less.

Pharmaceutical compositions

[056] The present invention provides methods that include administering an IL-4R antagonist to a patient, wherein the IL-4R antagonist (eg, an anti-IL-4R antibody) is contained in a pharmaceutical composition. Pharmaceutical compositions of the invention are formulated with suitable carriers, excipients, and other means that provide suitable transport, delivery, tolerability, and so on. A variety of suitable formulations can be found in the reference book known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipid containing lipid (cationic or anionic) vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorbable pastes, oil-in-water emulsions and water-in-oil, carbovax emulsions (polyethylene glycols of various molecular weights), semi-solid gels and semi-solid mixtures containing carbovax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[057] The dose of antibody administered to a patient, in accordance with the methods of the present invention, may vary depending on the age and size of the patient, symptoms, conditions, route of administration, and the like. The dose is usually calculated based on body weight and body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. Effective dosages and administration schedules for pharmaceutical compositions containing anti-IL-4R antibodies can be determined empirically; for example, the patient's progress can be monitored through periodic evaluation and the dose adjusted accordingly. Moreover, cross-species dosage scaling can be performed using methods well known in the art (eg, Mordenti et al. , 1991, Pharmaceut. Res. 8 :1351). Specific exemplary doses of anti-IL4R antibodies and administration regimens involving them that can be used in the context of the present invention are described herein.

[058] Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, for example, Wu et al., 1987, J Biol Chem 262:4429-4432). Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucosal surfaces (eg, oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with others. biologically active agents.

[059] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously using a standard needle and syringe. In addition, with respect to subcutaneous delivery, it is convenient to use a pen to deliver the pharmaceutical composition of the present invention. Such a syringe pen can be reusable or disposable. A refillable pen typically uses a replaceable cassette that contains a pharmaceutical composition. After all of the pharmaceutical composition has been introduced from the cassette and the cassette is empty, the empty cassette can be easily discarded and replaced with a new cassette that contains the pharmaceutical composition. The pen can then be used again. There is no replaceable cassette in the disposable syringe pen. Instead, the disposable pen comes pre-filled with the pharmaceutical composition contained in the reservoir of the device. Once the pharmaceutical composition reservoir is empty, the entire device is discarded.

[060] Numerous reusable pens and self-injection syringes are useful for subcutaneous delivery of the pharmaceutical composition of the present invention. Examples 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, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™ and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany), among others. Examples of disposable pens suitable for subcutaneous delivery of the pharmaceutical composition of the present invention include, but are not limited to, SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk) and KWIKPEN™ (Eli Lilly), syringe for SURECLICK™ self-injection (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA™ pen (Abbott Labs, Abbott Park IL), among others.

[061] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). 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 another embodiment, the controlled release system can be placed near the target of the composition and thus only a fraction of the systemic dose is required (see, for example, Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115 -138). Other controlled release systems are reviewed by Langer, 1990, Science 249:1527-1533.

[062] Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, etc. These injectable preparations can be obtained by known methods. For example, injectable preparations can be prepared, for example, by dissolving, suspending or emulsifying an antibody or salt thereof, as described above, in a sterile aqueous or oily medium commonly used for injection. As the aqueous injection medium, for example, physiological saline solution, isotonic solution containing glucose and other excipients, etc. are used, which can be used in combination with a suitable solubilizing agent such as alcohol (for example, ethanol), polyhydric alcohol (eg propylene glycol, polyethylene glycol), non-ionic surfactant [eg polysorbate 80, HCO-50 (polyoxyethylene (50 mol) hydrogenated castor oil adduct)], etc. As the oil medium, for example, sesame oil, soybean oil, etc. are used, which can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. An injection thus prepared can be filled into an appropriate ampoule.

[063] Preferably, the oral or parenteral pharmaceutical compositions described above are prepared in unit dose dosage forms suitable to accommodate a dose of the active ingredients. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, and the like.

[064] Illustrative pharmaceutical compositions containing an anti-IL-4R antibody that can be used in the context of the present invention are described, for example, in US patent No. 8945559.

Dosage

[065] The amount of an IL-4R antagonist (eg, an anti-IL-4R antibody) administered to an individual by the methods of the present invention is typically a therapeutically effective amount. Within the meaning of the invention, the term "therapeutically effective amount" means an amount of an IL-4R antagonist that results in one or more of: (a) prevention of allergy; (b) treating or reducing the severity of an allergic reaction; (c) reducing the level of serum allergen-specific IgE; (d) reducing allergen sensitization; and/or (e) reducing the susceptibility to an allergic reaction.

[066] In the case of an anti-IL-4R antibody, a therapeutically effective amount may be from about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1, 5 mg, approximately 2.0 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg , approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, etc. and 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, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, about 580 mg, about 590 mg, or about 600 mg of anti-IL-4R antibody. In some embodiments, the individual is administered 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg of an anti-IL-4R antibody.

[067] The amount of IL-4R antagonist contained in individual doses can be expressed in terms of milligrams of antibody per kilogram of the patient's body weight (ie, mg/kg). For example, an IL-4R antagonist may be administered to a patient at a dose of about 0.0001 to about 10 mg/kg of the patient's body weight.

Combined therapies

[068] The methods of the present invention, in certain embodiments, include administering to the individual one or more additional therapeutic agents in combination with an IL-4R antagonist. Within the scope of the invention, the expression "in combination with" means that additional therapeutic agents are administered before, after or simultaneously with a pharmaceutical composition containing an IL-4R antagonist. The term "in combination with" also includes the sequential or simultaneous administration of an IL-4R antagonist and a second therapeutic agent.

[069] For example, when administered "before" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered about 72 hours in advance, approximately 60 hours in advance, approximately 48 hours in advance, approximately 36 hours in advance, approximately 24 hours in advance, approximately 12 hours in advance, approximately 10 hours in advance, approximately 8 hours in advance, approximately 6 hours in advance, approximately 4 hours in advance, approximately 2 hours in advance, approximately 1 hour in advance, approximately 30 minutes in advance, approximately 15 minutes in advance, or approximately 10 minutes in advance of administration a pharmaceutical composition containing an IL-4R antagonist. When administered "after" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered at about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of a pharmaceutical composition containing an antagonist IL-4R. Administration "simultaneously" with or with a pharmaceutical composition containing an IL-4R antagonist means that the additional therapeutic agent is administered to an individual in a separate dosage form within less than 5 minutes (before, after, or simultaneously) of administration of the pharmaceutical composition containing an IL-4R antagonist , or administered to the individual in a single combined dosage formulation containing both an additional therapeutic agent and an IL-4R antagonist.

[070] An additional therapeutic agent may be, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, an IL-1 antagonist as described in US 6927044), an IL-6 antagonist, an IL-6R antagonist (including , for example, an anti-IL-6R antibody as described in US 7582298), IL-13 antagonist, tumor necrosis factor (TNF) antagonist, IL-8 antagonist, IL-9 antagonist, IL-17 antagonist, IL-5 antagonist, antagonist IgE, CD48 antagonist, IL-31 antagonist (including, for example, as indicated in US 7531637), thymic stromal lymphopoietin (TSLP) antagonist (including, for example, as indicated in US 2011/027468), interferon-based antibiotics -gamma (IFNγ), topical corticosteroids, tacrolimus, pimecrolimus, cyclosporine, azathioprine, methotrexate, cromolyn sodium, protease inhibitors, systemic corticosteroids, systemic immunotherapy, antihistamines, or combinations thereof. In some embodiments, a pharmaceutical composition containing an IL4R antagonist is administered to an individual in conjunction with non-pharmaceutical therapy, such as ultraviolet (UV) radiation therapy.

Modes of administration

[071] The present invention relates to methods comprising administering to an individual a pharmaceutical composition comprising an IL-4R antagonist 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 if a therapeutic response is achieved. In some embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a once weekly dosing of about 75 mg, 150 mg, 200 mg, or 300 mg may be used.

[072] According to certain embodiments of the present invention, multiple doses of an IL-4R antagonist may be administered to an individual over a given period of time. Methods according to this aspect of the invention include sequential administration of multiple doses of an IL-4R antagonist to an individual. In the context of the invention, "sequential administration" means that each dose of the IL-4R antagonist is administered to an individual at a different time point, eg, on different days separated by a predetermined interval (eg, hours, days, weeks, or months). The present invention relates to methods that include 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 one or more tertiary doses of an IL-4R antagonist.

[073] The terms "initial dose", "secondary doses" and "tertiary doses" refer to the time sequence of administration of the IL-4R antagonist. Thus, "initial dose" is the dose administered at the start of a treatment regimen (also referred to as "initial dose");"secondarydoses" are doses that are administered after the initial dose; and "tertiary doses" are doses that are administered after secondary doses. Initial, secondary and tertiary doses may contain the same amount of IL-4R antagonist, however, as a rule, may differ from each other in terms of frequency of administration. However, in some embodiments, the amount of IL-4R antagonist contained in the initial, secondary, and/or tertiary doses varies (eg, adjusted up or down as appropriate) during treatment. In some embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the start of a treatment regimen as "loading doses" followed by subsequent doses that are administered less frequently (e.g., "maintenance doses") . For example, an IL-4R antagonist may be administered to a patient with AD at a loading dose of about 400 mg or about 600 mg followed by one or more 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, e.g., 100 mg to 400 mg of an IL-4R antagonist, e.g., 100 mg, 150 mg, 200 mg , 250 mg, 300 mg, 400 mg, or 500 mg of an IL-4R antagonist. In some embodiments, the initial dose and one or more secondary doses each contain the same amount of an IL-4R antagonist. In other embodiments, the initial dose contains a first amount of an IL-4R antagonist, and one or more secondary doses in each case contain a second amount of an IL-4R antagonist. For example, the first amount of IL-4R antagonist may be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x or more than the second amount of IL-4R antagonist.

[074] In one exemplary embodiment of the present invention, each secondary and/or tertiary dose is administered 1-14 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7 , 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½ or more) weeks after the immediately preceding dose. The expression "immediately preceding dose", in the context of the invention, means, in the case of successive multiple administrations, the dose of the IL-4R antagonist that is administered to the patient prior to the administration of the next dose consecutively without intermediate doses.

[075] Methods according to this aspect of the invention may include administering any number of secondary and/or tertiary doses of an IL-4R antagonist to a patient. For example, in some embodiments, only one secondary dose is administered to the patient. In other embodiments, two or more (eg, 2, 3, 4, 5, 6, 7, 8 or more) secondary doses are administered to the patient. Similarly, in some embodiments, only one tertiary dose is administered to the patient. In other embodiments, two or more (eg, 2, 3, 4, 5, 6, 7, 8 or more) tertiary doses are administered to the patient.

[076] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to a patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to a patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which secondary and/or tertiary doses are administered to a patient may vary over the course of a treatment regimen. The frequency of administration can also be adjusted during the course of treatment by the physician, depending on the needs of the individual patient after clinical examination.

EXAMPLES

[077] The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors consider their invention. Efforts have been made to ensure the accuracy of the numbers used (eg quantities, temperatures, etc.), however some experimental errors and deviations should be taken into account. 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.

[078] Example 1: Clinical trial to investigate the efficacy of dupilumab in adult patients with moderate to severe AD

Scheme and objectives of the study

[079] This study was a 32-week, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety, efficacy, biomarker profile, functional concentrations, and immunogenicity of dupilumab administered weekly for 16 consecutive weeks in adult patients with moderate to moderate AD. heavy. Dupilumab is a fully human anti-IL-4R 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; a pair of amino acid sequences HCVR/LCVR containing SEQ ID NO: 1/2; and heavy and light chain CDR sequences comprising SEQ ID NOs: 3-8.

[080] Eligible patients were randomized 1:1 for subcutaneous (SC) administration of dupilumab or SC administration of placebo. Randomization was stratified by disease severity (moderate versus severe AD). After informed consent was obtained, patients were assessed for eligibility for enrollment in the study at the screening visit. Patients who met the eligibility criteria for inclusion were assessed on day 1/baseline, randomized, and then given a loading dose (400 mg sc of study drug) followed by weekly injections of study drug (200 mg sc). j) from 1 week to 15 weeks. During this time, patients were assessed weekly, mostly during clinic visits, but in some cases by telephone. Depending on patient preference and ability, patients and/or caregivers were taught to inject study drug at the first 5 treatment visits (Visits 2, 3, 4, 5, and 6) at the study site and then study drug was administered to them. outside the clinic at the times corresponding to visits 7, 9, 11, 13 and 15, which required only telephone contact. Evaluation of safety, laboratory parameters and clinical effect was carried out during special visits to the clinic. At the end of the treatment period at 16 weeks after the last dose of study drug, there was a visit when primary results were evaluated. Follow-up visits occurred every 2 weeks from weeks 18 to 32. The end-of-study visit occurred at 32 weeks.

[081]If necessary, patients were rescue therapy for AD (medication and/or phototherapy). Patients who required salvage therapy discontinued study treatment but continued to be followed up following the study's scoring scheme. Effectiveness scores (eg, IGA, EASI, etc.) were obtained prior to any salvage therapy.

[082] Sampling for clinical chemistry and hematology studies, drug concentrations, and anti-drug antibodies was performed at various time points during the course of the study. In addition, 1 sample for DNA analysis and several samples for RNA analysis were prepared.

[083]Distribution Treatments were randomized to avoid bias in assigning patients to a particular treatment group and to minimize systematic differences between groups in baseline variables that might affect outcome. The double-blind study design was designed to minimize any potential bias in clinical assessment and patient-reported results due to investigator or patient knowledge of treatment allocation. The placebo group provided a reliable control for any apparent effects of the study treatment. Patients assigned to the dupilumab arm received 200 mg once weekly (qw) after a loading dose of 400 for 1 day. Study treatment was administered for 16 weeks to stabilize systemic concentrations of functional dupilumab. After treatment, all patients were observed for 16 weeks (i.e., approximately 5 half-lives) to ensure that the elimination of dupilumab was substantially complete (plasma concentrations below the lower limit of quantitation) before the last study visit.

[084] The primary objective of the study was to evaluate the efficacy of dupilumab versus placebo in adult patients with moderate to severe AD.

[085] The secondary objectives of the study were: (1) to evaluate the safety of dupilumab compared to placebo; (2) evaluate dupilumab concentration; and (3) evaluate potential anti-drug antibody response to dupilumab versus placebo in adult patients with moderate to severe AD.

[086] The objectives of the study were: (1) to evaluate the effect of dupilumab on epidermal hyperplasia; (2) assessment of the pharmacodynamic (PD) effect of dupilumab on biomarkers over time; and (3) assessing the predictive value of thymus-regulated and activated chemokine (TARC) for EASI response.

[087] The target population included adults with moderate to severe AD that was not adequately controlled with topical drugs or where topical treatment was inappropriate (due to, for example, side effects or safety risk). Eligible patients were randomized 1:1 to subcutaneous (SC) administration of dupilumab or SC administration of placebo. Randomization was stratified by disease severity (moderate versus severe AD). Patients received a loading dose (400 mg s.c.) of study drug on day 1, followed by weekly injections of study drug (200 mg s.c.) from week 1 to week 15. Patients were required to apply a topical emollient twice daily from day -7 to day 8. Safety, laboratory parameters, and clinical response were assessed during special clinic visits. Sampling for clinical chemistry and hematology, drug concentrations, and anti-drug antibodies were performed at various time points throughout the study. In addition, 1 sample for DNA analysis and several samples for RNA analysis were prepared. The last visit in the study was at week 16, 1 week after the last study drug dose, when primary outcomes were evaluated. Follow-up visits occurred every 2 weeks from weeks 18 to 32. The last visit in the study was at 32 weeks.

[088] The primary outcome of the study was the percentage change in EASI score from baseline to week 16. Secondary outcomes included: (1) the proportion of patients who achieved an IGA of 0 (none) or 1 (virtually absent) at 16 weeks; (2) the proportion of patients achieving a reduction in IGA score ≥2 at week 16; (3) absolute and percentage change from baseline in itch scores (NRS and 4-point categorical scale); (4) absolute change in EASI scores from baseline to week 16; (5) absolute and percentage change in SCORAD scores from baseline to week 16; (6) proportion of patients achieving EASI-50, EASI-75, and EASI-90 (50%, 75%, and 90% reduction in EASI score from baseline) at week 16; (7) proportion of patients achieving SCORAD-50, SCORAD-75, and SCORAD-90 (50%, 75%, and 90% reduction in SCORAD score from baseline) at week 16; (8) absolute and percentage change in POEM scores from baseline; (9) changes from baseline in GISS components (erythema, infiltration/papules, excoriation and lichenification); (10) change in cumulative GISS score from baseline; (11) incidence of TEAE from baseline to 32 weeks; and (12) serum concentrations of dupilumab over time from baseline to week 32.

[089] The end results of the study include: (1) the proportion of patients with a histological response consisting of significantly reduced epidermal hyperplasia of damaged skin, and defined as a decrease of ≥40% of the baseline in the thickness of the epidermis and/or a reversal of K16 expression according to immunohistochemistry; (2) change in TARC from baseline to week 16; (3) change in IgE from baseline to 16 weeks; (4) change in allergen-specific IgE by week 16; and (5) correlation of baseline TARC and IgE with EASI response.

Patient Selection

[090] The target population included adults with moderate to severe AD that was not adequately controlled with topical drugs or where topical treatment was inappropriate (due to, for example, side effects or safety risks).

[091] Inclusion Criteria: The patient had to meet the following inclusion criteria for the study: (1) male or female, 18 years of age or older; (2) chronic AD that was present for at least 3 years before the screening visit; (3) EASI score ≥12 at screening visit and ≥16 at baseline visit; (4) IGA score ≥3 (0-4 IGA scale) at screening visit and at baseline visit; (5) Involvement in AD≥10% BSA at screening visit and at baseline visit; (6) patients with a documented recent history (within 6 months prior to the screening visit) of insufficient response to outpatient topical treatment or for whom topical treatment was otherwise inappropriate (eg, due to significant side effects or safety risks) [for the purpose of this Insufficient response was defined as failure to achieve and/or maintain remission or a state of low disease activity (e.g., IGA from 0=none to 2=mild) despite treatment with moderate to high efficacy topical corticosteroids (± topical calcineurin inhibitors as appropriate] To assess the lack of response to intensive treatment, topical treatment was applied every day for at least 28 days or for the maximum period of time recommended by the product prescribing information (for example, 14 days for heavy-duty topical corticosteroids), whichever period would l shorter. After intensive daily treatment, failure to respond was defined as failure to maintain a low disease activity state despite the use of topical drugs on a less intensive maintenance regimen (ie, 2 days per week). The presence of important side effects or safety risks that outweigh the potential benefits of treatment (eg, hypersensitivity reactions, significant skin atrophy, systemic effects, etc., or their threat) was taken into account when assessed by the investigator or the patient's physician. Appropriate documentation included up-to-date charts recording topical corticosteroid and/or topical calcineurin inhibitor prescription and treatment outcome, investigator documentation based on communication with the patient's primary care physician, or medical history provided by the patient when other forms of documentation were not available (e.g., patient not seen by a doctor for AD within the last 6 months)]; (7) patients should apply a stable dose of topical emollient (moisturizer) twice daily for at least 7 days prior to baseline visit; (8) willingness and ability to carry out all clinical visits and study-related procedures; (9) the ability to understand and complete survey-related questionnaires; and (10) providing signed informed consent.

[092] Exclusion Criteria: The following are exclusion criteria for the study: (1) prior participation in a clinical trial with dupilumab; (2) treatment with investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before visiting baseline; (3) the following treatments within 4 weeks prior to the baseline visit, or any condition that, in the opinion of the Investigator, would require such treatment(s) during the first 4 weeks of study treatment - systemic corticosteroids, immunosuppressive/immunomodulators (eg, cyclosporine, mycophenolate) mofetil, IFNγ, Janus kinase (JAK) inhibitors, azathioprine, or methotrexate), or phototherapy for AD; (4) treatment with topical corticosteroids, tacrolimus, and/or pimecrolimus within 1 week prior to baseline visit; (5) treatment with the following biologics: any cell-depleting agents, including but not limited to rituximab: within 6 months prior to baseline visit or until lymphocyte and CD 19+ lymphocyte counts return to normal, whichever longer; infliximab, adalimumab, golimumab, certolizumab pegol, apatacept, etanercept, anakinra: within 16 weeks of baseline visit for any indication or within 5 years for dermatological indications, other biologics: within 5 half-lives (if known) or 16 weeks, whichever is longer, before visiting baseline; (6) initiation of AD treatment with prescribed humectants or humectants containing additives such as ceramide, hyaluronic acid, urea, or filaggrin during the screening period (patients may continue to use stable doses of such humectants if they started prior to the screening visit); (7) regular visits (more than 2 visits per week) to an upright tanning salon/tanning salon within 4 weeks prior to baseline visit; (8) planned or anticipated use of prohibited drugs and procedures during investigational treatment; (9) live (attenuated) vaccine treatment within 12 weeks prior to baseline visit; (10) chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to the Screening Visit, or superficial skin infections within 1 week prior to the Screening Visit; (11) known or suspected immunosuppression, including a history of invasive opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocytosis, aspergillosis) despite resolution of the infection, or other recurrent infections with an abnormal frequency, or prolonged infections suggestive of immunodeficiency ; (12) a known history of human immunodeficiency virus (HIV) infection or HIV seropositivity at the screening visit; (13) positive or undetectable hepatitis B surface antigen (HBsAg), anti-hepatitis B core antigen (HBcAb), or anti-hepatitis C antibody at the Screening Visit; (14) elevated levels of transaminases (ALT and/or AST) greater than 3 times the upper limit of normal (>3×ULN) at the screening visit; (15) history of clinical endoparasitosis within 12 months prior to baseline visit other than treated vaginal trichomoniasis; (16) the presence of comorbid skin conditions that may preclude evaluation in the study; (17) history of malignancy within 5 years prior to baseline visit, excluding fully treated in situ cervical carcinoma and fully treated and resolved non-metastatic squamous or basal cell carcinoma of the skin; (18) history of non-malignant lymphoproliferative disorders; (19) high risk of parasitic infection, such as living in or recent travel (within 12 months prior to visiting baseline) in areas endemic for endoparasitosis where circumstances indicated exposure to parasites (eg, long stay, rural or slum, absence of tap water, ingestion of uncooked, undercooked or otherwise potentially contaminated food, close contact with carriers and vectors, etc.) unless subsequent medical evaluation (e.g. stool examination, blood test, etc.) does not rule out the possibility of a parasitic infection/ infestations; (20) history of alcohol or drug addiction within 2 years prior to screening visit; (21) severe comorbid disease(s) that may adversely affect the patient's participation in the study. Examples include, but are not limited to, patients with a short life expectancy, patients with uncontrolled diabetes (HbA1c ≥9%), patients with cardiovascular conditions (eg, New York Heart Association stage III or IV heart failure), severe kidney conditions (eg, dialysis patients), liver and biliary tract conditions (eg, Child-Pugh class B or C), neurological conditions (eg, demyelinating diseases), active significant autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrinological, gastrointestinal, metabolic, pulmonary or lymphatic diseases; (22) any other medical or psychological condition, including significant screening laboratory abnormalities that are indicative of a new and/or poorly understood disease, may pose an unreasonable risk to the study patient as a result of his/her participation in this clinical trial, may make the patient's participation unreliable or interfere with evaluation in the study. This includes hypersensitivity to local anesthetics, clotting disorders, anticoagulant treatment, or other conditions that may make a biopsy inappropriate; (23) planned major surgery during the patient's participation in the study; (24) pregnant or lactating women or women planning to become pregnant or breastfeeding during the course of the study; and (25) women who are unwilling to implement adequate contraception if they are of childbearing age and are sexually active.

Investigational treatment

[093] Patients were given a subcutaneous loading dose of 400 mg dupilumab on day 1 followed by 200 mg weekly (qw) from week 1 to week 15. Patients in the placebo group received a loading dose on day 1 followed by a weekly subcutaneous placebo dose from week 1 to week 15. Patients were required to apply a topical emollient twice daily from day -7 to day 8.

Procedures and evaluation

[094] The efficacy of dupilumab in this cohort was assessed using AD severity scores, quality of life (QOL) questionnaires, pruritus score, and patient-reported outcomes. Scores for AD severity included AD-associated clinical parameters such as eczema area and severity index (EASI), Investigator Global Score (IGA), Numerical Pruritus Rating Scale (NRS), Body Surface Area (BSA), 5-D Pruritus Score, atopic dermatitis scores (SCORAD), patient-centered measure of eczema (POEM), and global single sign score (GISS) as described in US Patent Application Publication No. US2014/0072583 (incorporated herein in its entirety). The Quality of Life (QOL) questionnaire included a patient's global assessment of disease status, dermatological quality of life index (DLQI), POEM, EQ-5D, Itchy QoL, and the Hospital Anxiety and Depression Scale (HADS) described in US2014/0072583 (included herein). as reference in full). Skin barrier function tests were also performed, photographs of the AD region and skin smear samples were obtained for diagnostic microbiome analysis. The safety of dupilumab in this population was assessed by TEAE assessment, a detailed medical history, physical examination, vital signs, electrocardiogram (ECG), and clinical laboratory testing. Information on concomitant medications and procedures was collected from informed consent through the end of the study. Blinded safety data were collected regularly. Blood samples were taken to determine drug concentrations and anti-dupilumab antibody levels at predetermined time points. Received samples for research and samples for diagnostic analysis of biomarkers. Skin biopsies were also obtained for diagnostic biomarker analysis.

Statistical analysis

[095] Primary and secondary continuous variables were analyzed using an analysis of covariance (ANCOVA) model with treatment, randomization stratum (moderate versus severe), and respective baseline endpoints as covariates. Efficacy data were considered absent after salvage therapy or after the patient discontinued participation in the study. All missing values were then entered using the Last Observation Data Transfer (LOCF) method. The EASI and NRS of pruritus were reported as root mean square (LS) mean (standard error [SE]) of percent change from baseline to week 16 obtained using the LOCF approach.

results

[096] Patient Distribution and Baseline Characteristics: 54 patients were randomly assigned to either placebo (n=27) or dupilumab 200 mg qw (n=27). Baseline demographic and clinical characteristics were balanced between treatment groups (Table 1). More than 75% of patients were using prior medications, including antihistamines, topical corticosteroids (groups I, II, and III, for efficacy), and drugs for obstructive airways disease. A higher proportion of patients in the placebo group used corticosteroids than patients in the dupilumab group.

Table 1: Baseline Patient Demographics and Clinical Characteristics by Treatment Group

Variable Placebo (n=27) Dupilumab 200 mg (n=27) Age, average (IQR), years 43 (20, 82) 35 (18, 71) Male sex, n (%) 14 (51.9) 16 (59.3) Duration of AD, mean ± SD, years 35.4 ± 16.3 26.3 ± 17.21 BSA, mean ± SD, % 54.5 ± 26.91 53.8 ± 29.72 EASI score (0-72), mean ± SD 34.2 ± 14.59 33.4 ± 15.41 Overall SCORAD score (0-103), mean ± SD 65.1 ± 13.36 64.2 ± 17.67 Maximum pruritus NRS score (0-10), mean ± SD 7.4 ± 2.04 7.1 ± 2.42 IGA score (0-4), n (%) Score=3 (moderate) 13 (48.1) 14 (51.9) Score=4 (heavy) 14 (51.9) 13 (48.1)

[097] Efficacy: Treatment with dupilumab significantly improved (reduced) EASI scores from baseline to week 16 compared with placebo (SE): - 75.2% (8.15) vs -5.8% (8.16); P < 0.0001 (Fig. 1). The maximum weekly NRS of pruritus was also significantly reduced from baseline to week 16 with dupilumab compared with placebo (SE): -51.5% (10.2) vs -6.3% (10.0); P= 0.0027 (Fig. 2). A higher proportion of patients in the dupilumab group [14/27 (51.9%)] achieved an IGA reduction of ≥ 2 points by week 16 compared with the placebo group [1/27 (3.7%)]. 37% of patients in the dupilumab group achieved a score of 0 (none) or 1 (virtually absent) by week 16 compared with no such patients in the placebo group. The proportions of patients who achieved a reduction in their EASI score by week 16 were significantly higher in the dupilumab group than in the placebo group, as evidenced by the proportions of patients with EASI-50 (21/27 [77.8%] for dupilumab vs. 6/27 [22.2%] for placebo, p<0.0001), EASI-75 (18/27 [66.7%] for dupilumab vs 4/27 [14.8%] for placebo, p=0.0001) , and EASI-90 (9/27 [33.3%] for dupilumab versus 0/27 [0%] for placebo, p=0.0011). LS mean (±SE) percent change in SCORAD score from baseline to week 16 was consistent with absolute mean SCORAD change (˗54.8 ± 5.40% for dupilumab vs. ˗8.2 ± 5.41%, p<0 ,0001). The proportions of patients who achieved a 50% reduction in SCORAD (SCORAD˗50) by week 16 were higher in the dupilumab group than in the placebo group (15/27 [55.6%] for dupilumab vs 2/27 [7.4%] for placebo, p=0.0002). The dupilumab group showed an LS mean (±SE) percentage reduction from baseline in BSA involvement from baseline to week 16 of 69.0±12.61%, while the placebo group showed an increase of 13.6±12.61%.

[098] Safety: Dupilumab was safe and well tolerated, and had an acceptable safety profile. 23/27 (85.2%) patients in the dupilumab group and 24/27 (88.9%) patients in the placebo group had at least 1 TEAE. Serious TEAEs were reported by 3/27 (11.1%) patients in the placebo group and none were reported in the dupilumab group. The severity of most TEAEs was mild or moderate. Frequent TEAEs (according to the Medical Dictionary for Regulatory Activities [MedDRA] Preferred Term) included nasopharyngitis (dupilumab: 3/27 [11.1%] patients; placebo: 5/27 [18.5%] patients), upper respiratory tract infection ( 4/27 [14.8%] and 4/27 [14.8%], respectively), viral infection of the upper respiratory tract (3/27 [11.1%] and 2/27 [7.4%], respectively ) and injection site response (according to MedDRA High Level Term; 5/27 [18.5%] and 1/27 [3.7%], respectively).

Example 2 Biomarker Analysis

A. Study A

[099] In study "A", serum biomarkers were quantified in samples from a clinical trial involving individuals with moderate to severe atopic dermatitis (AD). Individuals with AD were administered 16 weekly doses of either dupilumab (200 mg) or placebo; patients in the dupilumab group received a loading dose of 400 mg on day 1. AD-associated serum biomarkers such as thymus-activation-regulated chemokine (TARC), pulmonary activation-regulated chemokine (PARC), periostin, lactate dehydrogenase (LDH), eosinophils, total IgE, and antigen-specific IgE are described in US Patent Application Publication No. US2014 /0072583 (incorporated by reference in its entirety).

[0100]Serum biomarkers were quantified at various time points between screening and week 32 and included: serum TARC (Human CCL17/TARC Quantikine ELISA kit; R&D Systems, Minneapolis, MN, USA) and periostin (Human Periostin/OSF-2 DuoSet 15 Plate R&D Systems). Serum total IgE and allergen-specific IgE were determined using the ImmunoCap assay (ImmunoCAPR Fluorescent Enzyme Immunoassay; Thermo Scientific, Uppsala, Sweden). A panel of allergen-specific IgE was generated for the main aeroallergens for this region along with anti-enterotoxin IgE A and BS. aureus. For allergen-specific IgE, the lower limit of quantitation was 0.10 kU/L; a level ≥0.35 kU/l was considered a sign of allergen sensitization.

[0101] Diagnostic variables such as serum biomarkers TARC, PARC, periostin, and total IgE were plotted as mean (SE) percentage changes from baseline; antigen-specific IgE levels were reported as the median (interquartile range [IQR]) percentage change from baseline. After salvage therapy, data were considered missing. Variables were not corrected for multiplicity and thus nominal p values are presented.

Table 2: Baseline Biomarker Scores

Variable Placebo (n=27) Dupilumab 200 mg (n=27) Serum TARC, mean (SD), pg/mL 11360 (24670) 7722 (13590) Serum PARC, mean (SD), ng/mL 206 (188) 168 (127) Serum periostin, mean value (SD), ng/ml 147 (100) 154 (117) Serum total IgE, mean (SD), IU/mL 5641 (4706) 3868 (4248)

TARC, regulated by thymus and chemokine activation; SD, standard deviation; PARC, pulmonary activation-regulated chemokine

[0102] Table 2 shows baseline biomarkers in both treatment groups. Observed a rapid and significant decrease in serum levels of TARC, PARC and periostin (figure 3-5) in the case of treatment with dupilumab compared with placebo. Serum levels of total IgE steadily decreased over the course of the treatment period, showing a significant decrease at week 16 in the dupilumab group compared to placebo (FIG. 6).

[0103] The mean and median decrease in antigen-specific IgE from baseline from week 1 to the end of the study (week 32) was noted for induced IgE against all allergen panels tested that contained gray alder, black rot, bermuda grass, warty birch, cat dander , cladosporium, cockroach (red), Dermatophagoides farinae (tick), D. pteronyssinus , dog dander, elm, Johnson grass, white oak, short ragweed, wormwood, timothy (Phleum), white ash, white candida, Malasezzia furfur , Pityrosporum orbiculare , mold, staphylococcal enterotoxin A, or staphylococcal enterotoxin B. Dupilumab significantly suppressed a wide range of serum allegen-specific IgE compared with placebo (Fig. 7; median baseline value (IQR) and median percentage change (IQR) from baseline to 16 weeks).

B. Study B

[0104] In "study B", serum biomarkers were quantified in samples from a clinical trial involving individuals with moderate to severe AD. Individuals with AD were randomized 1:1:1:1:1:1 to receive treatment for 16 weeks with weekly subcutaneous placebo; or dupilumab 100 mg every 4 weeks (q4w), 300 mg q4w, 200 mg every 2 weeks (q2w), 300 mg q2w, or 300 mg weekly (qw). Patients in the 300 mg dose groups received a loading dose of 600 mg, while patients in the 200 and 100 mg dose groups received 400 mg for 1 day. The 16 week treatment period was followed by a safety observation period of 16 weeks (total study period 32 weeks). AD-associated serum biomarkers such as thymus and activation-regulated chemokine (TARC), pulmonary activation-regulated chemokine (PARC), periostin, lactate dehydrogenase, eosinophils, total IgE, and antigen-specific IgE are described in US Patent Application Publication No. US2014/0072583 ( incorporated by reference in its entirety).

[0105] Serum biomarkers that were quantified at various time points between screening and week 32 included: serum TARC (Human CCL17/TARC Quantikine ELISA kit; R&D Systems, Minneapolis, MN, USA); serum periostin (Human Periostin/OSF-2 DuoSet 15 Plate; R&D Systems); LDH (Roche Modular and Cobas Analyzers (Roche Diagnostics, Indianapolis, IN, USA); eosinophil count determined as part of a differential cell count; and serum total IgE and antigen-specific IgE (measured by ImmunoCap assay (ImmunoCAPR Fluorescent Enzyme Immunoassay; Thermo Scientific, Phadia AB, Uppsala, Sweden).

[0106] For allergen-specific IgE, the lower limit of quantitation (LLQ) was 0.10 kU/L; a level ≥0.35 kU/l was considered a sign of allergen sensitization.

[0107] Mean percentage change in serum biomarkers TARC, periostin and LDH, and median percentage change in total IgE and allergen-specific IgE were compared at 16 weeks for each dosing regimen of dupilumab versus placebo using covariate analysis with baseline as covariate.

[0108]For dupilumab versus placebo observed decrease from baseline to week 16 in multiple serum antigen-specific IgE, including enterotoxin-specific IgES. aureus(Fig.8 and 9).

Example 3 Skin Colonization Staphylococcus aureus

[0109]Analysis microbial colonization of the skin was performed on samples obtained from individuals who participated in a clinical trial of dupilumab. Individuals with moderate to severe atopic dermatitis (AD) were administered 16 weekly doses of either dupilumab (200 mg) or placebo; patients in the dupilumab group received a loading dose of 400 mg on day 1. Colonization and infectionS. aureuswas determined on damaged and intact skin in AD between screening and 32 weeks. Skin swabs (pre-moistened with Tris-EDTA buffer) were collected from pre-measured skin areas (~10 cm x 10 cm) and tested for the presence ofS. aureus. The bacterial cells contained in the smear were lysed and the total genomic DNA was purified. ContentS. aureus-specific femA DNA in total bacterial genomic DNA was determined using quantitative real-time PCR (qPCR). Relative Colony Forming Units (rCFU)S. aureusdetermined using a standard curve generated for genomic DNA from a known amount of CFUS. aureus. ContentS. aureus reported as median (interquartile range [IQR]) percentage change from baseline. After salvage therapy, data were considered missing. Variables were not corrected for multiplicity and thus nominal p values are provided.

[0110] Dupilumab significantly reduced S. aureus in AD lesions (median % change from baseline to week 16 compared with placebo [ P= 0.0125; Table 3]), and there was an overall reduction from baseline of 16 week of average content of S. aureus compared with placebo (Fig.10).

Table 3: Contents S. aureus in damaged and intact skin in AD after treatment for 16 weeks

Placebo qw (n=27) Dupilumab 200 mg qw (n=27) Baseline median (Q1,Q3), rCFU/area Median % change (Q1,Q3), rCFU/area Baseline median (Q1,Q3), rCFU/area Median % change (Q1,Q3), rCFU/area Damaged skin in AD 1289 (239.0, 16149.0) -49 (-87.7, 635.8) 1630 (287.3, 15442.5) -99 (-99.9, -94.1)* Intact skin in AD 166 (101.2, 4755.6) -11 (-90.7, 1063.4) 374 (84.8, 3146.4) -89 (-97.5, -21.6)

*P<0.05 vs placebo; Q1, lower quartile of the interquartile range; Q3, upper quartile of the interquartile range; rCFU, relative number of colony forming units; qw, once a week.

[0111] In AD-intact skin, the dupilumab group demonstrated a numerically greater reduction in S. aureus compared to placebo (median % change from baseline to week 16 [Table 3; P = 0.9865]) and an overall median reduction from baseline at week 16 compared to placebo (FIG. 11).

Example 4: Dupilumab Improves Symptoms of Perennial Allergic Rhinitis (PAR) in Patients with Uncontrolled Persistent Asthma with Comorbid PAR

[0112] Dupilumab, a monoclonal antibody against interleukin (IL)-4 receptor α, inhibits signaling of IL-4 and IL-13, key triggers of type 2 inflammation. In a phase 2b pilot trial (NCT01854047), dupilumab improved forced expiratory volume in 1 second, reduced severe asthma exacerbations, improved quality of life, and was generally well tolerated in patients with uncontrolled persistent asthma despite moderate to high dose inhaled corticosteroids plus agonists. β ₂ long-acting (ICS+LABA). This post hoc analysis examines the effect of dupilumab on the overall score of the Nasal and Sinus Outcome Test (SNOT-22) as well as on individual scores commonly associated with allergic rhinitis (nasal congestion, runny nose, sneezing, and postnasal drip) in patients. with perennial allergic rhinitis (PAR), a common asthma comorbidity. PAR is determined by the presence of specific IgE≥0.35 kU/l against year-round antigens ( Aspergillus fumigatus , cat dander, D. farinae , D. pteronyssinus , dog dander, red cockroach or black cockroach) at study entry. Due to possible confounding effects, patients with concomitant nasal polyposis were excluded from the analysis. Data are reported for the intent-to-treat population treated with placebo and either of the dupilumab 200 or 300 mg every 2 weeks [q2w] regimens, currently in a phase 3 trial (NCT02414854). Endpoints were change from baseline to week 24 in total SNOT-22 score, as well as individual scores, postnasal mucus runoff, nasal congestion, runny nose, and sneezing. Of 392 patients treated with dupilumab (200 or 300 mg q2w) or placebo, 241 (61%) had PAR. In patients with PAR, dupilumab 300 mg q2w showed a significant improvement in total SNOT-22 score (LS mean difference -5.98 [95% CI, -10.45 to -1.51], P = 0.009 vs. placebo) and all 4 allergic rhinitis-associated symptoms as defined above relative to placebo (nasal congestion: -0.60 [95% CI, -0.96 to -0.25]; runny nose: -0.67 [95% CI, -1.04 to -0.31]; sneezing: -0.55 [95% CI, -0.89 to -0.21]; and postnasal mucus drip: -0.49 [95% CI, from -0.83 to -0.16]; all P < 0.01 vs. placebo); dupilumab 200 mg q2w demonstrated a numerical but not statistically significant reduction in total SNOT-22 score (-1.82 [95% CI, -6.46 to 2.83], P = 0.443), as well as 4 associated with allergic rhinitis symptoms. No difference was observed relative to placebo in patients without PAR total SNOT-22 and 4 symptoms associated with allergic rhinitis. In conclusion, dupilumab 300 mg q2w significantly improved sinonasal symptoms in patients with uncontrolled persistent asthma and co-morbid PAR.

[0113] The scope of the present invention is not limited to the specific embodiments described herein. Indeed, various modifications of the invention in addition to the modifications described in the present description will become clear to experts in this field from the foregoing description and the accompanying drawings. Such modifications are intended to be within the scope of the appended claims.

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<220>

<223> HCDR2

<400> 4

Ile Ser Gly Ser Gly Gly Asn Thr

fifteen

<210> 5

<211> 18

<212> PROTEIN

<213> Artificial sequence

<220>

<223> HCDR3

<400> 5

Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu

1 5 10 15

Asp Val

<210> 6

<211> 11

<212> PROTEIN

<213> Artificial sequence

<220>

<223> LCDR1

<400> 6

Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr

1 5 10

<210> 7

<211> 3

<212> PROTEIN

<213> Artificial sequence

<220>

<223> LCDR2

<400> 7

Leu Gly Ser

one

<210> 8

<211> 9

<212> PROTEIN

<213> Artificial sequence

<220>

<223> LCDR3

<400> 8

Met Gln Ala Leu Gln Thr Pro Tyr Thr

fifteen

<210> 9

<211> 451

<212> PROTEIN

<213> Artificial sequence

<220>

<223>HC

a.k. 1-124: HCVR

a.k. 125-451: HC constant

<400> 9

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu

100 105 110

Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr

115 120 125

Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser

130 135 140

Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu

145 150 155 160

Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His

165 170 175

Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser

180 185 190

Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys

195 200 205

Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu

210 215 220

Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu

225 230 235 240

Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu

245 250 255

Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser

260 265 270

Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu

275 280 285

Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr

290 295 300

Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn

305 310 315 320

Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser

325 330 335

Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln

340 345 350

Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val

355 360 365

Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val

370 375 380

Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro

385 390 395 400

Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr

405 410 415

Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val

420 425 430

Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu

435 440 445

Ser Leu Gly

450

<210> 10

<211> 219

<212> PROTEIN

<213> Artificial sequence

<220>

<223>LC

a.k. 1-112: LCVR

a.k. 113-219: LC constant

<400> 10

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser

20 25 30

Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala

85 90 95

Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 11

<211> 207

<212> PROTEIN

<213> Artificial sequence

<220>

<223> hIL-4R-alpha

<400> 11

Met Lys Val Leu Gln Glu Pro Thr Cys Val Ser Asp Tyr Met Ser Ile

1 5 10 15

Ser Thr Cys Glu Trp Lys Met Asn Gly Pro Thr Asn Cys Ser Thr Glu

20 25 30

Leu Arg Leu Leu Tyr Gln Leu Val Phe Leu Leu Ser Glu Ala His Thr

35 40 45

Cys Ile Pro Glu Asn Asn Gly Gly Ala Gly Cys Val Cys His Leu Leu

50 55 60

Met Asp Asp Val Val Ser Ala Asp Asn Tyr Thr Leu Asp Leu Trp Ala

65 70 75 80

Gly Gln Gln Leu Leu Trp Lys Gly Ser Phe Lys Pro Ser Glu His Val

85 90 95

Lys Pro Arg Ala Pro Gly Asn Leu Thr Val His Thr Asn Val Ser Asp

100 105 110

Thr Leu Leu Leu Thr Trp Ser Asn Pro Tyr Pro Pro Asp Asn Tyr Leu

115 120 125

Tyr Asn His Leu Thr Tyr Ala Val Asn Ile Trp Ser Glu Asn Asp Pro

130 135 140

Ala Asp Phe Arg Ile Tyr Asn Val Thr Tyr Leu Glu Pro Ser Leu Arg

145 150 155 160

Ile Ala Ala Ser Thr Leu Lys Ser Gly Ile Ser Tyr Arg Ala Arg Val

165 170 175

Arg Ala Trp Ala Gln Cys Tyr Asn Thr Thr Trp Ser Glu Trp Ser Pro

180 185 190

Ser Thr Lys Trp His Asn Ser Tyr Arg Glu Pro Phe Glu Gln His

195 200 205

<---

Claims (28)

1. A method for reducing serum allergen-specific IgE in a patient, comprising: administration to a patient having atopic dermatitis, asthma and/or allergic rhinitis, a therapeutically effective amount of an interleukin-4 receptor (IL-4R) antagonist, and before or during treatment, the patient has a serum allergen-specific IgE level ≥ 0.35 kU / ml at determination by immunoassay, wherein the allergen originates from a source selected from the group consisting of gray alder, black rot, Bermuda grass, warty birch, cat dander, cladosporium, cockroach, Dermatophagoides farinae , D. pteronyssinus , dog dander, elm, Johnson grass, white oak, common ragweed, timothy grass, white ash, white candida, Malasezzia furfur , Pityrosporum orbiculare , mould, staphylococcal enterotoxin A and staphylococcal enterotoxin B; wherein the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4Rα and contains three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), where 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, wherein the IL-4R antagonist is administered for at least 16 weeks, wherein the IL-4R antagonist is administered at an initial dose followed by one or more secondary doses, wherein each secondary dose is administered 1 to 4 weeks after the immediately preceding dose, and wherein i) the initial dose contains 600 mg and each secondary dose contains 300 mg of the IL-4R antagonist or ii) the initial dose contains 400 mg and each secondary dose contains 200 mg of the IL-4R antagonist. 2. The method of claim. 1, where the patient has atopic dermatitis. 3. The method of claim 2 wherein the patient has moderate to severe atopic dermatitis. 4. The method according to any one of paragraphs. 1-3, where the patient has asthma and concomitant perennial allergic rhinitis. 5. The method of claim 4 wherein the initial dose contains 600 mg and each secondary dose contains 300 mg of the IL-4R antagonist. 6. The method of claim 4 wherein the initial dose contains 400 mg and each secondary dose contains 200 mg of the IL-4R antagonist. 7. The method according to any one of paragraphs. 1-6, where each secondary dose is administered one week after the immediately preceding dose. 8. The method according to any one of paragraphs. 1-6, where each secondary dose is administered 2 weeks after the immediately preceding dose. 9. The method according to any one of paragraphs. 1-8 wherein the IL-4R antagonist is administered subcutaneously to the patient. 10. The method according to any one of paragraphs. 1-9, further comprising administering a second therapeutic agent to the patient, wherein the second therapeutic agent is administered to the patient before, after, or simultaneously with the IL-4R antagonist. 11. The method of claim 10 wherein the second therapeutic agent is selected from the group consisting of an antihistamine, systemic immunotherapy, a corticosteroid, a long acting β2 agonist, a tumor necrosis factor (TNF) inhibitor, an interleukin 1 (IL-1) inhibitor, an IL inhibitor -5, IL-8 inhibitor, IgE inhibitor, non-steroidal anti-inflammatory drug (NSAID) and interferon-gamma (IFNγ). 12. The method according to any one of paragraphs. 1-11, where the antibody to IL-4Rα contains a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. 13. The method according to any one of paragraphs. 1-12, where the antibody to IL-4Rα contains 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. 14. The method according to any one of paragraphs. 1-13, where the IL-4R antagonist is dupilumab or its bioequivalent. 15. The method according to any one of paragraphs. 1-14, where the IL-4R antagonist is contained in a syringe. 16. The method according to any one of paragraphs. 1-15 wherein the IL-4R antagonist is contained in a pen delivery device. 17. The method of claim 16 wherein the pen delivery device is pre-filled. 18. The method according to any one of paragraphs. 1-14 wherein the IL-4R antagonist is contained in a self-injection syringe. 19. Use of an interleukin-4 receptor (IL-4R) antagonist to reduce serum allergen-specific IgE in a patient having an elevated serum allergen-specific IgE level, wherein the patient has atopic dermatitis, asthma and/or allergic rhinitis and has a serum allergen-specific IgE level. specific IgE, constituting ≥ 0.35 kU / ml before or during treatment, as determined by immunoassay; wherein the IL-4R antagonist is administered to the patient for at least 16 weeks, wherein the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4Rα and contains three complementarity-determining heavy chain regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), where 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, and wherein the allergen originates from a source selected from the group consisting of gray alder, black rot, bermuda grass, warty birch, cat dander, cladosporium, cockroach, Dermatophagoides farinae , D. pteronyssinus , dog dander, elm, Johnson grass, white oak, ragweed short, timothy, white ash, white candida, Malasezzia furfur , Pityrosporum orbiculare , mould, staphylococcal enterotoxin A and staphylococcal enterotoxin B, wherein the IL-4R antagonist is administered at an initial dose followed by one or more secondary doses, where each secondary dose is administered 1-4 weeks after the immediately preceding dose, and wherein: i) the initial dose contains 600 mg and each secondary dose contains 300 mg of an IL-4R antagonist or ii) the initial dose contains 400 mg and each secondary dose contains 200 mg of an IL-4R antagonist . 20. The use of an interleukin-4 receptor (IL-4R) antagonist for the manufacture of a medicament for reducing serum allergen-specific IgE in a patient having an elevated level of serum allergen-specific IgE, wherein the patient has atopic dermatitis, asthma and/or allergic rhinitis and has a serum allergen-specific IgE level of ≥ 0.35 kU/ml before or during treatment as determined by immunoassay; and wherein a therapeutically effective amount of an IL-4R antagonist is administered to the patient, wherein the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds IL-4Rα and contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three complementarity of the light chain region (LCDR1, LCDR2 and LCDR3), where 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; and the IL-4R antagonist is administered for at least 16 weeks; and wherein the allergen originates from a source selected from the group consisting of gray alder, black rot, bermuda grass, warty birch, cat dander, cladosporium, cockroach, Dermatophagoides farinae , D. pteronyssinus , dog dander, elm, Johnson grass, white oak, ragweed short, timothy, white ash, white candida, Malasezzia furfur , Pityrosporum orbiculare , mould, staphylococcal enterotoxin A and staphylococcal enterotoxin B, wherein the IL-4R antagonist is administered at an initial dose followed by one or more secondary doses, where each secondary dose is administered 1-4 weeks after the immediately preceding dose, and wherein: i) the initial dose contains 600 mg and each secondary dose contains 300 mg of an IL-4R antagonist or ii) the initial dose contains 400 mg and each secondary dose contains 200 mg of an IL-4R antagonist . 21. Use according to claim 19 or 20, wherein the initial dose contains 600 mg and each secondary dose contains 300 mg of an IL-4R antagonist. 22. Use according to claim 19 or 20, wherein the initial dose contains 400 mg and each secondary dose contains 200 mg of an IL-4R antagonist. 23. Use according to claim 21 or 22, wherein each secondary dose is administered one week or two weeks after the immediately preceding dose.

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