Method for attenuating the atopic march by administering an IL-4 / IL-13 antagonist

Abstract

Methods are provided for preventing the onset of a new allergic condition or the worsening of an existing concomitant allergic condition in a subject with an atopic disease, such as atopic dermatitis, in one embodiment, the method comprises administering to the subject a course of therapy of an IL-4 / IL-13 antagonist, such as an anti-IL-4R antibody or antigen-binding fragment thereof.

Description

[Technical field]

[0001] A reference to the array list XML This application contains a Sequence Listing that has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference. Created on December 21, 2022, this XML file is named 40848_0114WOU1_SL.xml and is 267,820 bytes in size.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application is scheduled to be filed on December 29, 2022 as a PCT international patent application claiming priority to U.S. Provisional Application No. 63 / 295,113, filed on December 30, 2021, the contents of which are incorporated herein by reference. [Background technology]

[0003] Atopic march is defined as the natural progression of allergic disease that develops over the course of a person's lifespan. The successive acquisition of new and worsening allergies was first recognized by AF Coco and RA Cooke almost a century ago after the first case of clinically significant allergic constitution (Non-Patent Document 1). Subsequently, important features of allergic immune responses were discovered, such as the role of allergen-specific immunoglobulin E (IgE), the discovery of T helper (TH) cell subsets, and antigen-specific TH2 cells that give rise to cytokine patterns (IL-4, IL-5, and IL-13) (see, for example, Non-Patent Document 2; Non-Patent Document 3; Non-Patent Document 4).

[0004] The relationship between the successive acquisition of allergic conditions is thought to be a complex process influenced by multiple genetic and environmental factors (Non-Patent Document 5; Non-Patent Document 6). The presence of one allergic condition is a risk factor for the development of the others, resulting in the cumulative (and often consecutive) features of the atopic march and increased disease burden (see, for example, Non-Patent Document 7). The classical progression of the atopic march begins with atopic dermatitis (AD), which can progress to IgE-mediated food allergy, asthma, and allergic rhinitis (Non-Patent Document 8; Non-Patent Document 9). In AD, type 2 inflammation may be associated with or preceded by epidermal properties associated with increased skin permeability that provide a route for allergen penetration of the skin, and may promote the initiation of a systemic TH2 response. Thus, skin barrier dysfunction may lead to allergic sensitization in susceptible patients (Non-Patent Document 10). A significant proportion of AD patients have mutations in the gene encoding filaggrin, an important skin barrier protein, the insufficiency of which is strongly associated with barrier dysfunction (Non-Patent Document 11). Antimicrobial peptides are also important for skin homeostasis and, together with microbiota diversity, are reduced in the skin of people with AD (Non-Patent Document 12). For example, numerous environmental factors, such as exposure to pets, dust, and childhood antibiotics, among others, have also been implicated in the progression of AD and atopy. Thus, the pathogenesis of AD and the possible progression of the atopic march are complex and likely result from interactions between altered epidermal function, microbiota, allergen sensitization, and the immune system. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Hill et al., Ann Allergy Asthma Immunol 2018, 120:131~7 [Non-Patent Document 2] Ishizaka et al., J Immunol 1966, 97:75~85 [Non-Patent Document 3] Bottomly et al., Semin Immunol 1989, 1:21~31 [Non-Patent Document 4] Springer et al., Immunol Rev 1982, 68:171~95 [Non-Patent Document 5] Holguin, Lancet Resp Med 2014, 2:88~90 [Non-Patent Document 6] Paller et al., J Allergy Clin Immunol 2019, 143:46~55 [Non-Patent Document 7] Hill et al., BMC Pediatr 2016, 16:133 [Non-Patent Document 8] Asher et al., Clin Exp Allergy 1998, 28 Suppl 5:52~66 [Non-Patent Document 9] Somanunt et al., Asian Pac J Allergy Immunol 2017, 35:137~43 [Non-Patent Document 10] Brunner et al., J Invest Dermatol 2017, 137:18-25 [Non-Patent Document 11] Saunders et al., J Allergy Clin Immunol 2016, 137:482~91 [Non-Patent Document 12] Pellefigues, Antibodies 2020, 9:47 [Non-Patent Document 13] Jimenez et al., Ann Allergy Asthma Immnol 2021, 127:289~290 [Non-Patent Document 14] Schneider et al., Pediatr Dermatol 2016, 33:388~398 [Non-Patent Document 15] Spergel et al., J Allergy Clin Immunol 2003, 112:S118~27 [Non-Patent Document 16] Paller et al., J Allergy Clin Immunol 2019, 143:46~55 Summary of the Invention [Problem to be solved by the invention]

[0006] To date, no therapeutic intervention has been demonstrated to alleviate the atopic march. A clinical trial examining the prevention of AD in very young children with topical alleviators found no evidence of prevention (see Non-Patent Document 13), and a long-term clinical trial of pimecrolimus in infants with recent-onset AD found no significant difference in the percentage of patients who developed asthma or other allergic conditions (Non-Patent Document 14). Although unsuccessful, other trials have used preventative antihistamines, prenatal and postnatal probiotics, and ceramide-dominant emollients to attempt to eliminate the atopic march (Non-Patent Document 15; see Non-Patent Document 16). As a result, there is an unmet medical need for effective therapies to slow or prevent the progression of the atopic march. [Means for solving the problem]

[0007] In one aspect, the disclosure provides a method for attenuating the progression of the atopic march (e.g., attenuating, slowing, or preventing the worsening of an existing concomitant allergic condition or the acquisition or development of a new allergic condition, or reducing the risk of developing a new allergic condition or worsening of an existing allergic condition) in a subject with an atopic disease by administering an IL-4 / IL-13 antagonist.

[0008] In some embodiments, the method includes selecting a subject having an atopic disease (e.g., atopic dermatitis (AD)) at risk of developing a new allergic condition or an exacerbation of an allergic condition, and administering to the subject a course of treatment comprising an IL-4 / IL-13 antagonist, where after the course of treatment, the subject does not exhibit any new allergic condition or exacerbation of any existing concomitant allergic condition.

[0009] In some embodiments, the subject has moderate to severe AD. In some embodiments, the subject has the following characteristics: (i) early onset of AD by age 2 years; (ii) onset of AD after age 2 years and age ≤35 years at the start of treatment with an IL-4 / IL-13 antagonist; (iii) severe AD; (iv) age ≤18 years at the start of treatment with an IL-4 / IL-13 antagonist; (v) baseline IgE level between 375 IU / mL and 2000 IU / mL; (vi) ≥ 2 concomitant allergic conditions; and / or (vii) Concomitant asthma If a person has one or more of the following, they are at risk of developing a new allergic condition or having an exacerbated allergic condition.

[0010] In some embodiments, the subject has (i) early onset of AD by age 2, or (ii) onset of AD after age 2 and an age of ≦35 years at the start of treatment with an IL-4 / IL-13 antagonist.

[0011] In some embodiments, the subject has early onset AD by age 2. In some embodiments, the subject has early onset AD by age 2 and further has one or more of characteristics (iii), (iv), (v), (vi), or (vii).

[0012] In some embodiments, the subject has onset of AD after age 2 and has an age of ≦35 years at the initiation of treatment with an IL-4 / IL-13 antagonist. In some embodiments, the subject has onset of AD after age 2, an age of ≦35 years at the initiation of treatment with an IL-4 / IL-13 antagonist, and further has one or more of characteristics (iii), (iv), (v), (vi), or (vii).

[0013] In some embodiments, the subject has severe AD.

[0014] In some embodiments, the subject is ≦18 years old at the start of treatment. In some embodiments, the subject is >18 years old at the start of treatment.

[0015] In some embodiments, the subject has a baseline IgE level of between 375 IU / mL and 2000 IU / mL.

[0016] In some embodiments, the subject has ≧2 concomitant allergic conditions. In some embodiments, the subject has 2 or 3 concomitant allergic conditions. In some embodiments, the subject has at least 3 concomitant allergic conditions. In some embodiments, the concomitant allergic conditions are selected from the group consisting of environmental allergies, aspirin sensitivity, asthma, allergic conjunctivitis, contact dermatitis, drug hypersensitivity, eosinophilic esophagitis, food allergies, ichthyosis, nasal polyps, oral allergy syndrome, pruritus, rhinitis, sinusitis, and urticaria. In some embodiments, the subject has concomitant asthma.

[0017] In some embodiments, the method comprises: Selecting subjects with atopic dermatitis (AD) and further having one or more of the following characteristics: (i) early onset of AD by age 2 years; (ii) onset of AD after age 2 years and age ≦35 years at the start of treatment; (iii) baseline IgE level of 375 IU / mL to 2000 IU / mL at the start of treatment; (iv) ≧2 concomitant allergic conditions; and / or (v) concomitant asthma; and administering to the subject a course of treatment comprising an IL-4 / IL-13 antagonist. Includes.

[0018] In some embodiments, the subject has moderate to severe atopic dermatitis, hi some embodiments, the subject has severe atopic dermatitis.

[0019] In some embodiments, the subject has onset AD at ≦2 years of age; or, the subject has onset AD at >2 years of age, where the subject is ≦35 years of age at the initiation of treatment with an IL-4 / IL-13 antagonist. In some embodiments, the subject has onset AD at ≦2 years of age. In some embodiments, the subject has onset AD at >2 years of age, where the subject is ≦35 years of age at the initiation of treatment with an IL-4 / IL-13 antagonist.

[0020] In some embodiments, the subject has a baseline IgE level of between 375 IU / mL and 2000 IU / mL.

[0021] In some embodiments, the subject has ≧2 concomitant allergic conditions. In some embodiments, the subject has 2 or 3 concomitant allergic conditions. In some embodiments, the subject has at least 3 concomitant allergic conditions. In some embodiments, the concomitant allergic conditions are selected from the group consisting of environmental allergies, aspirin sensitivity, asthma, allergic conjunctivitis, contact dermatitis, drug hypersensitivity, eosinophilic esophagitis, food allergies, ichthyosis, nasal polyps, oral allergy syndrome, pruritus, rhinitis, sinusitis, and urticaria. In some embodiments, the subject has concomitant asthma.

[0022] In some embodiments, the subject being treated is < 18 years old. In some embodiments, the subject being treated is > 18 years old.

[0023] In some embodiments, treatment with an IL-4 / IL-13 antagonist attenuates, slows, or prevents the acquisition of a new allergic condition in a subject, or reduces the risk of acquiring a new allergic condition in a subject. In some embodiments, treatment with an IL-4 / IL-13 antagonist attenuates, slows, or prevents the worsening of an existing allergic condition in a subject, or reduces the risk of worsening of an existing allergic condition in a subject.

[0024] In some embodiments, the IL-4 / IL-13 antagonist is an IL-4R antagonist, hi some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof.

[0025] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0026] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab.

[0027] In some embodiments, the IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is administered for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, or at least 52 weeks. In some embodiments, the IL-4 / IL-13 antagonist is administered every week (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

[0028] In some embodiments, the IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is administered at a dose of 75 mg to 600 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered at a dose of 100 mg, 200 mg, or 300 mg.

[0029] In some embodiments, the IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is administered in an initial dose of 600 mg followed by a secondary dose of 300 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered in an initial dose of 400 mg followed by a secondary dose of 200 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered in an initial dose of 200 mg or 400 mg followed by a secondary dose of 100 mg. In some embodiments, the secondary doses are administered QW, Q2W, or Q4W.

[0030] In some embodiments, the IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is administered in combination with a local therapy. In some embodiments, the IL-4 / IL-13 antagonist is administered in combination with a topical corticosteroid.

[0031] In some embodiments, the IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an auto-injector. In some embodiments, the IL-4 / IL-13 antagonist is contained in a syringe (e.g., a pre-filled syringe). In some embodiments, the IL-4 / IL-13 antagonist is contained in a pen delivery device. In some embodiments, the IL-4 / IL-13 antagonist is contained in an auto-injector.

[0032] In another aspect, the disclosure provides an IL-4 / IL-13 antagonist for use in attenuating the progression of the atopic march in a subject with an atopic disease (e.g., attenuating, slowing, or preventing the worsening of an existing concomitant allergic condition or the acquisition of a new allergic condition, or reducing the risk of developing a new allergic condition or worsening an existing allergic condition). In some embodiments, the IL-4 / IL-13 antagonist is an IL-4R antagonist, such as an anti-IL-4R antibody, or an antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0033] In another aspect, the disclosure provides a pharmaceutical composition for use in attenuating the progression of the atopic march in a subject with atopic disease (e.g., attenuating, slowing, or preventing the worsening of an existing concomitant allergic condition or the acquisition of a new allergic condition, or reducing the risk of developing a new allergic condition or worsening of an existing allergic condition), wherein the pharmaceutical composition comprises an IL-4 / IL-13 antagonist. In some embodiments, the IL-4 / IL-13 antagonist is an IL-4R antagonist, e.g., an anti-IL-4R antibody, or an antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0034] In yet another aspect, the disclosure provides the use of an IL-4 / IL-13 antagonist for the manufacture of a medicament for attenuating the progression of atopic march in a subject with an atopic disease (e.g., attenuating, slowing, or preventing the worsening of an existing concomitant allergic condition or the acquisition of a new allergic condition, or reducing the risk of developing a new allergic condition or worsening an existing allergic condition). In some embodiments, the IL-4 / IL-13 antagonist is an IL-4R antagonist, such as an anti-IL-4R antibody, or an antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), where HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0035] Other embodiments will become apparent from a review of the following detailed description. [Brief description of the drawings]

[0036] [Figure 1A] (A) Forest plots by allergy category for new and worsening events during treatment, and (B) by allergy category for new events during treatment. CI, confidence interval; IRR, incidence rate. [Figure 1B] (A) Forest plots by allergy category for new and worsening events during treatment, and (B) by allergy category for new events during treatment. CI, confidence interval; IRR, incidence rate. [Figure 2A] FIG. 13. Forest plot with antigen-specific IgE for study R668-AD-1224. One-stage analysis: for each antigen, new events are defined as below the lower limit of quantification (LLOQ) at baseline and above the LLOQ at week 52; worsening events are defined as above the LLOQ at baseline and an increase of at least 1-fold at week 52. Two-stage analysis: for each antigen, new events are defined as below the LLOQ at baseline and at least 2-fold the magnitude of the LLOQ at week 52; worsening events are defined as above the LLOQ at baseline and an increase of at least 2-fold at week 52. (A) One-stage analysis: for new and worsening events, (B) One-stage analysis: for new events only, (C) Two-stage analysis: for new and worsening events, (D) Two-stage analysis: for new events only. [Figure 2B]FIG. 13. Forest plot with antigen-specific IgE for study R668-AD-1224. One-stage analysis: for each antigen, new events are defined as below the lower limit of quantification (LLOQ) at baseline and above the LLOQ at week 52; worsening events are defined as above the LLOQ at baseline and an increase of at least 1-fold at week 52. Two-stage analysis: for each antigen, new events are defined as below the LLOQ at baseline and at least 2-fold the magnitude of the LLOQ at week 52; worsening events are defined as above the LLOQ at baseline and an increase of at least 2-fold at week 52. (A) One-stage analysis: for new and worsening events, (B) One-stage analysis: for new events only, (C) Two-stage analysis: for new and worsening events, (D) Two-stage analysis: for new events only. [Figure 2C] FIG. 13. Forest plot with antigen-specific IgE for study R668-AD-1224. One-stage analysis: for each antigen, new events are defined as below the lower limit of quantification (LLOQ) at baseline and above the LLOQ at week 52; worsening events are defined as above the LLOQ at baseline and an increase of at least 1-fold at week 52. Two-stage analysis: for each antigen, new events are defined as below the LLOQ at baseline and at least 2-fold the magnitude of the LLOQ at week 52; worsening events are defined as above the LLOQ at baseline and an increase of at least 2-fold at week 52. (A) One-stage analysis: for new and worsening events, (B) One-stage analysis: for new events only, (C) Two-stage analysis: for new and worsening events, (D) Two-stage analysis: for new events only. [Figure 2D]FIG. 13. Forest plot with antigen-specific IgE for study R668-AD-1224. One-stage analysis: for each antigen, new events are defined as below the lower limit of quantification (LLOQ) at baseline and above the LLOQ at week 52; worsening events are defined as above the LLOQ at baseline and an increase of at least 1-fold at week 52. Two-stage analysis: for each antigen, new events are defined as below the LLOQ at baseline and at least 2-fold the magnitude of the LLOQ at week 52; worsening events are defined as above the LLOQ at baseline and an increase of at least 2-fold at week 52. (A) One-stage analysis: for new and worsening events, (B) One-stage analysis: for new events only, (C) Two-stage analysis: for new and worsening events, (D) Two-stage analysis: for new events only. [Figure 3A] Forest plots of (A) studies for new and worsening events during treatment, (B) studies for new events during treatment, (C) studies for new and worsening events during treatment (including one-step increase in IgE), and (D) studies for new and worsening events during treatment (including two-step increase in IgE). [Figure 3B] Forest plots of (A) studies for new and worsening events during treatment, (B) studies for new events during treatment, (C) studies for new and worsening events during treatment (including one-step increase in IgE), and (D) studies for new and worsening events during treatment (including two-step increase in IgE). [Figure 3C] Forest plots of (A) studies for new and worsening events during treatment, (B) studies for new events during treatment, (C) studies for new and worsening events during treatment (including one-step increase in IgE), and (D) studies for new and worsening events during treatment (including two-step increase in IgE). [Figure 3D]Forest plots of (A) studies for new and worsening events during treatment, (B) studies for new events during treatment, (C) studies for new and worsening events during treatment (including one-step increase in IgE), and (D) studies for new and worsening events during treatment (including two-step increase in IgE). [Figure 4A] Skin events: Sensitivity analysis by removing contact dermatitis, pruritus. (A) Forest plot by study for new and worsening events during treatment, (B) by study for new events during treatment. [Figure 4B] Skin events: Sensitivity analysis by removing contact dermatitis, pruritus. (A) Forest plot by study for new and worsening events during treatment, (B) by study for new events during treatment. [Figure 5A] (A) Forest plots by study for new and worsening events during the study period, and (B) by study for new events during the study period. [Figure 5B] (A) Forest plots by study for new and worsening events during the study period, and (B) by study for new events during the study period. [Figure 6A] Forest plots of (A) by study for new and worsening events during the drug holiday period and (B) by study for new events during the drug holiday period. [Figure 6B] Forest plots of (A) by study for new and worsening events during the drug holiday period and (B) by study for new events during the drug holiday period. [Figure 7A] Forest plots by (A) age subgroup, B) age at onset subgroup, (C) region, (D) race, (E) AD severity, (F) baseline IgE subgroup, (G) presence of asthma at baseline, and (H) baseline allergy burden. [Figure 7B]Forest plots by (A) age subgroup, B) age at onset subgroup, (C) region, (D) race, (E) AD severity, (F) baseline IgE subgroup, (G) presence of asthma at baseline, and (H) baseline allergy burden. [Figure 7C] Forest plots by (A) age subgroup, B) age at onset subgroup, (C) region, (D) race, (E) AD severity, (F) baseline IgE subgroup, (G) presence of asthma at baseline, and (H) baseline allergy burden. [Figure 7D] Forest plots by (A) age subgroup, B) age at onset subgroup, (C) region, (D) race, (E) AD severity, (F) baseline IgE subgroup, (G) presence of asthma at baseline, and (H) baseline allergy burden. [Figure 7E] Forest plots by (A) age subgroup, B) age at onset subgroup, (C) region, (D) race, (E) AD severity, (F) baseline IgE subgroup, (G) presence of asthma at baseline, and (H) baseline allergy burden. [Figure 7F] Forest plots by (A) age subgroup, B) age at onset subgroup, (C) region, (D) race, (E) AD severity, (F) baseline IgE subgroup, (G) presence of asthma at baseline, and (H) baseline allergy burden. [Figure 7G] Forest plots by (A) age subgroup, B) age at onset subgroup, (C) region, (D) race, (E) AD severity, (F) baseline IgE subgroup, (G) presence of asthma at baseline, and (H) baseline allergy burden. [Figure 7H]Forest plots by (A) age subgroup, B) age at onset subgroup, (C) region, (D) race, (E) AD severity, (F) baseline IgE subgroup, (G) presence of asthma at baseline, and (H) baseline allergy burden. [Figure 8] Forest plot by baseline IgE quartile subgroups. Unequal sample sizes in subgroups resulted in a significant number of patients with baseline IgE >= 5000 IU / mL all being imputed at 10,000 IU / mL, which led to many ties in the data. IgE, immunoglobulin E; IRR, incidence rate; TEAE, treatment-emergent adverse events. [Figure 9] FIG. 11 Forest plots by subgroups of age at onset of treatment (≦35 and >35) and age at onset of AD (≦2 and >2 years) for new and worsening events and new events during the treatment and study periods. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] definition Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, since such methods and conditions may vary. It should also be understood that the terms used herein are for the purpose of describing specific embodiments only, and are not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0039] As used herein, the term "about" when used in reference to a particular stated numerical value means that the value may vary from the stated value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0040] As used herein, terms such as "treat" or "treating" mean to alleviate symptoms, to eliminate the cause of symptoms, either temporarily or permanently, or to prevent or delay the onset of symptoms of the specified disorder or condition.

[0041] As used herein, "atopic march" refers to the sequential development of atopic disease in a subject. As used herein, "atopic march" includes the acquisition of one or more new allergic conditions in a subject as well as the progression or worsening of one or more pre-existing allergic conditions in a subject.

[0042] As used herein, the term "subject in need thereof" refers to a human or non-human animal having an atopic disease, such as atopic dermatitis (e.g., moderate to severe AD or severe AD). In some embodiments, the term "subject in need thereof" refers to a patient having two or more concomitant atopic diseases (e.g., atopic dermatitis and one, two, three, or more concomitant atopic conditions). The terms "subject" and "patient" are used interchangeably herein.

[0043] The term "antibody," as used herein, refers to an antigen-binding molecule or molecular complex that comprises a set of complementarity determining regions (CDRs) that specifically bind to or interact with a particular antigen (e.g., IL-4R or IL-4Rα). The term "antibody," as used herein, encompasses immunoglobulin molecules that comprise four polypeptide chains, two heavy chains (H) and two light chains (L), interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (referred to herein as HCVR or VVR). H The heavy chain constant region is made up of three domains: H 1. C H 2, and C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L The regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged in the following order from amino-terminus to carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an antibody (or an antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on comparative analysis of two or more CDRs.

[0044] The term "antibody" as used herein also includes antigen-binding fragments of full-length antibody molecules. Terms such as "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and "antigen-binding domain" as used herein include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from full-length antibody molecules using any suitable standard technique, such as, for example, proteolytic digestion, or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding antibody variable domains and optionally constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to place one or more variable and / or constant domains in a suitable configuration, or to introduce codons, to create cysteine ​​residues, to modify, add, or delete amino acids.

[0045] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable regions of an antibody (e.g., isolated complementarity determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Domain-specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other engineered molecules such as shark variable IgNAR domains are also encompassed by the term "antigen-binding fragments" as used herein.

[0046] An antigen-binding fragment of an antibody will typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and generally contains at least one CDR adjacent to or in frame with one or more framework sequences. H Domain is V L In the antigen-binding fragment associated with the V domain, H and V L The domains may be positioned relative to one another in any suitable configuration. For example, the variable region may be a dimer, with the V H -V H , V H -V L , or V L -V L Alternatively, the antigen-binding fragment of the antibody may comprise a monomeric V H or V L It may also include a domain.

[0047] In certain 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 exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody include the following: (i) V H -C H 1;(ii)V H -C H 2;(iii)V H -C H 3;(iv)V H -C H 1-C H 2;(v)V H -C H 1-C H 2-C H 3;(vi)V H -C H 2-C H 3;(vii)V H -C L ;(viii)V L -C H 1;(ix)VL -C H 2;(x)V L -C H 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to each other or linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that provide a flexible or semi-flexible link between adjacent variable and / or constant domains within a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies may be linked to each other and / or to one or more monomeric V H Or V L It may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above, in which the domains are non-covalently associated (e.g., by disulfide bonds).

[0048] The term "antibody" as used herein also includes multispecific (e.g., bispecific) antibodies. A multispecific antibody or antigen-binding fragment of an antibody will typically include at least two different variable domains, each capable of specifically binding to a separate antigen or a different epitope of the same antigen. Any multispecific antibody format can be constructed for use in the context of the antibodies or antigen-binding fragments of antibodies of the present disclosure using routine techniques available in the art. For example, the present disclosure includes methods that include the use of bispecific antibodies, where one arm of the immunoglobulin is specific for IL-4R or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present disclosure include, but are not limited to, for example, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab 2 Bispecific formats include (for a review of the above formats, see, for example, Klein et al., 2012, mAbs 4:6, pp. 1-11, and references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation. For example, unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates. The conjugates then self-assemble to form multimeric complexes with defined composition, valency, and shape. (See, for example, Kazane et al., J. Am. Chem. Soc. [Epub: December 4, 2012]).

[0049] The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of the present disclosure may contain amino acid residues (e.g., mutations introduced by random or site-specific mutagenesis in vitro or somatic mutation in vivo), e.g., in the CDRs, particularly in CDR3, that are not encoded by human germline immunoglobulin sequences. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0050] The term "recombinant antibody," as used herein, is intended to encompass all antibodies prepared, expressed, generated, or isolated by recombinant means. The term encompasses, but is not limited to, antibodies expressed using a recombinant expression vector transfected into a host cell (e.g., Chinese Hamster Ovary (CHO) cell) or cell expression system, antibodies isolated from a recombinant combinatorial human antibody library, and antibodies isolated from a non-human animal (e.g., a mouse, e.g., a mouse transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295)). In some embodiments, the recombinant antibody is a recombinant human antibody. In some embodiments, the recombinant human antibody has variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies have been subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the V and VL of the recombinant antibody may be modified. H Area and V L The amino acid sequence of the region is H Array and V LThese are sequences that are derived from and related to sequences, but may not naturally occur within the human germline repertoire in vivo.

[0051] An "isolated antibody" refers to an antibody that has been identified, separated, and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ within a recombinant cell. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0052] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, exemplary methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0053] Treatment method In one aspect, a method of attenuating the progression of atopic march in a subject is provided, comprising administering one or more doses of an interleukin-4 (IL-4) / interleukin-13 (IL-13) antagonist. As described in the Examples section below, it was surprisingly found that in patients with atopic dermatitis, treatment with the IL-4 / IL-13 antagonist dupilumab was associated with fewer new allergic conditions or worsening of allergic conditions compared to placebo. This data suggests that dupilumab can modify the progression of allergic manifestations of the atopic march in highly atopic patients. Furthermore, as described herein, treatment with dupilumab reduces the occurrence of new allergic conditions and worsening of existing allergic conditions not only in younger patients (≦18 years old) but also in adults, such as adults with early onset of childhood AD.

[0054] In some embodiments, the subject being treated has an atopic disease. In some embodiments, the subject being treated has atopic dermatitis (AD). In some embodiments, the subject has moderate to severe AD. In some embodiments, the subject has severe AD.

[0055] In some embodiments, the subject being treated has moderate to severe AD that has responded inadequately to one or more local therapies (e.g., TCS with or without a local calcineurin inhibitor (TCI)) or for which local therapy is not recommended (e.g., due to adverse side effects or safety risks). In some embodiments, the subject has a documented history of inadequate response to a full course of outpatient treatment with local AD medications. In some embodiments, the subject has an "inadequate response" to local therapy if the subject fails to achieve and maintain remission or a state of low disease activity (corresponding to an Physician's Global Assessment [IGA] of 0 (=none) to 2 (=mild)) despite at least 28 days of treatment with a local therapy (e.g., a regimen of moderate to high potency TCS, ±TCI if necessary). In some embodiments, the subject being treated has moderate to severe AD and is a candidate for systemic therapy. In some embodiments, the subject being treated has moderate to severe AD and has previously received systemic therapy for AD.

[0056] In some embodiments, the subject is >18 years old. In some embodiments, the subject is >18 years old and ≦80 years old. In some embodiments, the subject is ≦65 years old, ≦40 years old, ≦35 years old, or ≦30 years old. In some embodiments, the subject is ≦18 years old. In some embodiments, the subject is ≧12 years old. In some embodiments, the subject is ≧12 years old and ≦17 years old. In some embodiments, the subject is <12 years old, e.g., ≧6 years old and ≦11 years old, or ≧6 months old and ≦11 years old. In some embodiments, the subject is <6 years old, e.g., ≧6 months old and <2 years old, or ≧2 years old and <6 years old.

[0057] In some embodiments, the subject has AD that developed by age 2. In some embodiments, the subject has AD that developed after age 2. In some embodiments, the subject has AD that developed by age 17, e.g., by age 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In some embodiments, the subject has AD that developed by age 12.

[0058] In some embodiments, the subject has AD with onset by age 2 and is ≧18 years old before treatment begins. In some embodiments, the subject has AD with onset by age 2 and is <18 years old, e.g., <12 years old or <6 years old, before treatment begins. In some embodiments, the subject has AD with onset after age 2 and is ≦35 years old before treatment begins.

[0059] In some embodiments, the subject has one or more concomitant allergic conditions. In some embodiments, the subject has AD (e.g., moderate to severe AD) and at least two, three, four, or more concomitant allergic conditions (i.e., excluding AD). In some embodiments, the concomitant allergic conditions are selected from the allergic conditions listed in Table 2. In some embodiments, the concomitant allergic condition is any of the following: allergies (e.g., environmental allergies to allergens such as, for example, cat dander, dog dander, pollen, grasses, weeds, dust mites, mold, or cockroaches; food allergies to allergens such as, for example, peanuts, tree nuts, sesame, soy, eggs, fish, milk, shellfish, mollusks, mustard, celery, or gluten; and / or allergies to other allergens such as, for example, latex, medicines, insects, or chemicals), asthma (e.g., persistent asthma, moderate-severe or severe asthma, allergic asthma, or eosinophilic asthma), allergic conjunctivitis, chemical allergies, and / or allergies to certain allergens such as, for example, nausea, vomiting, vomiting, and / or vomiting ... The symptoms may include one or more of: skin rash or drug sensitivity (e.g., aspirin sensitivity), contact dermatitis, drug or food hypersensitivity, eosinophilic digestive system disease (e.g., eosinophilic esophagitis, eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE), enteritis (EEn), or eosinophilic colitis (EC)), ichthyosis, nasal polyps, oral allergy syndrome, pruritus, rhinitis (e.g., allergic rhinitis or perennial allergic rhinitis), sinusitis (e.g., allergic sinusitis, chronic sinusitis, chronic rhinosinusitis, or chronic rhinosinusitis with nasal polyps), and urticaria (e.g., chronic spontaneous urticaria, induced urticaria, or cold-induced urticaria). In some embodiments, the subject has AD and has concomitant asthma. In some embodiments, the subject has AD and has concomitant asthma and at least one or more concomitant allergic conditions. In some embodiments, the concomitant allergic conditions exclude skin conditions or skin events (e.g., contact dermatitis or pruritus).

[0060] In some embodiments, the subject has a baseline IgE level of at least 375 IU / mL at the start of treatment with the IL-4 / IL-13 antagonist. In some embodiments, the subject has a baseline IgE level of 375 IU / mL to about 3000 IU / mL at the start of treatment. In some embodiments, the subject has a baseline IgE level of 375 IU / mL to 2850 IU / mL at the start of treatment. In some embodiments, the subject has a baseline IgE level of 375 IU / mL to 2000 IU / mL at the start of treatment. In some embodiments, the subject has a baseline IgE level that is about 500 IU / mL to about 3000 IU / mL, about 500 IU / mL to about 2500 IU / mL, about 500 IU / mL to about 2000 IU / mL, about 750 IU / mL to about 3000 IU / mL, or about 750 IU / mL to about 2000 IU / mL.

[0061] In some embodiments, treatment with an IL-4 / IL-13 antagonist attenuates, slows, or prevents the worsening of an existing concomitant allergic condition in a subject, or reduces the risk of developing a new allergic condition, e.g., compared to a control subject treated with a standard of care (e.g., a local or systemic therapy). In some embodiments, treatment with an IL-4 / IL-13 antagonist attenuates, slows, or prevents the onset or acquisition of a new allergic condition, or reduces the risk of developing a new allergic condition or disorder, e.g., compared to a control subject treated with a standard of care (e.g., a local or systemic therapy).

[0062] In some embodiments, to identify whether the progression of the atopic march is attenuated in a subject with atopic disease, the degree or severity of an existing or newly occurring concomitant allergic condition in the subject is quantified at baseline and at one or more time points after administration of the pharmaceutical composition of the present disclosure. For example, in some embodiments, in the case of a subject with atopic dermatitis, the degree or severity of an existing or newly occurring concomitant allergic condition (i.e., excluding atopic dermatitis) is quantified. In some embodiments, the degree or severity of the concomitant allergic condition is quantified at the following time points after initial treatment with the pharmaceutical composition of the present disclosure: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 14 days, 15 days, 22 days, 25 days, 29 days, 36 days, 43 days, 50 days, 57 days, 64 days, 71 days, 85 days; or and at the end of weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 28, 32, 36, 40, 44, 48, 52, or more. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to ascertain whether there has been a "attenuation" (e.g., improvement or stabilization) of the concomitant allergic condition.

[0063] In some embodiments, the presence, absence, degree, or severity of a concomitant allergic condition can be identified by evaluating the subject for treatment-emergent adverse events (TEAEs). In some embodiments, a "new" allergic condition is identified when a subject is identified as experiencing an allergic event or condition (e.g., an event or condition defined in Table 2) that he or she did not experience before starting treatment (e.g., as captured in the subject's medical history or current or past medical condition). As a non-limiting example, if a subject with grass allergy at baseline newly reports allergic symptoms in a different organ (e.g., asthma) after a course of treatment, the subject will be considered to have a "new" allergic condition. In some embodiments, a "worsening" of an allergic condition is identified when a subject is identified as having an allergic event or condition (e.g., an event or condition defined in Table 2) at the start of treatment and this allergic event or condition becomes more severe during a course of treatment. As a non-limiting example, if a subject with grass allergy at baseline newly reports an additional allergy, such as a tree allergy, after a course of treatment, the subject will be considered to have a "worsening" of an allergic condition.

[0064] In some embodiments, IgE levels are measured in subjects at baseline and at one or more time points after administration of the pharmaceutical composition of the present disclosure to identify whether there is a change (e.g., improvement or deterioration) in IgE. Methods for detecting and / or quantifying IgE are known in the art. For example, Phadiatop™ is a commercially available variant of a serum-specific or antigen-specific IgE assay test introduced for screening allergic sensitization (Merrett et al., 1987, Allergy 17: 409-416). This test provides a simultaneous test of serum-specific IgE against a mixture of relevant allergens that cause common inhalant allergies. This test gives a qualitative result, either positive or negative, depending on the fluorescence response obtained. If the patient sample gives a fluorescence response equal to or greater than the reference, a positive test result is indicated. A patient sample with a lower fluorescence response indicates a negative test result.

[0065] IL-4 / IL-13 antagonists In some embodiments, the method of the present disclosure comprises administering an IL-4 / IL-13 antagonist to a subject in need thereof. As used herein, an "IL-4 / IL-13 antagonist" (also referred to herein as an "IL-4 / IL-13 inhibitor") is any agent that inhibits or attenuates at least one of the following: (i) binding of IL-4 and / or IL-13 to their respective receptors; (ii) signaling and / or activity of IL-4 and / or IL-13; and / or (iii) downstream signaling / activity resulting from binding of IL-4 and / or IL-13 to their respective receptors. Exemplary IL-4 / IL-13 pathway inhibitors include, but are not limited to, anti-IL-4 antibodies or antigen-binding fragments (e.g., those disclosed in U.S. Pat. No. 7,740,843 and U.S. Patent Application Publication Nos. 2010 / 0297110 and 2016 / 0207995), anti-IL-13 antibodies or antigen-binding fragments (e.g., those disclosed in U.S. Pat. Nos. 7,501,121; 7,674,459; 7,807,788; 7,910,708; 7,915,388; 7,935,343; 8,088,618; 8,691,233; and No. 9,605,065, U.S. Patent Application Publication Nos. 2006 / 0073148 and 2008 / 0044420, and European Patent No. 2627673(B1)), bispecific or multispecific antibodies or antigen-binding fragments that bind IL-4 and IL-13 (e.g., the antibodies disclosed in U.S. Patent No. 8,388,965 and U.S. Patent Application Publication Nos. 2011 / 0008345, 2013 / 0251718, and 2016 / 0207995), and IL-4 receptor (IL-4R) inhibitors (described below).

[0066] In some embodiments, the IL-4 / IL-13 antagonist is an interleukin-4 receptor (IL-4R) antagonist. As used herein, an "IL-4R antagonist" (also referred to herein as an "IL-4R inhibitor", "IL-4R blocker", or "IL-4Rα antagonist") is any agent that binds to or interacts with IL-4Rα or an IL-4R ligand and inhibits or attenuates the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. Type 1 IL-4 receptor is a dimeric receptor that includes an IL-4Rα chain and a γc chain. Type 2 IL-4 receptor is a dimeric receptor that includes an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptor interacts with and is stimulated by IL-4, whereas type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, IL-4R antagonists that can be used in the methods of the present disclosure can function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4-mediated and IL-13-mediated signaling. Thus, the IL-4R antagonists of the present disclosure can prevent the interaction of IL-4 and / or IL-13 with type 1 or type 2 receptors.

[0067] Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor-bodies" (e.g., engineered molecules that contain the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0068] Anti-IL-4Rα antibodies and their antigen-binding fragments In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα. The term "specifically binds" as used herein means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art, and include, for example, equilibrium dialysis and surface plasmon resonance. In some embodiments, an antibody that "specifically binds" to IL-4Rα binds to IL-4Rα, or a portion thereof, with an equilibrium dissociation constant (KD) of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 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 a surface plasmon resonance assay (e.g., BIAcore™, Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) may also specifically bind to another antigen, e.g., an ortholog of the target antigen. For example, in some embodiments, an isolated antibody that specifically binds human IL-4Rα exhibits cross-reactivity to other antigens, such as IL-4Rα molecules from other (non-human) species.

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

[0070] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCDR1 comprising the amino acid sequence GFTFRDYA (SEQ ID NO:3), an HCDR2 comprising the amino acid sequence ISGSGGNT (SEQ ID NO:4), an HCDR3 comprising the amino acid sequence AKDRLSITIRPRYYGLDV (SEQ ID NO:5), an LCDR1 comprising the amino acid sequence QSLLYSIGYNY (SEQ ID NO:6), an LCDR2 comprising the amino acid sequence LGS, and an LCDR3 comprising the amino acid sequence MQALQTPYT (SEQ ID NO:8), and further comprises a HCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acids of SEQ ID NO:1 and a LCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acids of SEQ ID NO:2. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO:1 and a LCVR comprising SEQ ID NO:2.

[0071] In some embodiments, the anti-IL-4R 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.

[0072] An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10 is a fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the disclosure include the use of dupilumab. As used herein, "dupilumab" also encompasses biological equivalents of dupilumab. The term "biological equivalent," as used herein with respect to dupilumab, refers to anti-IL-4R antibodies or IL-4R binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical substitutes whose rate and / or extent of absorption do not show significant differences from those of dupilumab when administered at the same molar dose under similar experimental conditions, whether in a single dose or multiple doses. In some embodiments, the term refers to antigen binding proteins that bind to IL-4R whose safety, purity, and / or potency do not show clinically meaningful differences from dupilumab.

[0073] Other anti-IL-4Rα antibodies that can be used in connection with the methods of the present disclosure include, for example, antibodies known in the art referred to as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or MEDI 9314, or those described in U.S. Pat. Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, 8,877,189, 10,774,141, International Patent Publication No. 2020 / 096381, International Patent Publication No. 2020 / 0096382, and International Patent Publication No. 2020 / 0096383. 182197, International Patent Publication No. 2020 / 239134, International Patent Publication No. 2021 / 213329, International Patent Publication No. 2022 / 052974, International Patent Publication No. 2022 / 136669, or International Patent Publication No. 2022 / 136675, the contents of each of which are incorporated herein by reference.

[0074] In some embodiments, an anti-IL-4R antibody or antigen-binding fragment thereof for use in the methods of the disclosure comprises one or more CDR, HCVR, and / or LCVR sequences shown in Table 6 below.

[0075] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of: (i) SEQ ID NO:32 (SCB-VH-59), SEQ ID NO:33 (SCB-VH-60), SEQ ID NO:34 (SCB-VH-61), SEQ ID NO:35 (SCB-VH-62), SEQ ID NO:36 (SCB-VH-63), SEQ ID NO:37 (SCB-VH-64), SEQ ID NO:38 (SCB-VH-65), SEQ ID NO:39 (SCB-VH-66). , SEQ ID NO: 40 (SCB-VH-67), SEQ ID NO: 41 (SCB-VH-68), SEQ ID NO: 42 (SCB-VH-69), SEQ ID NO: 43 (SCB-VH-70), SEQ ID NO: 44 (SCB-VH-71), SEQ ID NO: 45 (SCB-VH-72), SEQ ID NO: 46 (SCB-VH-73), SEQ ID NO: 47 (SCB-VH-74), SEQ ID NO: 48 (SCB-VH-75), SEQ ID NO: 49 (SCB-VH-80), SEQ ID NO: 50 (SCB-VH-81), SEQ ID NO: 51 (SCB-VH-82), SEQ ID NO: 52 (SCB-VH-83), SEQ ID NO: 53 (SCB-VH-84), SEQ ID NO: 54 (SCB-VH-85), SEQ ID NO: 55 (SCB-VH-86), SEQ ID NO: 56 (SCB-VH-87), SEQ ID NO: 57 (SCB-VH-88), SEQ ID NO: 58 (SCB-VH-89), SEQ ID NO: 59 (SCB-VH-90), SEQ ID NO: 60 (SCB-VH-91), SEQ ID NO: 61 (SCB-VH-92), SEQ ID NO: 62 (SCB-VH-93), SEQ ID NO: 63 (SCB-VH-94), SEQ ID NO: 64 (SCB-VH-95), SEQ ID NO: 65 (SCB-VH-96), SEQ ID NO: 66 (SCB-VH-97), SEQ ID NO: 67 (SCB-VH-98), SEQ ID NO: 9 (SCB-VH-76), SEQ ID NO:50 (SCB-VH-77), SEQ ID NO:51 (SCB-VH-78), SEQ ID NO:52 (SCB-VH-79), SEQ ID NO:53 (SCB-VH-80), SEQ ID NO:54 (SCB-VH-81), SEQ ID NO:55 (SCB-VH-82), SEQ ID NO:56 (SCB-VH-83), SEQ ID NO:57 (SCB-VH-84), SEQ ID NO:58 (SCB- VH-85), SEQ ID NO:59 (SCB-VH-86), SEQ ID NO:60 (SCB-VH-87), SEQ ID NO:61 (SCB-VH-88), SEQ ID NO:62 (SCB-VH-89), SEQ ID NO:63 (SCB-VH-90), SEQ ID NO:64 (SCB-VH-91), SEQ ID NO:65 (SCB-VH-92), or SEQ ID NO:66 (SCB-VH-93);and (ii) SEQ ID NO:12 (SCB-VL-39), SEQ ID NO:13 (SCB-VL-40), SEQ ID NO:14 (SCB-VL-41), SEQ ID NO:15 (SCB-VL-42), SEQ ID NO:16 (SCB-VL-43), SEQ ID NO:17 (SCB-VL-44), SEQ ID NO:18 (SCB-VL-45), SEQ ID NO:19 (SCB-VL-46), SEQ ID NO:20 (SCB-VL-47), SEQ ID NO:21 (SCB-VL-48), SEQ ID NO:22. (SCB-VL-49), SEQ ID NO:23 (SCB-VL-50), SEQ ID NO:24 (SCB-VL-51), SEQ ID NO:25 (SCB-VL-52), SEQ ID NO:26 (SCB-VL-53), SEQ ID NO:27 (SCB-VL-54), SEQ ID NO:28 (SCB-VL-55), SEQ ID NO:29 (SCB-VL-56), SEQ ID NO:30 (SCB-VL-57), or SEQ ID NO:31 (SCB-VL-58). In some embodiments, the anti-IL-4Rα antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO:64 (SCB-VH-91) and a LCVR comprising the amino acid sequence of SEQ ID NO:17 (SCB-VL-44), SEQ ID NO:27 (SCB-VL-54), or SEQ ID NO:28 (SCB-VL-55).

[0076] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of SEQ ID NOs: 67 / 68 (MEDI-1-VH / MEDI-1-VL); SEQ ID NOs: 69 / 70 (MEDI-2-VH / MEDI-2-VL); SEQ ID NOs: 71 / 72 (MEDI-3-VH / MEDI-3-VL); SEQ ID NOs: 73 / 74 (MEDI-4-VH / MEDI-4-VL); SEQ ID NOs: 75 / 76 (MEDI-5-VH / MEDI-5-VL); SEQ ID NOs: 77 / 78 (MEDI-6-VH / MEDI-6 / VL); SEQ ID NOs: 79 / 80 (MEDI-7-VH / MEDI-7-VL); SEQ ID NOs: 81 / 8 SEQ ID NO:83 / 84 (MEDI-9-VH / MEDI-9-VL); SEQ ID NO:85 / 86 (MEDI-10-VH / MEDI-10-VL); SEQ ID NO:87 / 88 (MEDI-11-VH / MEDI-11 / VL); SEQ ID NO:89 / 90 (MEDI-12-VH / MEDI-12-VL); SEQ ID NO:91 / 92 (MEDI-13-VH / MEDI-13-VL); SEQ ID NO:93 / 94 (MEDI-14-VH / MEDI-14-VL); SEQ ID NO:95 / 96 (MEDI-15-VH / MEDI-1 SEQ ID NO: 97 / 98 (MEDI-16-VH / MEDI-16 / VL); SEQ ID NO: 99 / 100 (MEDI-17-VH / MEDI-17-VL); SEQ ID NO: 101 / 102 (MEDI-18-VH / MEDI-18-VL); SEQ ID NO: 103 / 104 (MEDI-19-VH / MEDI-19-VL); SEQ ID NO: 105 / 106 (MEDI-20-VH / MEDI-20-VL); SEQ ID NO: 107 / 108 (MEDI-21-VH / MEDI-21-VL); SEQ ID NO: 109 / 110 (MEDI-22-VH / MEDI-22-VL ); SEQ ID NOs:111 / 112 (MEDI-23-VH / MEDI-23-VL); SEQ ID NOs:113 / 114 (MEDI-24-VH / MEDI-24-VL); SEQ ID NOs:115 / 116 (MEDI-25-VH / MEDI-25-VL); SEQ ID NOs:117 / 118 (MEDI-26-VH / MEDI-26-VL); SEQ ID NOs:119 / 120 (MEDI-27-VH / MEDI-27-VL); SEQ ID NOs:121 / 122 (MEDI-28-VH / MEDI-28-VL); SEQ ID NOs:123 / 124 (MEDI-29-VH / MEDI-29-VL);SEQ ID NO:125 / 126 (MEDI-30-VH / MEDI-30-VL); SEQ ID NO:127 / 128 (MEDI-31-VH / MEDI-31-VL); SEQ ID NO:129 / 130 (MEDI-32-VH / MEDI-32-VL); SEQ ID NO:131 / 132 (MEDI-33-VH / MEDI-33-VL); SEQ ID NO:133 / 134 (MEDI-34-VH / MEDI-34-VL); SEQ ID NO:135 / 136 (MEDI-35-VH / MEDI-35-VL); SEQ ID NO:137 / 138 (MEDI-36-VH / MEDI-36-VL); SEQ ID NO:139 / 140 (MEDI-37-VH / MEDI-37-VL); MEDI-37-VH / MEDI-37-VL); SEQ ID NO:141 / 142 (MEDI-38-VH / MEDI-38-VL); SEQ ID NO:143 / 144 (MEDI-39-VH / MEDI-39-VL); SEQ ID NO:145 / 146 (MEDI-40-VH / MEDI-40-VL); SEQ ID NO:147 / 148 (MEDI-41-VH / MEDI-41-VL); SEQ ID NO:149 / 150 (MEDI-42-VH / MEDI-42-VL); and SEQ ID NO:151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).

[0077] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of: (i) SEQ ID NO: 153 (AJOU-1-VH), SEQ ID NO: 154 (AJOU-2-VH), SEQ ID NO: 155 (AJOU-3-VH), SEQ ID NO: 156 (AJOU-4-VH), SEQ ID NO: 157 (AJOU-5-VH), SEQ ID NO: 158 (AJOU-6-VH), SEQ ID NO: 159 (AJOU-7-VH), SEQ ID NO: 160 (AJOU-8-VH), SEQ ID NO: 161 (AJOU-9-VH), SEQ ID NO: 162 (AJOU-10-VH), SEQ ID NO: 163 (AJOU-11-VH), SEQ ID NO: 164 (AJOU-12-VH), SEQ ID NO: 165 (AJOU-13-VH), SEQ ID NO: 166 (AJOU-14-VH), SEQ ID NO: 167 (AJOU-15-VH), SEQ ID NO: 168 (AJOU-16-VH), SEQ ID NO: 169 (AJOU-17-VH), SEQ ID NO: 170 (AJOU-18-VH), SEQ ID NO: 171 (AJOU-19-VH), SEQ ID NO: 172 (AJOU-20-VH), SEQ ID NO: 173 (AJOU-21-VH), SEQ ID NO: 174 (AJOU-22-VH), SEQ ID NO: 175 (AJOU-23-VH), SEQ ID NO: 176 (AJOU-24-VH), SEQ ID NO: 177 (AJOU-25 -VH), SEQ ID NO: 162 (AJOU-10-VH), SEQ ID NO: 163 (AJOU-69-VH), SEQ ID NO: 164 (AJOU-70-VH), SEQ ID NO: 165 (AJOU-71-VH), SEQ ID NO: 166 (AJOU-72-VH), or SEQ ID NO: 167 (AJOU-83-VH); and (ii) a HCVR comprising the amino acid sequence of SEQ ID NO: 168 (AJOU-33-VL), SEQ ID NO: 169 (AJOU-34-VL), SEQ ID NO: 170 (AJOU-35-VL), SEQ ID NO: 171 (AJOU-36-VL), SEQ ID NO: 172 (AJOU-37-VL), SEQ ID NO: 173 (AJOU-38-VL), SEQ ID NO: 174 (AJOU-39-VL), SEQ ID NO: 175 (AJOU-40-VL), SEQ ID NO: 176 (AJOU-41-VL), SEQ ID NO: 177 (AJOU-42-VL), SEQ ID NO: 178 (AJOU-77-VL), SEQ ID NO: 179 (AJOU-40-VL), SEQ ID NO: 179 (AJOU-41-VL), SEQ ID NO: 180 (AJOU-41-VL), SEQ ID NO: 181 (AJOU-41-VL), SEQ ID NO: 182 (AJOU-41-VL), SEQ ID NO: 183 (AJOU-41-VL), SEQ ID NO: 184 (AJOU-41-VL), SEQ ID NO: 185 (AJOU-41-VL), SEQ ID NO: 186 (AJOU-41-VL), SEQ ID NO: 187 (AJOU-41-VL), SEQ ID NO: 188 (AJOU-41-VL), SEQ ID NO: 189 (AJOU-41-VL), SEQ ID NO: 190 (AJOU-41-VL), SEQ ID NO: 191 (AJOU-41-VL), SEQ ID NO: 192 (AJOU-41-VL), SEQ ID NO: 193 (AJOU-41-VL), SEQ ID NO: 194 (A and an LCVR comprising the amino acid sequence of SEQ ID NO: 183 (AJOU-87-VL), SEQ ID NO: 184 (AJOU-88-VL), SEQ ID NO: 185 (AJOU-89-VL), SEQ ID NO: 186 (AJOU-90-VL), or SEQ ID NO: 187 (AJOU-91-VL).

[0078] In some embodiments, the anti-IL-4Rα antibody (i) comprises the amino acid sequence of SEQ ID NO: 188 (REGN-VH-3), SEQ ID NO: 189 (REGN-VH-19), SEQ ID NO: 190 (REGN-VH-35), SEQ ID NO: 191 (REGN-VH-51), SEQ ID NO: 192 (REGN-VH-67), SEQ ID NO: 193 (REGN-VH-83), SEQ ID NO: 194 (REGN-VH-99), SEQ ID NO: 195 (REGN-VH-115), SEQ ID NO: 196 (REGN-VH-147), or SEQ ID NO: 197 (REGN-VH-163). and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO:198 (REGN-VL-11), SEQ ID NO:199 (REGN-VL-27), SEQ ID NO:200 (REGN-VL-43), SEQ ID NO:201 (REGN-VL-59), SEQ ID NO:202 (REGN-VL-75), SEQ ID NO:203 (REGN-VL-91), SEQ ID NO:204 (REGN-VL-107), SEQ ID NO:205 (REGN-VL-123), SEQ ID NO:206 (REGN-VL-155), or SEQ ID NO:207 (REGN-VL-171).

[0079] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of: (i) SEQ ID NO:208 (STSA-C27-VH), SEQ ID NO:209 (STSA-C27-6-33-VH), SEQ ID NO:210 (STSA-C27-7-33-VH), SEQ ID NO:211 (STSA-C27-24-56-VH), SEQ ID NO:212 (STSA-C27-47-56-VH), SEQ ID NO:213 (STSA-C27-33-33-VH), SEQ ID NO:214 (STSA-C27-56-56-VH), SEQ ID NO:215 (STSA-C27-78-78-VH), SEQ ID NO:216 (STSA-C27-82-58-VH), a HCVR comprising the amino acid sequence of SEQ ID NO:217 (STSA-C27-54-54-VH), SEQ ID NO:218 (STSA-C27-36-36-VH), SEQ ID NO:219 (STSA-C27-53-53-VH), SEQ ID NO:220 (STSA-C27-67-67-VH), SEQ ID NO:221 (STSA-C27-55-55-VH), SEQ ID NO:222 (STSA-C27-59-59-VH), SEQ ID NO:223 (STSA-C27-58-58-VH), SEQ ID NO:224 (STSA-C27-52-52-VH), or SEQ ID NO:225 (STSA-C27-Y2-Y2-VH);and (ii) SEQ ID NO: 226 (STSA-C27-VL), SEQ ID NO: 227 (STSA-C27-6-33-VL), SEQ ID NO: 228 (STSA-C27-7-33-VL), SEQ ID NO: 229 (STSA-C27-24-56-VL), SEQ ID NO: 230 (STSA-C27-47-56-VL), SEQ ID NO: 231 (STSA-C27-33-33-VL), SEQ ID NO: 232 (STSA-C27-56-56-VL), SEQ ID NO: 233 (STSA-C27-78-78-VL), SEQ ID NO: 234 (STSA-C27-82-58-VL), SEQ ID NO: 235 (STSA-C27-82-58-VL), SEQ ID NO: 236 (STSA-C27-82-58-VL), SEQ ID NO: 237 (STSA-C27-82-58-VL), SEQ ID NO: 238 (STSA-C27-82-58-VL), SEQ ID NO: 239 (STSA-C27-82-58-VL), SEQ ID NO: 240 (STSA-C27-82-58-VL), SEQ ID NO: 241 (STSA-C27-82-58-VL), SEQ ID NO: 242 (STSA-C27-82-58-VL), SEQ ID NO: 243 (STSA-C27-82-58-VL), SEQ ID NO: 244 (STSA-C27-82-58-VL), SEQ ID NO: 245 (STSA-C27-82-5 and a LCVR comprising the amino acid sequence of SEQ ID NO:236 (STSA-C27-36-36-VL), SEQ ID NO:237 (STSA-C27-53-53-VL), SEQ ID NO:238 (STSA-C27-67-67-VL), SEQ ID NO:239 (STSA-C27-55-55-VL), SEQ ID NO:240 (STSA-C27-59-59-VL), SEQ ID NO:241 (STSA-C27-58-58-VL), SEQ ID NO:242 (STSA-C27-52-52-VL), or SEQ ID NO:243 (STSA-C27-Y2-Y2-VL);

[0080] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of: (i) SEQ ID NO:244 (Y0188-1VH), SEQ ID NO:245 (Y0188-2VH), SEQ ID NO:246 (Y0188-3VH), SEQ ID NO:247 (Y0188-4VH), SEQ ID NO:248 (Y0188-6VH), SEQ ID NO:249 (Y0188-8VH), SEQ ID NO:250 (Y0188-9VH), SEQ ID NO:251 (Y0188-10VH), SEQ ID NO:252 (Y0188-11VH), SEQ ID NO:253 (Y0188-12VH), SEQ ID NO:254 (Y0188-13VH), SEQ ID NO:255 (Y0188-14VH), SEQ ID NO:256 (Y0188-15VH), SEQ ID NO:257 (Y0188-16VH), SEQ ID NO:258 (Y0188-17VH), SEQ ID NO:259 (Y0188-20VH), SEQ ID NO:260 (Y0188-21VH), SEQ ID NO:261 (Y0188-22VH), SEQ ID NO:262 (Y0188-23VH), SEQ ID NO:263 (Y0188-24VH), SEQ ID NO:264 (Y0188-25VH), SEQ ID NO:265 (Y0188-26VH), SEQ ID NO:266 (Y0188-27VH), SEQ ID NO:267 (Y0188-28VH), SEQ ID NO:268 (Y0188 VH), SEQ ID NO: 252 (Y0188-14VH), SEQ ID NO: 253 (HV3-15-14VH), SEQ ID NO: 254 (HV3-48-14VH), SEQ ID NO: 255 (HV3-73*2-14VH), SEQ ID NO: 256 (HV3-72-14VH), SEQ ID NO: 257 (Y01-14VH), SEQ ID NO: 258 (162-14VH), or SEQ ID NO: 259 (VH73-14VH). and (ii) an HCVR comprising SEQ ID NO:260 (Y0188-1VL), SEQ ID NO:261 (Y0188-2VL), SEQ ID NO:262 (Y0188-3VL), SEQ ID NO:263 (Y0188-4VL), SEQ ID NO:264 (Y0188-6VL), SEQ ID NO:265 (Y0188-8VL), SEQ ID NO:266 (Y0188-9VL), SEQ ID NO:267 (Y0188-10VL), SEQ ID NO:2 68 (Y0188-14VL), SEQ ID NO:269 (Y01-14VL), SEQ ID NO:270 (164-14VL), SEQ ID NO:271 (KV4-14VL), SEQ ID NO:272 (KV1-27-14VL), SEQ ID NO:273 (KV1-9-14VL), SEQ ID NO:274 (KV1-NL1-14VL), or SEQ ID NO:275 (KV1D-43-14VL).

[0081] In some embodiments, the anti-IL-4Rα antibody used in the methods of the present disclosure may have pH-dependent binding properties. For example, an anti-IL-4Rα antibody for use as disclosed herein may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody for use as disclosed herein may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The term "acidic pH" includes pH values ​​less than about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or lower. As used herein, the term "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0082] In certain instances, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" refers to the K D K value of antibody binding to IL-4Rα at neutral pH D For example, an antibody or antigen-binding fragment thereof may have an acidic / neutral K of about 3.0 or greater. D In certain exemplary embodiments, the acidic / neutral K ratio of an antibody or antigen-binding fragment of the present disclosure is: D The ratio 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.

[0083] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. In addition, antibodies with pH-dependent characteristics can be generated by modifying the antigen-binding domain at the amino acid level. For example, an antibody can be obtained that has reduced antigen-binding properties at acidic pH compared to neutral pH by replacing one or more amino acids in the antigen-binding domain (e.g., in the CDR) with histidine residues.

[0084] Preparation of human antibodies Methods for generating human antibodies in transgenic mice are known in the art. In the context of the present disclosure, any such known method can be used to generate human antibodies that specifically bind to human IL-4, IL-13, or IL-4 and / or IL-13 receptors (e.g., IL-4R).

[0085] Using VELOCIMMUNE™ technology (see, e.g., U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, a high affinity chimeric antibody (e.g., against IL-4R) having a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves generating a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to an endogenous mouse constant region locus such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. DNA encoding the variable regions of the antibody heavy and light chains is isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing a fully human antibody.

[0086] In general, VELOCIMMUNE® mice are loaded with an antigen of interest and lymphoid cells (such as B cells) are harvested from the mice that express antibodies. The lymphoid cells are fused with a myeloma cell line to prepare immortal hybridoma cell lines, which are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy and light chains may be isolated and linked to the desired isotype constant regions of the heavy and light chains. Such antibody proteins may be produced in cells such as CHO cells. Alternatively, DNA encoding the antigen-specific chimeric antibodies or the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes.

[0087] First, a high affinity chimeric antibody having a human variable region and a mouse constant region is isolated. Using standard procedures known to those skilled in the art, the antibody is characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc. The mouse constant region is replaced with the desired human constant region to generate a fully human antibody of the present disclosure, such as a wild-type or modified IgG1 or IgG4. The constant region selected may vary depending on the particular use, but the high affinity antigen binding characteristics and target specificity characteristics reside in the variable region.

[0088] Generally, the antibody that can be used in the method of the present disclosure has high affinity as described above, measured by binding to either solid-phase immobilized or liquid-phase antigen.The mouse constant region is replaced with the desired human constant region to generate the fully human antibody of the present disclosure.The constant region selected can vary depending on the specific use, but the high affinity antigen binding characteristics and target specificity characteristics are present in the variable region.

[0089] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R and can be used in the methods disclosed herein comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO:1, and three light chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO:2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within a given HCVR and / or LCVR amino acid sequence disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies.

[0090] Pharmaceutical Compositions In one aspect, the disclosure provides a method comprising administering to a subject an IL-4 / IL-13 antagonist, wherein the IL-4 / IL-13 antagonist (e.g., an IL-4R antagonist, such as an anti-IL-4R antibody or antigen-binding fragment disclosed herein) is contained within a pharmaceutical composition comprising one or more pharma- ceutically acceptable vehicles, carriers, and / or excipients. A variety of pharma- ceutically acceptable carriers and excipients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.

[0091] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other biologically active agents. In some embodiments, the pharmaceutical compositions as disclosed herein are administered intravenously. In some embodiments, the pharmaceutical compositions as disclosed herein are administered subcutaneously.

[0092] In some embodiments, the pharmaceutical composition includes an injectable preparation, such as a dosage form for intravenous, subcutaneous, intradermal, and intramuscular injection, drip infusion, etc. Such an injectable preparation can be prepared by a known method. For example, the injectable preparation can be prepared, for example, by dissolving, suspending, or emulsifying the antibody or its salt described above in a sterile aqueous or oily medium conventionally used for injection. The aqueous medium for injection includes, for example, saline, isotonic solutions containing glucose and other auxiliary agents, and these can be used in combination with a suitable solubilizing agent such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. As the oily medium, for example, sesame oil, soybean oil, etc. can be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared can be filled into a suitable ampule.

[0093] The dose of the antibody administered to a subject according to the method of the present disclosure may vary depending on the age and size of the subject, symptoms, condition, and route of administration, etc. The dose is typically calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. Effective dosages and schedules for administering pharmaceutical compositions containing IL-4 / IL-13 antagonists (e.g., anti-IL-4R antibodies) can be empirically determined. For example, subject progress can be monitored by periodic evaluation, and dosages can be adjusted accordingly. Furthermore, inter-species scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Specific exemplary doses and administration regimens including the same of IL-4 / IL-13 antagonists (e.g., anti-IL-4R antibodies) that can be used in the context of the present disclosure are disclosed elsewhere herein.

[0094] In some embodiments, the IL-4 / IL-13 antagonist or pharmaceutical composition of the present disclosure is contained within a container. Thus, in another aspect, a container is provided that comprises an IL-4 / IL-13 antagonist or pharmaceutical composition as disclosed herein. For example, in some embodiments, the pharmaceutical composition is contained within a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an autoinjector.

[0095] In some embodiments, the pharmaceutical composition of the present disclosure is delivered subcutaneously or intravenously, for example, using a standard needle and syringe. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, the pharmaceutical composition of the present disclosure is delivered using a pen delivery device or an autoinjector (e.g., for subcutaneous delivery). The pen delivery device may be reusable or disposable. Typically, a reusable pen delivery device uses a replaceable cartridge that contains the pharmaceutical composition. Once the pharmaceutical composition in the cartridge is administered and the cartridge is emptied, the empty cartridge can be easily discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device is provided pre-filled with the pharmaceutical composition that is held in a reservoir within the device. Once the reservoir of the pharmaceutical composition is emptied, the entire device is discarded.

[0096] Examples of suitable pen and autoinjector delivery devices include, but are not limited to, the 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). Examples of disposable pen delivery devices having application for subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, Calif.), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ pen (Abbott Labs, Abbott Park, Ill.).

[0097] In some embodiments, the pharmaceutical composition is delivered using a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. vol. 14:201). In another embodiment, a polymeric material may be used: see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres, Boca Raton, Fla. In yet another embodiment, the controlled release system can be placed in the vicinity of the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, Medical Applications of Controlled Release, supra, vol. 2:115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science vol. 249:1527-1533. Other delivery systems, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis, are known and can be used to deliver pharmaceutical compositions (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432).

[0098] In some embodiments, the pharmaceutical composition comprising an anti-IL-4R antibody is administered using a drug delivery device that is a needle-based injection system, as described in Table 1 of Section 5.2 of ISO 11608-1:2014(E). As described in ISO 11608-1:2014(E), needle-based injection systems can be broadly distinguished into multi-dose container systems and single-dose (partially or fully emptied) container systems. The container can be an exchangeable container or an integrated non-exchangeable container.

[0099] As detailed in ISO 11608-1:2014(E), a multi-dose container system may involve an injection device using a needle with an exchangeable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user). Another multi-dose container system may involve an injection device using a needle with an integral non-exchangeable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).

[0100] As detailed in ISO 11608-1:2014(E), a single-dose container system may involve an injection device using an injection needle with a replaceable container. In one embodiment of such a system, each container holds a single dose, whereby the entire deliverable amount is expelled (full expulsion). In a further embodiment, each container holds a single dose, whereby a portion of the deliverable amount is expelled (partial expulsion). As also described in ISO 11608-1:2014(E), a single-dose container system may involve an injection device using an injection needle with an integral non-replaceable container. In one embodiment for such a system, each container holds a single dose, whereby the entire deliverable amount is expelled (full expulsion). In a further embodiment, each container holds a single dose, whereby a portion of the deliverable amount is expelled (partial expulsion).

[0101] An exemplary sleeve-triggered autoinjector with manual needle insertion is described in WO 2015 / 004052. An exemplary audible end-of-dose feedback mechanism is described in WO 2016 / 193346 and WO 2016 / 193348. An exemplary needle safety mechanism after use of the autoinjector is described in WO 2016 / 193352. An exemplary needle sheath removal mechanism for a syringe autoinjector is described in WO 2016 / 193353. An exemplary support mechanism for supporting the axial position of the syringe is described in WO 2016 / 193355.

[0102] In some embodiments, the pharmaceutical composition for use as described herein is prepared in a dosage form suitable for the dosage of active ingredient.Such dosage forms of unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0103] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present disclosure are disclosed, for example, in US Pat. No. 8,945,559.

[0104] Dosage and Administration In some embodiments, an IL-4 / IL-13 antagonist (e.g., an IL-4R antagonist, such as an anti-IL-4R antibody or antigen-binding fragment thereof disclosed herein) is administered to a subject according to the methods of the present disclosure in a therapeutically effective amount. As used herein with respect to an IL-4 / IL-13 antagonist, the phrase "therapeutically effective amount" means an amount of IL-4 / IL-13 antagonist that results in one or more of the following: (a) amelioration, stabilization, or slowing or preventing the worsening of an existing concomitant allergic condition in the subject, or (b) slowing or preventing the acquisition of a new allergic condition.

[0105] In some embodiments, for example, in the case of an anti-IL-4R antibody as disclosed herein, a therapeutically effective amount is from about 0.05 mg to about 600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg , about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg of the anti-IL-4R antibody. In some embodiments, the therapeutically effective amount is about 50 mg to about 600 mg, about 100 mg to about 600 mg, or about 200 mg to about 600 mg. In certain embodiments, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 300 mg of an anti-IL-4R antibody is administered to the subject.

[0106] The amount of IL-4 / IL-13 antagonist (e.g., anti-IL-4R antibody) contained within an individual dose may be expressed in milligrams of antibody per kilogram of the subject's body weight (i.e., mg / kg). For example, the IL-4 / IL-13 antagonist may be administered to the subject at a dose of about 0.0001 to about 10 mg / kg of the subject's body weight, e.g., at a dose of about 1 to about 10 mg / kg, at a dose of about 2 to about 9 mg / kg, or at a dose of about 3 to about 8 mg / kg. In some embodiments, the IL-4 / IL-13 antagonist is administered to the subject at a dose of about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg.

[0107] In some embodiments, the methods disclosed herein include administering an IL-4 / IL-13 antagonist to a subject at a dosing frequency of about 4 times per week, twice per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently as long as a therapeutic response is achieved. In some embodiments, the methods disclosed herein include administering an IL-4 / IL-13 antagonist to a subject once per week, once every 2 weeks, or once every 4 weeks.

[0108] In some embodiments, multiple doses of IL-4 / IL-13 antagonist are administered to the subject over a defined time course. In some embodiments, the method of the present disclosure includes sequentially administering multiple doses of IL-4 / IL-13 antagonist to the subject. As used herein, "sequential administration" means that each dose of IL-4 / IL-13 antagonist is administered to the subject at different times, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the method of the present disclosure includes sequentially administering to the patient a single initial dose of IL-4 / IL-13 antagonist, followed by one or more secondary doses of IL-4 / IL-13 antagonist, and optionally followed by one or more tertiary doses of IL-4 / IL-13 antagonist.

[0109] The terms "initial dose", "secondary dose", and "tertiary dose" refer to the temporal order of administration of an IL-4 / IL-13 antagonist. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also called a "loading dose"); a "secondary dose" is a dose administered after the initial dose; and a "tertiary dose" is a dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4 / IL-13 antagonist, but generally may differ from each other in terms of frequency of administration. However, in certain embodiments, the amount of IL-4 / IL-13 antagonist contained in the initial, secondary, and / or tertiary doses differs from each other over the course of treatment (e.g., adjusted upwards or downwards as necessary). In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the beginning of a treatment regimen as a "loading dose", followed by subsequent doses (e.g., "maintenance doses") administered less frequently. In some embodiments, the initial dose or loading dose and the one or more secondary or maintenance doses each contain the same amount of IL-4 / IL-13 antagonist. In other embodiments, the initial dose contains a first amount of IL-4 / IL-13 antagonist, and the one or more secondary doses each contain a second amount of IL-4 / IL-13 antagonist. For example, the first amount of IL-4 / IL-13 antagonist may be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x, or more, greater than the second amount of IL-4 / IL-13 antagonist. In some embodiments, the one or more maintenance doses of IL-4 / IL-13 antagonist are administered without a loading dose.

[0110] In some embodiments, the loading dose is a "split dose" administered as two or more doses (e.g., two, three, four, or five doses) administered on separate days. In some embodiments, the loading dose is administered as a split dose, with two or more doses administered at least about one week apart. In some embodiments, the loading dose is administered as a split dose, with two or more doses administered at about one, two, three, or four weeks apart. In some embodiments, the loading dose is evenly split into two or more doses (e.g., half of the loading dose is administered as a first portion and half of the loading dose is administered as a second portion). In some embodiments, the loading dose is unequally split into two or more doses (e.g., more than half of the loading dose is administered as a first portion and less than half of the loading dose is administered as a second portion).

[0111] In some embodiments, each secondary and / or tertiary dose is administered 1-14 (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or more) weeks after the immediately preceding dose. The phrase "immediately preceding dose" as used herein refers to a dose of an IL-4 / IL-13 antagonist administered to a patient without an intervening dose prior to administration of the immediately succeeding dose in a multiple administration sequence.

[0112] The disclosed methods may include administering any number of secondary and / or tertiary doses of an IL-4 / IL-13 antagonist to a patient. For example, in certain embodiments, only a single secondary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to a patient. Similarly, in certain embodiments, only a single tertiary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to a patient.

[0113] In some embodiments that include multiple secondary doses, each secondary dose is administered at the same frequency as other secondary doses. For example, each secondary dose may be administered to the patient 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose. Similarly, in some embodiments that include multiple tertiary doses, each tertiary dose is administered at the same frequency as other tertiary doses. For example, each tertiary dose may be administered to the patient 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and / or tertiary doses are administered to the patient may vary over the course of the treatment regimen. Also, the frequency of administration may be adjusted during the course of treatment by the physician according to the needs of the individual patient after clinical examination.

[0114] In some embodiments, a therapeutically effective amount of an IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody comprising CDRs having the amino acid sequences of SEQ ID NO:3-6, LGS, and SEQ ID NO:8) comprises 100 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered every week (QW) at a dose of 100 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered every two weeks (Q2W) at a dose of 100 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered every three weeks (Q3W) at a dose of 100 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered every four weeks (Q4W) at a dose of 100 mg.

[0115] In some embodiments, a therapeutically effective amount of an IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody comprising CDRs having the amino acid sequences of SEQ ID NO:3-6, LGS, and SEQ ID NO:8) comprises 200 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered every week (QW) at a dose of 200 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered every two weeks (Q2W) at a dose of 200 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered every three weeks (Q3W) at a dose of 200 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered every four weeks (Q4W) at a dose of 200 mg.

[0116] In some embodiments, a therapeutically effective amount of an IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody comprising CDRs having the amino acid sequences of SEQ ID NOs:3-6, LGS, and SEQ ID NO:8) comprises 300 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered QW at a dose of 300 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered Q2W at a dose of 300 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered Q3W at a dose of 300 mg. In some embodiments, the IL-4 / IL-13 antagonist is administered Q4W at a dose of 300 mg.

[0117] In some embodiments, a therapeutically effective amount of an IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody comprising CDRs having the amino acid sequences of SEQ ID NOs:3-6, LGS, and SEQ ID NO:8) comprises an initial (loading) dose of 200 mg or 400 mg and a secondary (maintenance) dose of 100 mg. In some embodiments, each secondary dose is administered QW from the immediately preceding dose. In some embodiments, each secondary dose is administered Q2W from the immediately preceding dose. In some embodiments, each secondary dose is administered Q3W from the immediately preceding dose. In some embodiments, each secondary dose is administered Q4W from the immediately preceding dose.

[0118] In some embodiments, a therapeutically effective amount of an IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody comprising CDRs having the amino acid sequences of SEQ ID NOs:3-6, LGS, and SEQ ID NO:8) comprises an initial (loading) dose of 400 mg and a secondary (maintenance) dose of 200 mg. In some embodiments, each secondary dose is administered QW from the immediately preceding dose. In some embodiments, each secondary dose is administered Q2W from the immediately preceding dose. In some embodiments, each secondary dose is administered Q3W from the immediately preceding dose. In some embodiments, each secondary dose is administered Q4W from the immediately preceding dose.

[0119] In some embodiments, a therapeutically effective amount of an IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody comprising CDRs having the amino acid sequences of SEQ ID NOs:3-6, LGS, and SEQ ID NO:8) comprises an initial (loading) dose of 600 mg and a secondary (maintenance) dose of 300 mg. In some embodiments, each secondary dose is administered QW from the immediately preceding dose. In some embodiments, each secondary dose is administered Q2W from the immediately preceding dose. In some embodiments, each secondary dose is administered Q3W from the immediately preceding dose. In some embodiments, each secondary dose is administered Q4W from the immediately preceding dose.

[0120] In some embodiments, the IL-4 / IL-13 antagonist (e.g., an anti-IL-4R antibody, e.g., an anti-IL-4R antibody comprising CDRs having the amino acid sequences of SEQ ID NOs:3-6, LGS, and SEQ ID NO:8) is administered for at least 4 weeks, e.g., at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 48 weeks, or at least 52 weeks. In some embodiments, the IL-4 / IL-13 antagonist is administered for at least 16 weeks.

[0121] Combination therapy In some embodiments, the method of the present disclosure includes administering to a subject an IL-4 / IL-13 antagonist according to the present disclosure (e.g., an anti-IL-4Rα antibody) in combination with one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is a local therapeutic agent, such as TCS or a topical nonsteroidal drug, such as a TCI (e.g., pimecrolimus or tacrolimus), or crisaborole. As used herein, the phrase "in combination with" means that the local therapeutic agent (e.g., TCS) is administered before, after, or simultaneously with the IL-4 / IL-13 antagonist. The phrase "in combination with" also encompasses sequential or simultaneous administration of the IL-4 / IL-13 antagonist and the local therapeutic agent (e.g., TCS).

[0122] For example, when administered "before" a pharmaceutical composition comprising an IL-4 / IL-13 antagonist, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition comprising an IL-4 / IL-13 antagonist. When administered "after" a pharmaceutical composition comprising an IL-4 / IL-13 antagonist, the additional therapeutic agent may be administered 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 the pharmaceutical composition comprising an IL-4 / IL-13 antagonist. Administration "concurrently" or with a pharmaceutical composition comprising an IL-4 / IL-13 antagonist means that the additional therapeutic agent is administered to the subject within less than about 10 minutes (before, after, or simultaneously) of administration of the pharmaceutical composition comprising an IL-4 / IL-13 antagonist, in a separate dosage form, or alternatively, is administered to the subject as a single combined dosage formulation including both the additional therapeutic agent and the IL-4 / IL-13 antagonist.

[0123] In some embodiments, the additional therapeutic agent is TCS. In some embodiments, the TCS is a medium potency TCS. In some embodiments, the TCS is a low potency TCS. In some embodiments, the additional therapeutic agent is a TCI. In some embodiments, the additional therapeutic agent is crisaborole. EXAMPLES

[0124] The following examples are presented to provide those skilled in the art with a complete disclosure and description of how to make and use the disclosed methods and compositions, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. EXAMPLES

[0125] Meta-analysis of pooled atopic dermatitis populations for evidence of attenuation of the atopic march Study design and objectives This analysis was performed to determine whether dupilumab prevents the acquisition of new allergic conditions or the worsening of existing allergic conditions for participants listed in a large AD clinical trial database. A meta-analysis of pooled AD populations after 4-52 weeks assessed dupilumab's potential as an immune modulator that can modify the progression of allergic manifestations of the atopic march in this highly atopic population. Dupilumab is a fully human anti-IL-4R antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10; a HCVR / LCVR amino acid sequence pair comprising SEQ ID NO:1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NO:3-6, LGS, and SEQ ID NO:8.

[0126] To be eligible for the meta-analysis of adverse events for the purpose, the study had to be a randomized, placebo-controlled, double-blind, parallel-group trial of dupilumab in the treatment of AD. We identified 12 such studies that were completed as of June 2019 (internal study ID numbers in parentheses): NCT03054428 (R668-AD-1526), ​​NCT02755649 (R668-AD-1424), NCT02277769 (R668-AD-1416), NCT02277743 (R668-AD-1334), NCT02260986 (R668-AD-1224), and NCT02277747 (R668-AD-1334). 210780 (R668-AD-1314), NCT01979016 (R668-AD-1307), NCT01859988 (R668-AD-1021), NCT01639040 (R668-AD-1121), NCT01548404 (R668-AD-1117), NCT01385657 (R668-AD-1026), and NCT01259323 (R668-AD-0914).

[0127] To be eligible for enrollment in the study, all subjects had moderate to severe AD at baseline that was not adequately controlled by topical medications, an Investigator's Global Assessment severity score of at least 3 (5-point scale; score 0–4), and an Eczema Area and Severity Index score generally ≥16 (maximum 72). Dupilumab dosing regimens in the 12 studies ranged from 100 mg every 4 weeks (Q4W) to 300 mg weekly (QW), where most patients received 300 mg QW or Q2W, including all dupilumab-treated patients in the larger pivotal study. The majority of the trials studied dupilumab as monotherapy, while one long-term study added dupilumab or placebo to topical corticosteroids. Treatment duration ranged from 4 weeks to 52 weeks. Patients were rescued with topical corticosteroids while continuing the study drug. However, if patients received rescue therapy with systemic corticosteroids, nonsteroidal immunosuppressants, or phototherapy, the study drug was discontinued. An overview of the study designs of the individual trials is shown in Table 1.

[0128] [Table 1]

[0129] Endpoints To track new allergic conditions or to identify effects on existing allergic conditions, treatment-emergent adverse events (TEAEs) were assessed separately from the primary effect on atopic dermatitis, which was the primary endpoint of these studies. The International Medical Terminology Glossary preferred terms from baseline medical history, specific atopic disease questionnaires, and TEAEs were pooled together to identify allergic events across all studies and treatment groups. Because all subjects had AD, this term mapped to AD was not included for the evaluation of atopic march. All subjects had moderate to severe AD at the start of the study; improvement meant efficacy, whereas deterioration was considered treatment failure leading to rescue therapy.

[0130] To combine terms referring to similar allergic events, selected preferred terms were assigned to allergy categories. The selection process and categorization were performed independently by board-certified allergists blinded to study and treatment assignment. A list of allergy categories and associated preferred terms is presented in Table 2.

[0131] "New" allergic TEAEs were defined as events that were not present at study entry (i.e., not captured in the list of current or past medical conditions), and "worsened" TEAEs were defined as allergic conditions that were not identified in medical history or were present at study entry and worsened during the course of the study. This approach to adverse event capture is standard in controlled clinical trials. "New" and "worsened" IgE categories were defined based on categorical shifts from baseline during the treatment period as shown in Table 3. IgE categories were analyzed using both one-step and two-step increments. A one-step increment constituted the minimum amount that could be considered to represent a significant change as previously specified. These minimal changes are substantial, but to assess the contribution of IgE changes to the atopic march, as a sensitivity analysis, we included a more conservative two-step increment (Table 3). Each new or worsening event in a category was considered one stage of the atopic march. Any single term coded from the category constituted an endpoint. Multiple terms from one TEAE event category (e.g., different pollen reports of pollen sensitization) were considered to represent a single change in that category (i.e., allergy to plants). Thus, subjects considered to have acquired a new sensitization (e.g., a grass allergy at baseline with a new reported tree allergy) were not considered to have acquired a new allergic predisposition, but instead to have had an exacerbation of the allergy. If the allergic manifestation involved a different organ (e.g., asthma), it was considered a new category of allergy.

[0132] [Table 2]

[0133] [Table 3]

[0134] statistical analysis In the meta-analysis, patients were analyzed as treated in the dupilumab or placebo arm from 12 trials. Demographics and baseline allergy burden and age at AD onset were aggregated by dupilumab vs. placebo treatment group. Mean, standard deviation, median, and interquartile range were used for continuous variables. Percentages at each level were aggregated for all categorical variables. Additionally, study-adapted analysis of variance was used to assess baseline allergy burden among treatment groups. Associations between baseline burden and baseline IgE were estimated by negative binomial regression. Time to end of treatment among treatment groups was analyzed using the log-rank test stratified by study.

[0135] Incidence rates (IRR) were defined as the number of events divided by exposure (patient-years). Taking into account differential treatment duration in studies and individuals due to early dropout, IRR was used as a metric to quantify treatment effect in the meta-analysis. No apparent dose-response trend in the incidence of allergic TEAE events was observed in the included studies, so all dupilumab dose levels were combined in the meta-analysis. Both fixed-effect models (assuming homogeneity of treatment effect across studies) and random-effect models (assuming heterogeneity of treatment effect across studies) were used for the meta-analysis. Heterogeneity of treatment effect was measured using the I 2 Use statistics to evaluate and I 2 A heterogeneity of ≥ 50% was considered significant. If heterogeneity was not present, results from the fixed-effects model were reported, otherwise results from the random-effects model were reported. Analyses were performed separately for new and worsening TEAE events combined, new TEAE events only, new and worsening TEAE events combined, and new and worsening IgE events for the treatment period (from the date of first exposure to treatment to the end of treatment) and for the entire study period (from the date of first exposure to treatment to the end of the study, i.e., both the treatment period and the drug-free follow-up period).

[0136] To assess the level of differential treatment effect, descriptive subgroup analyses were completed for the following variables: age, age at AD onset, region, race, AD severity, baseline IgE, presence of asthma at baseline, and baseline burden.

[0137] All analyses were performed using R, and for meta-analysis the R package “meta” was used.

[0138] result The pooled analytic dataset included 3525 subjects (n = 2296, dupilumab; n = 1229, placebo). Among the placebo subgroup, total treatment time was 482 patient-years; total dupilumab exposure was 877 patient-years. Patient demographics were balanced between the dupilumab and placebo groups in the combined dataset (Table 4). Mean age was 36 years (median, 35; range, 12-88). Median age at onset of AD was 2 years (mean, 9.1 years; range, 0-80); mean duration of AD was 27 years. Baseline allergy burden was comparable between treatment arms across studies (P = .672), with mean baseline concomitant allergy burden being 3.4 categories (excluding AD). Percentage increase in burden was significantly associated with increased IgE (P < .001, Table 5).

[0139] Log-rank tests stratified by study showed that there was differential dropout between placebo and dupilumab, as significantly more subjects in the placebo group dropped out before the end of the scheduled treatment period compared with the dupilumab group (P<.001). The imbalance in dropout rates between the active treatment arm and the placebo arm resulted in a more conservative estimate of the treatment effect of dupilumab on atopic march, as the incidence of allergic events in the placebo arm was disproportionately suppressed by the shorter follow-up period.

[0140] As can be seen in Figures 1A and 1B, among the 17 categories contributing to allergic TEAE events, asthma, pruritus, and urticaria were particularly noteworthy contributors to the overall positive treatment effect of dupilumab. There were very few IgE events that were novel, likely due to the small number of these AD subjects with baseline IgE levels of <30 IU / mL at study entry. However, the statistically significant reduction in IgE events (shown as a one- or two-step increase) in dupilumab vs. placebo was driven by worsening IgE in the placebo arm and attenuated in the dupilumab arm, which led to an IRR of 0.32 (95% confidence interval [CI; 0.15-0.67]; Figure 1A). Further validation of allergen-specific IgE data from the largest study, this one available, R668-AD-1224, showed a decrease in new and new and exacerbated allergen-specific IgE with dupilumab treatment from baseline to the end of the study when compared to subjects treated with placebo, suggesting attenuation of acquisition of allergen sensitivity in subjects treated with dupilumab versus those receiving placebo (Figures 2A-D).

[0141] In all analyses, the only uncommon category that appeared to trend in the opposite direction to dupilumab (not statistically significant) was "seasonal allergy-undefined" (new + worsening: X vs. Y: IRR 1.83; 95% CI, 0.74 to 4.56; new: IRR 1.92; 95% CI, 0.63 to 5.84), which may be due to the small number of events in this category and the wide confidence interval.

[0142] [Table 4]

[0143] [Table 5]

[0144] Treatment effects in all studies show combined IRR results favoring dupilumab (Figures 3A-3D). During the treatment period, dupilumab reduced the risk of new or worsening allergies by 34% (IRR 0.66; 95% CI, 0.52-0.84, Figure 2a) and new allergies by 37% (IRR 0.63; 95% CI, 0.48-0.83, Figure 3b) versus placebo, respectively. When IgE category shifts (one-level increase) were taken into account, a larger reduction in IRR of 54% (IRR 0.46; 95% CI, 0.37-0.56, Figure 3c) was observed for combined new / worsening TEAEs. Applying a more conservative two-stage definition of IgE change resulted in an IRR of 39% reduction in new or worsening allergies (IRR 0.61; 95% CI, 0.49-0.76, Figure 3D). Only the longest and most data-dense study (R668-AD-1224) showed a statistically significant reduction in allergic TEAE events with dupilumab treatment for new and worsening allergies during the treatment period (IRR 0.59; 95% CI, 0.41-0.85, Figure 3A). Sensitivity analysis excluding cutaneous events showed results consistent with the primary analysis approach, indicating that the reduction in the incidence of new and worsening allergic events in subjects treated with dupilumab was maintained (Figures 4A-B). When analyzed for the entire study period (both on-treatment and off-treatment follow-up periods), the treatment effect of dupilumab was suppressed (new + worsening: IRR 0.72; 95% CI, 0.58-0.90, Figure 5A; new: IRR 0.69; 95% CI, 0.54-0.88, Figure 5B), likely due to a reduced treatment effect during the off-treatment period when dupilumab was not administered (see Figures 6A-6B).

[0145] We assessed differential effects by age at onset of AD (as a gauge of the strength of the atopic march, with onset at an earlier age and longer duration occurring in later life), severity of AD at study entry (possibly indicating strong type 2 disease), and comorbid asthma (suggesting that a second stage in the atopic march was already observed). In addition, we explored the role of demographic characteristics (age, sex, race, ethnicity) and environment (geography), as well as their relationship to baseline IgE and baseline allergy burden. Based on the shift in estimates in these subgroup analyses, as shown in Figures 7A-7H, treatment benefit appeared to be higher in younger patients (<18 years) (Figure 7A), patients with earlier onset of AD (≤2 years) (Figure 7B), patients with more severe AD at baseline (Figure 7E), and patients with asthma at baseline versus no asthma (Figure 7G). Sensitivity analyses suggested that treatment benefit was observed continuously from later age at onset of AD up to 12 years (data not shown). North American and European patients had more allergic conditions at baseline and showed a higher treatment benefit compared to patients from Asia / Oceania (Figure 7C). This difference in geography persisted, in part, until the analysis by ethnicity, where a higher effect of treatment was seen in Caucasians compared to Asians (Figure 7D). Furthermore, patients with baseline IgE levels between 375 (IU / mL) and 2000 (IU / mL) appeared to benefit more compared to other patients (Figure 7F). Furthermore, treatment benefit appeared to be higher for patients with a higher allergic burden (≥2 concomitant allergic conditions) at baseline (Figure 7H).

[0146] Interestingly, no conclusive relationship between treatment effect and serum IgE levels at baseline was observed. We noted a "U"-shaped relationship for subgroup analysis defined by baseline IgE levels. Treatment effects were noted regardless of IgE levels, but higher treatment effects were observed in the middle of the IgE range. More specifically, patients with baseline IgE levels between 375 and 2000 IU / mL, empirically and prospectively defined as thresholds, seemed to benefit most from dupilumab (Figure 7F). When baseline IgE was analyzed by quadrant, the data showed a similar trend (Figure 8). It is unclear whether this occurred by chance or reflects differences in the intensity of type 2 inflammation (low or moderate grade intensity is more easily extinguished than very severe type 2 inflammatory responses) or whether the relationship between dupilumab and IgE in subjects with the highest IgE levels may indicate a more consistent effect with longer periods of dupilumab exposure.

[0147] Of note, the effect of dupilumab was more evident in subjects with a more active atopic march using other indicators of the degree of allergic sensitization, such as earlier age at onset of AD, as well as asthma and higher allergy burden at study entry. However, additional analyses showed that even for patients with age at onset of AD after age 2, being younger than 35 years at the time of treatment with dupilumab offers an opportunity to attenuate the atopic march (Figure 9).

[0148] Consideration The current analysis was performed on what is currently the largest and most comprehensive clinical trials database for moderate-to-severe AD. This pooled study population, mostly adults (mean, 36 years; median, 35 years; range, 12-88 years), provides evidence of the atopic march in older subjects, temporally distant from the most active period of childhood allergy acquisition. This analysis showed that dupilumab can prevent the atopic march. Dupilumab reduced both the occurrence of new allergies and the worsening of existing allergic conditions compared with controls treated with standard of care.

[0149] Shifts in estimates in subgroup analyses revealed that the treatment benefit of dupilumab appeared to be higher for younger patients (≤18 years), patients with earlier onset of AD (≤2 years), more severe AD at baseline, and baseline asthma vs. no asthma. A better treatment benefit was also observed in the atopic Caucasian population compared to the Asian population. This is likely due to the greater number of allergies at baseline in the Caucasian group, providing a higher chance for exacerbation and therefore a greater opportunity to demonstrate treatment benefit. Compared to the Asian study population, others noted that Caucasian patients may also be predisposed to develop more severe allergic conditions, which is influenced by the degree of bias of the immune response towards type 2 inflammation (Ruiter et al., Seminars in Immunopathology, 2012, 34:617-32).

[0150] A sustained but attenuated effect was observed by discontinuing dupilumab therapy during the washout period; however, no rebound of allergic events was noted after dupilumab treatment was discontinued, as evidenced by the continued therapeutic benefit observed during the follow-up period following cessation of therapy. Thus, dupilumab treatment may have provided some sustained disease modification, at least over the follow-up period (greater than five dupilumab half-lives) of patients treated in this study.

[0151] Taken together, this meta-analysis provides the first known evidence that dupilumab can be disease-modifying and that it can substantially slow the atopic march.

[0152] The present invention should not be limited in scope by the specific embodiments described herein. Indeed, various modifications of the present invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0153] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12]

Table 6-13

Table 6-14

Table 6-15

Table 6-16

Claims

1. 1. A pharmaceutical composition comprising an IL-4 / IL-13 antagonist for use in a method for preventing or reducing the risk of developing a new allergic condition or preventing or reducing the risk of exacerbation of an existing allergic condition in a subject, comprising: The method includes administering to the subject an IL-4 / IL-13 antagonist; The subject has moderate to severe atopic dermatitis (AD) and one or more of the following characteristics: (i) early onset of AD by age 2 years; (ii) onset of AD after age 2 years and age ≦35 years at the start of treatment; (iii) baseline IgE level of 375 IU / mL to 2000 IU / mL; (iv) ≧2 concomitant allergic conditions; and / or (v) concomitant asthma. A pharmaceutical composition, wherein the IL-4 / IL-13 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα, wherein the antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

2. 1. A pharmaceutical composition comprising an IL-4 / IL-13 antagonist for use in a method for preventing or reducing the risk of developing a new allergic condition or preventing or reducing the risk of exacerbation of an existing allergic condition in a subject, comprising: The method includes administering to the subject a course of treatment comprising an IL-4 / IL-13 antagonist; The IL-4R / IL-13 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα, and the antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, and HCDR2 comprises the amino acid sequence of SEQ ID NO:

4. HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8; The subject has atopic dermatitis (AD) and is at risk of developing a new allergic condition or an exacerbated allergic condition; A pharmaceutical composition wherein after a course of treatment, the subject does not exhibit any new allergic conditions or worsening of any existing concomitant allergic conditions.

3. The pharmaceutical composition of claim 2, wherein the subject has moderate to severe AD.

4. Subjects at risk for developing a new or worsening allergic condition have the following characteristics: (i) early onset of AD by age 2 years; (ii) onset of AD after age 2 years and age ≤35 years at the start of treatment with an IL-4 / IL-13 antagonist; (iii) severe AD; (iv) ≤18 years of age at the start of treatment with an IL-4 / IL-13 antagonist; (v) age ≥18 years at the start of treatment with an IL-4 / IL-13 antagonist; (vi) baseline IgE levels between 375 IU / mL and 2000 IU / mL; (vii) ≥ 2 concomitant allergic conditions; and / or (viii) Paraneoplastic asthma 3. The pharmaceutical composition of claim 2, comprising one or more of:

5. The target is: (i) have AD with onset at age ≦2 years; or (ii) The pharmaceutical composition of claim 1 or 2, wherein the subject has AD with onset >2 years of age and the subject is ≦35 years of age at the start of treatment with the IL-4 / IL-13 antagonist.

6. 6. The pharmaceutical composition of claim 5, wherein the subject has AD with onset at age ≦2 years.

7. 6. The pharmaceutical composition of claim 5, wherein the subject has AD with onset >2 years of age and is ≦35 years of age at the start of treatment with the IL-4 / IL-13 antagonist.

8. 3. The pharmaceutical composition of claim 1 or 2, wherein the subject has a baseline IgE level of 375 IU / mL to 2000 IU / mL.

9. 3. The pharmaceutical composition of claim 1 or 2, wherein the subject has ≥ 2 concomitant allergic conditions.

10. 10. The pharmaceutical composition of claim 9, wherein the subject has at least three concomitant allergic conditions.

11. 10. The pharmaceutical composition of claim 9, wherein the concomitant allergic condition is selected from the group consisting of environmental allergies, aspirin sensitivity, asthma, allergic conjunctivitis, contact dermatitis, drug hypersensitivity, eosinophilic esophagitis, food allergies, ichthyosis, nasal polyps, oral allergy syndrome, pruritus, rhinitis, sinusitis, and urticaria.

12. The pharmaceutical composition of claim 1 or 2, wherein the subject has concomitant asthma.

13. The pharmaceutical composition of claim 1 or 2, wherein the subject has severe AD.

14. 3. The pharmaceutical composition of claim 1 or 2, wherein the subject is ≦18 years of age at the start of treatment.

15. 3. The pharmaceutical composition of claim 1 or 2, wherein the subject is >18 years of age at the start of treatment.

16. 1. A pharmaceutical composition comprising an IL-4 / IL-13 antagonist for use in a method of attenuating the progression of atopic march in a subject, comprising: The method includes administering to the subject a course of treatment comprising an IL-4 / IL-13 antagonist; The IL-4R / IL-13 antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4Rα, wherein the antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8; The subject has atopic dermatitis (AD) and further has one or more of the following characteristics: (i) early onset of AD by age 2 years; (ii) onset of AD after age 2 years and age ≦35 years at the start of treatment; (iii) baseline IgE level of 375 IU / mL to 2000 IU / mL; (iv) ≧2 concomitant allergic conditions; and / or (v) concomitant asthma.

17. This applies to: have AD with onset at age ≦2 years; or 17. The pharmaceutical composition of claim 16, wherein the subject has AD with onset >2 years of age and the subject is ≤35 years of age at the start of treatment.

18. 17. The pharmaceutical composition of claim 16, wherein the subject has AD with onset at age ≦2 years.

19. 17. The pharmaceutical composition of claim 16, wherein the subject has AD with onset >2 years of age and is ≦35 years of age at the start of treatment.

20. 17. The pharmaceutical composition of claim 16, wherein the subject has a baseline IgE level of 375 IU / mL to 2000 IU / mL.

21. 17. The pharmaceutical composition of claim 16, wherein the subject has > 2 concomitant allergic conditions.

22. 22. The pharmaceutical composition of claim 21, wherein the subject has at least three concomitant allergic conditions.

23. 22. The pharmaceutical composition of claim 21, wherein the concomitant allergic condition is selected from the group consisting of environmental allergies, aspirin sensitivity, asthma, allergic conjunctivitis, contact dermatitis, drug hypersensitivity, eosinophilic esophagitis, food allergies, ichthyosis, nasal polyps, oral allergy syndrome, pruritus, rhinitis, sinusitis, and urticaria.

24. 17. The pharmaceutical composition of claim 16, wherein the subject being treated has concomitant asthma.

25. The pharmaceutical composition of claim 16, wherein the subject has moderate to severe AD.

26. 26. The pharmaceutical composition of claim 25, wherein the subject has severe AD.

27. 17. The pharmaceutical composition of claim 16, wherein the subject to be treated is ≦18 years old.

28. 17. The pharmaceutical composition of claim 16, wherein the subject to be treated is >18 years old.

29. 17. The pharmaceutical composition of claim 16, wherein treatment with the IL-4 / IL-13 antagonist attenuates, slows, or prevents the acquisition of a new allergic condition in a subject.

30. 17. The pharmaceutical composition of claim 16, wherein treatment with the IL-4 / IL-13 antagonist attenuates, slows, or prevents the exacerbation of an existing allergic condition in a subject.

31. The pharmaceutical composition of any one of claims 1, 2 and 16, wherein the IL-4 / IL-13 antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof comprising a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

32. The pharmaceutical composition of any one of claims 1, 2 and 16, wherein the IL-4 / IL-13 antagonist is an anti-IL-4R antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

33. The pharmaceutical composition of any one of claims 1, 2 and 16, wherein the IL-4 / IL-13 antagonist is dupilumab.

34. 17. The pharmaceutical composition of any one of claims 1, 2 and 16, wherein the IL-4 / IL-13 antagonist is administered subcutaneously.

35. 17. The pharmaceutical composition of any one of claims 1, 2 and 16, wherein the IL-4 / IL-13 antagonist is administered for at least 16 weeks.

36. 17. The pharmaceutical composition of any one of claims 1, 2 and 16, wherein the IL-4 / IL-13 antagonist is administered for at least 52 weeks.

37. 17. The pharmaceutical composition of any one of claims 1, 2 and 16, wherein the IL-4 / IL-13 antagonist is administered in a dose of 75 mg to 600 mg.

38. 38. The pharmaceutical composition of claim 37, wherein the IL-4 / IL-13 antagonist is administered in a dose of 100 mg, 200 mg, or 300 mg.

39. 38. The pharmaceutical composition of claim 37, wherein the IL-4 / IL-13 antagonist is administered every week (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

40. 38. The pharmaceutical composition of claim 37, wherein the IL-4 / IL-13 antagonist is administered in an initial dose of 600 mg followed by secondary doses of 300 mg.

41. 38. The pharmaceutical composition of claim 37, wherein the IL-4 / IL-13 antagonist is administered in an initial dose of 400 mg followed by secondary doses of 200 mg.

42. 41. The pharmaceutical composition of claim 40, wherein the secondary doses are administered QW, Q2W, Q3W, or Q4W.

43. 17. The pharmaceutical composition of any one of claims 1, 2 and 16, wherein the IL-4 / IL-13 antagonist is administered in combination with a topical therapy.

44. 44. The pharmaceutical composition of claim 43, wherein the IL-4 / IL-13 antagonist is administered in combination with a topical corticosteroid.

45. 17. The pharmaceutical composition of any one of claims 1, 2 and 16, wherein the IL-4 / IL-13 antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an auto-injector.

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