Treatment methods for eosinophilic gastroenteritis induced by IL-4R antagonist administration

Abstract

A method for treating eosinophilic gastritis or eosinophilic gastroenteritis is provided. In one embodiment, the method comprises administering to a subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or its antigen-binding fragment.

Description

Technical Field

[0001] Cross - reference to related applications This application is filed as a PCT international patent application on March 26, 2024, and claims priority to U.S. Provisional Patent Application No. 63 / 492,425, filed on March 27, 2023, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] Reference to Sequence Listing This application includes a sequence listing submitted electronically in XML format. This sequence listing XML is hereby incorporated by reference. The XML file created on March 14, 2024, is named 40848_0120WOU1_SL.xml and has a size of 269,767 bytes.

[0003] The present disclosure relates to the use of an interleukin - 4 receptor (IL - 4R) inhibitor for treating or preventing eosinophilic gastroenteritis, such as eosinophilic gastritis with or without eosinophilic duodenitis, in a subject who needs it.

Background Art

[0004] Eosinophilic gastrointestinal disorders (EGID) are rare chronic allergic / immune - mediated diseases that affect the gastrointestinal (GI) tract. EGID can occur in pediatric and adult patients, and any single region of the GI tract (i.e., esophagus, stomach, small intestine, and colon) or combination of regions can be involved (Rossi, et al., Clin Transl Allergy, 2022, 12:e12146).

[0005] Eosinophilic gastritis (EoG) is a rare gastric disease distinct from eosinophilic esophagitis (EoE). EoG is characterized by patchy or diffuse infiltration of eosinophils in the stomach (Collins, et al., Front Med, 2017, 4:261). Patients with EoG may also have co-occurring eosinophilic duodenitis (EoD), which is characterized by patchy or diffuse infiltration of eosinophils in the small intestine. Mucosal biopsies of EoG and EoD patients show more than 30 eosinophils (eos) per 5-high magnification field (hpf) in the stomach and more than 30 eosinophils per 3-hpf in the small intestine, respectively. These are also used as diagnostic criteria for EoG and EoD, respectively (Dellon, et al., N Engl J Med, 2020, 383:1624-1634). Eosinophilic gastroenteritis (EGE) can occur in both the stomach and small intestine and encompasses EoG and EoD.

[0006] The diagnosis of eosinophilic gastrointestinal gland oogonia (EoG) with or without EoD is based on clinical symptoms combined with eosinophilic infiltration in gastric biopsy specimens with or without eosinophilic inflammation of the duodenum, and the absence of other causes of eosinophilia (e.g., malignancy, parasitic infection). The signs and symptoms of EoG with and without EoD depend on the location, extent, and layer(s) of the intestine involved in the eosinophilic infiltration (Mendez Sanchez, et al., Dig Dis Sci, 2007, 52:2904-2911). The most frequent symptoms of mucosal eosinophilic infiltration are nausea, early satiety, vomiting, flatulence, abdominal pain, abdominal cramps, loss of appetite, diarrhea, and weight loss. Patients with muscular eosinophilic infiltration may have symptoms of intestinal obstruction with nausea, vomiting, and abdominal distension. Patients with subserosal involvement may present with isolated ascites or ascites combined with symptoms characteristic of mucosal and / or muscular diseases. The majority of patients have a chronic course. This disease involves deeper layers of the affected gastrointestinal tract and may lead to complications (e.g., bowel obstruction) (Pineton de Chambrun, et al., Clin Gastroenterol Hepatol, 2011, 9:950-956).

[0007] Approximately 70%–90% of EoG patients (with or without EoD) have a history of atopic / allergic diseases, including asthma, food allergies, atopic dermatitis, urticaria, allergic conjunctivitis, and / or allergic rhinitis / sinusitis (Chehade, et al., J Allergy Clin Immunol Pract, 2021, 9:2050-2059). Approximately 25% of patients have comorbid EoE. Peripheral eosinophil counts are elevated in approximately 80% of patients, ranging from 5% to 35%, with a mean absolute peripheral eosinophil count of 1000 cells / μL (Chang, et al., Clin Gastroenterol Hepatol, 2010, 8:669-675).

[0008] Patients with EoG (with or without EoD) experience a significantly reduced quality of life (QoL) and suffer psychological, social, economic, and physical image impacts. Patients were found to experience post-illness depression, emotional distress associated with dietary restrictions, and economic impacts of the illness, directly through the cost of special foods or indirectly through the inability to work or attend school (Bedell, et al., Dig Sic Sci, 2018, 63:1148-1157).

[0009] In the United States, Europe, or Japan, there are no approved treatments for eoG (with or without eoD). Two main strategies exist for disease management of eoG (with or without eoD): dietary modifications and off-label pharmacological interventions, primarily systemic corticosteroids. Dietary modifications and / or drug therapy may be effective in treating some patients. However, maintaining effectiveness requires strict adherence to treatment and dietary restrictions, and pharmacological therapies such as systemic corticosteroids are not a solution for long-term treatment due to numerous systemic side effects. Therefore, there remains an unmet need for safe and effective long-term therapies that address the underlying inflammation of eoG (with or without eoD), prevent disease progression, and improve clinical symptoms. [Overview of the project]

[0010] In one embodiment, the present disclosure provides a method for treating, preventing, or improving at least one symptom of eosinophilic gastroenteritis. In some embodiments, the method comprises administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to a subject having eosinophilic gastroenteritis.

[0011] In another embodiment, the disclosure provides a method for treating, preventing, or improving at least one symptom of eosinophilic gastritis. In some embodiments, the method comprises administering one or more doses of an IL-4R antagonist to a subject having eosinophilic gastritis.

[0012] In another aspect, the disclosure provides an interleukin-4 receptor (IL-4R) antagonist for use in treating, preventing, or improving at least one symptom of eosinophilic gastroenteritis in a subject.

[0013] In another aspect, the disclosure provides an IL-4R antagonist for use in treating, preventing, or improving at least one symptom of eosinophilic gastritis in a subject.

[0014] In another aspect, the disclosure provides an interleukin-4 receptor (IL-4R) antagonist for use in the preparation of a pharmaceutical product for treating, preventing, or improving at least one symptom of eosinophilic gastroenteritis in a subject.

[0015] In another embodiment, the disclosure provides an IL-4R antagonist for use in the preparation of a pharmaceutical product for treating, preventing, or improving at least one symptom of eosinophilic gastritis in a subject.

[0016] In another embodiment, the disclosure provides a method for reducing the use of systemic corticosteroids or topical corticosteroids in subjects with eosinophilic gastroenteritis by administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to the subject. In some embodiments, at the initiation of treatment with the IL-4R antagonist, the subject is taking a stable dose of maintenance therapy systemic corticosteroids or topical corticosteroids. In some embodiments, treatment with the IL-4R antagonist reduces the subject's dependence on systemic corticosteroids or topical corticosteroids. In some embodiments, treatment with the IL-4R antagonist eliminates the need for systemic corticosteroids or topical corticosteroids.

[0017] In some embodiments, the subject has eosinophilic gastritis (EoG) with eosinophilic duodenitis (EoD). In some embodiments, the subject has EoG without EoD. In some embodiments, the subject has EoD without EoG. In some embodiments, the subject has eosinophilic gastroenteritis with esophageal involvement (e.g., EoG, EoG with EoD, or EoD). In some embodiments, the subject has eosinophilic gastroenteritis (e.g., EoG, EoG with EoD, or EoD) but does not have eosinophilic esophagitis (EoE).

[0018] In some embodiments, the subjects have been previously treated with systemic corticosteroids or topical corticosteroids. In some embodiments, the subjects are unresponsive, poorly responding to, or intolerant of treatment with systemic corticosteroids or topical corticosteroids, or treatment with standard therapy is contraindicated.

[0019] In some embodiments, the subjects are 12 years of age or older. In some embodiments, the subjects are adults. In some embodiments, the subjects are young adults.

[0020] In some embodiments, the subject has a concomitant atopic condition. In some embodiments, the concomitant atopic condition is food allergy, atopic dermatitis, asthma, chronic sinusitis, allergic rhinitis, or allergic conjunctivitis. In some embodiments, the subject has a concomitant atopic condition other than eosinophilic esophagitis.

[0021] In some embodiments, subjects have an eosinophil count ≥ 30 eos / hpf as measured by endoscopic biopsy of at least five distinct regions of the stomach, and / or an eosinophil count ≥ 30 eos / hpf as measured by endoscopic biopsy of at least three distinct regions of the small intestine, prior to the initiation of treatment with an IL-4R antagonist. In some embodiments, subjects have a baseline total symptom score (TSS) of 20 or higher as measured by the EoG / EoD symptom questionnaire, prior to the initiation of treatment with an IL-4R antagonist. In some embodiments, subjects have a baseline mean severity score of 4 or higher per week for at least two weeks for at least two components of the EoG / EoD-SQ prior to the initiation of treatment with an IL-4R antagonist, where the components are selected from the group consisting of stomach pain, gastric cramps, nausea, flatulence, early satiety, and loss of appetite. In some embodiments, subjects have a history of at least two EoG symptom episodes per week for at least eight weeks prior to the initiation of treatment with an IL-4R antagonist, where the symptoms are selected from the group consisting of stomach pain, gastric cramps, nausea, flatulence, early satiety, and loss of appetite.

[0022] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment having one or more CDR, HCVR, and / or LCVR sequences listed in Table 1. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment 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 of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R receptor antagonist is dupilumab.

[0023] In some embodiments, the IL-4R antagonist is administered in doses of approximately 50 mg to approximately 600 mg. In some embodiments, the IL-4R antagonist is administered once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the IL-4R antagonist is administered quarterly (QW) at a dose of approximately 300 mg. In some embodiments, the IL-4R antagonist is administered quarterly (Q2W) at a dose of approximately 300 mg. In some embodiments, the IL-4R antagonist is administered subcutaneously.

[0024] In some embodiments, the IL-4R antagonist is administered in combination with a second therapeutic agent or therapy.

[0025] In some embodiments, the IL-4R antagonist is contained in a container selected from the group consisting of glass vials, syringes, pre-filled syringes, pen-type delivery devices, and auto-injectors. In some embodiments, the IL-4R antagonist is contained in a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose pre-filled syringe. In some embodiments, the IL-4R antagonist is contained in an auto-injector. In some embodiments, the IL-4R antagonist is contained in a pen-type delivery device.

[0026] In another embodiment, the Disclosure provides a method for treating subjects having eosinophilic gastroenteritis (e.g., EoG and / or EoD) by administering a combination therapy. In some embodiments, the combination therapy comprises (i) an interleukin-4 receptor (IL-4R) antagonist and (ii) a systemic corticosteroid or a swallowing topical corticosteroid. In some embodiments, the combination therapy comprises an IL-4R antagonist disclosed herein (e.g., an anti-IL-4R antibody or its antigen-binding fragment, e.g., dupilumab) and a systemic corticosteroid (e.g., prednisone or prednisolone). In some embodiments, the combination therapy comprises an IL-4R antagonist disclosed herein (e.g., an anti-IL-4R antibody or its antigen-binding fragment, e.g., dupilumab) and a swallowing topical corticosteroid (e.g., budesonide or fluticasone).

[0027] In other embodiments, the Disclosure provides combinations for treating subjects having eosinophilic gastroenteritis (e.g., EoG and / or EoD). In some embodiments, the combination comprises (i) an IL-4R antagonist and (ii) a systemic corticosteroid or a swallowing topical corticosteroid. In some embodiments, the combination comprises an IL-4R antagonist disclosed herein (e.g., an anti-IL-4R antibody or its antigen-binding fragment, e.g., dupilumab) and a systemic corticosteroid (e.g., prednisone or prednisolone). In some embodiments, the combination comprises an IL-4R antagonist disclosed herein (e.g., an anti-IL-4R antibody or its antigen-binding fragment, e.g., dupilumab) and a swallowing topical corticosteroid (e.g., budesonide or fluticasone).

[0028] Other embodiments will become apparent from the overview of the detailed description below. [Brief explanation of the drawing]

[0029] [Figure 1] This study demonstrates that treatment with an IL-4R antagonist significantly reduced the frequency of eosinophils in gastric tissue of a mouse model of eosinophilic gastritis. Female C57BL / 6J mice (n=5-7 / group at baseline) were administered a single dose of 25 μg of mIL-25 plasmid DNA or vector-control plasmid DNA via IV injection using HDD on day 0. On days 4, 1, and 3, mice were administered 25 mg / kg of REGN1103, isotype control antibody, or antibody-free control via SC injection. Data are expressed as group mean ± SD, and symbols indicate data from individual animals. Normality was tested using the Shapiro-Wilk test. Statistical significance was determined using the Brown-Forsythe and Welch ANOVA tests, and multiple comparisons were performed using Dunnett's T3 multiple comparison test. Throughout the study, three mice (no more than two per group) died before the end of the experiment and were excluded from the analysis. *, p≦0.05, **, p≦0.01, ***, p≦0.001. [Figure 2A]This study demonstrates that treatment with an IL-4R antagonist significantly reduced Ccl11 mRNA levels in gastric tissue of a mouse model of eosinophilic gastritis. Female C57BL / 6J mice (n=5-7 / group at baseline) were administered a single dose of 25 μg of mIL-25 plasmid DNA or vector-control plasmid DNA via IV injection using HDD on day 0. On days 4, 1, and 3, mice were administered 25 mg / kg of REGN1103, isotype control antibody, or antibody-free control via SC injection. Samples were collected on day 8. Ccl11 mRNA levels relative to Actb mRNA levels in gastric tissue were measured. Data are expressed as group mean ± SD, and symbols indicate data from individual animals. Normality was tested using the Shapiro-Wilk test. P-values ​​were determined using the Kruskal-Wallis test, and multiple comparisons were performed using Dunn's multiple comparison test. Throughout the experiment, three mice (two or fewer per group) died before the end of the experiment and were therefore excluded from the analysis. *, p ≤ 0.05; **, p ≤ 0.01. [Figure 2B] This study demonstrates that treatment with an IL-4R antagonist significantly reduced Ccl24 mRNA levels in gastric tissue of a mouse model of eosinophilic gastritis. Female C57BL / 6J mice (n=5-7 / group at baseline) were administered a single dose of 25 μg of mIL-25 plasmid DNA or vector-control plasmid DNA via IV injection using HDD on day 0. On days 4, 1, and 3, mice were administered 25 mg / kg of REGN1103, isotype control antibody, or antibody-free control via SC injection. Samples were collected on day 8. Ccl24 mRNA levels relative to Actb mRNA levels in gastric tissue were measured. Data are expressed as group mean ± SD, and symbols indicate data from individual animals. Normality was tested using the Shapiro-Wilk test. P-values ​​were determined using the Kruskal-Wallis test, and multiple comparisons were performed using Dunn's multiple comparison test. Throughout the experiment, three mice (two or fewer per group) died before the end of the experiment and were therefore excluded from the analysis. *, p ≤ 0.05; **, p ≤ 0.01. [Figure 3A]This study demonstrates that treatment with an IL-4R antagonist significantly prevented the progression of eosinophilic gastritis in a mouse model. Female C57BL / 6J mice (n=5-7 / group at baseline) were administered a single dose of 25 μg of mIL-25 plasmid DNA or vector-control plasmid DNA via IV injection using HDD on day 0. On days 4, 1, and 3, mice were administered 25 mg / kg of REGN1103, isotype control antibody, or antibody-free control via SC injection. Samples were collected, sectioned, and stained with hematoxylin and eosin on day 8. Group mean total disease status scores from non-glandular and glandular gastric tissues for each group are shown. Data are expressed as group mean ± SD of total disease status score, and symbols indicate data from individual animals. Statistical significance was determined using one-way ANOVA followed by Tukey's HSD test. Throughout the experiment, three mice (two or fewer per group) died before the end of the experiment and were therefore excluded from the analysis. **, p≦0.01, ***, p≦0.001, ****, p≦0.0001. [Figure 3B] This study demonstrates that treatment with an IL-4R antagonist significantly prevented the progression of eosinophilic gastritis in a mouse model. Female C57BL / 6J mice (n=5-7 / group at baseline) were administered a single dose of 25 μg of mIL-25 plasmid DNA or vector-control plasmid DNA via IV injection using HDD on day 0. On days 4, 1, and 3, mice were administered 25 mg / kg of REGN1103, isotype control antibody, or antibody-free control via SC injection. Samples were collected, sectioned, and stained with hematoxylin and eosin on day 8. Representative images from each group are shown. The vertical and horizontal lines in the images are scale bars representing a length of 2 mm. [Modes for carrying out the invention]

[0030] 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, and that the methods and conditions may be modified accordingly. Furthermore, it should be understood that the terms used herein are for the purpose of describing specific embodiments only, and that the scope of the present invention is not intended to be limited, but is limited solely by the appended claims.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains.

[0032] As used herein, the term “about” means that, when used in reference to a particular numerical value, that value may vary by no more than 1% from the stated value. For example, as used herein, the expression “about 100” includes 99 and 101, as well as all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0033] As used herein, terms such as “to treat” and “to treat” mean to alleviate symptoms, to eliminate the cause of symptoms, whether temporarily or permanently, or to prevent or delay the appearance of symptoms of the disorder or condition.

[0034] Eosinophilic gastritis, or EoG, is an inflammatory disease characterized by abnormal eosinophilic inflammation in the stomach. Major symptoms of EoG include, but are not limited to, nausea, early satiety, vomiting, flatulence, abdominal pain, abdominal cramps, loss of appetite, diarrhea, and weight loss. EoG is typically diagnosed based on clinical symptoms combined with eosinophilic infiltration in gastric biopsy specimens. The current diagnostic criterion for EoG is 30 or more eosinophils (eos) per high-magnification field (hpf) in the stomach.

[0035] Eosinophilic duodenitis, or EoD, is an inflammatory disease characterized by patchy or diffuse infiltration of eosinophils in the small intestine. Major symptoms of EoD include, but are not limited to, nausea, early satiety, vomiting, flatulence, abdominal pain, abdominal cramps, loss of appetite, diarrhea, and weight loss. EoD is typically diagnosed based on clinical symptoms combined with eosinophilic infiltration in biopsy specimens from the small intestine. The current diagnostic criterion for EoD is 30 or more eosinophils (eos) per high-magnification field (hpf) in the small intestine.

[0036] As used herein, the term “subject requiring it” refers to a human or non-human animal exhibiting one or more symptoms or signs of eosinophilic gastroenteritis and / or diagnosed with eosinophilic gastroenteritis, e.g., EoG and / or EoD. In certain embodiments, this term includes subjects exhibiting elevated levels of one or more EGE-related biomarkers (as described elsewhere herein). For example, in some embodiments, subjects treated according to the methods of this disclosure are subjects with elevated levels of IgE, serum TARC, neotaxin-3, CCL11, or CCL24. As used herein, the terms “subject” and “patient” are used interchangeably.

[0037] The term “subjects requiring it” may also include subjects who, prior to treatment, exhibit (or have exhibited) one or more signs of EGE, such as eosinophilic infiltration of the gastrointestinal tract, nausea, early satiety, vomiting, flatulence, abdominal pain, abdominal cramps, loss of appetite, diarrhea, weight loss, and / or elevated levels of EGE-related biomarkers. The term also includes subjects with elevated peripheral eosinophil counts (e.g., ≥100, ≥150, ≥200, or ≥300 cells / μL) or elevated serum IgE (e.g., >150 kU / L).

[0038] The term "eosinophilic infiltration" refers to the presence of eosinophils in organs or tissues including the subject's blood, esophagus, stomach, duodenum, jejunum, ileum, and colon. In the context of the present disclosure, the term "eosinophilic infiltration" refers to the presence of eosinophils in the inner mucosal layer of regions of the gastrointestinal tract including, but not limited to, the stomach and small intestine (e.g., in the inner mucosal layer of such region(s)). Eosinophilic infiltration is analyzed, for example, using tissue biopsies. According to some embodiments, "eosinophilic infiltration" refers to the presence of 30 or more eosinophils per high power field in the stomach or two, three, four, five, or more separate regions of this area (e.g., the stomach or small intestine). The term "high power field" refers to, for example, a standard total magnification of 400x by a microscope used to view eosinophils in tissue from the subject's stomach or small intestine. Thus, in some embodiments, "a subject who needs it" refers to a subject showing the presence of 30 or more eosinophils ("eos") per high power field ("hpf") in two, three, four, five, or more of the proximal, middle, and distal regions of the gastrointestinal tract, such as the stomach or small intestine. In certain embodiments, "eosinophilic infiltration" includes infiltration of tissues by white blood cells, such as lymphocytes, neutrophils, and mast cells. For example, leukocyte infiltration into gastrointestinal tissue can be detected by cell surface markers such as macrophage-specific markers (e.g., CD11b + , F4 / 80 + , CD14 + , EMR1 + , and CD68 + ), neutrophil-specific markers (e.g., CD11b + , Ly6G + , Ly6C + , CD11b + , and CD66b + ), and T cell-specific markers (e.g., CD3 + , CD4 + , and CD8 + ).

[0039] Methods and materials similar to or equivalent to those described herein may be used in the practice of this application, but typical methods and materials are described here. All publications referenced herein are incorporated herein in their entirety by reference.

[0040] Treatment method In one embodiment, a method is provided for treating, preventing, or improving at least one symptom of eosinophilic gastroenteritis (EGE) in a subject. In some embodiments, the subject to be treated has eosinophilic gastritis (EoG). In some embodiments, the subject to be treated has EoG accompanied by eosinophilic duodenitis (EoD). In some embodiments, the subject to be treated has EoG without EoD. In some embodiments, the subject to be treated has EoD without EoG. In some embodiments, the subject to be treated has EGE with esophageal involvement (e.g., EoG and / or EoD). In some embodiments, the subject has concomitant eosinophilic esophagitis (EoE). In some embodiments, the subject does not have EoE.

[0041] In some embodiments, the subjects are 12 years of age or older. In some embodiments, the subjects are adolescents. In some embodiments, the subjects are adults. In some embodiments, the subjects are under 18 years of age, for example, children under 12 years of age. In some embodiments, the subjects have a weight of 40 kg or more. In some embodiments, the subjects are 12 years of age or older and have a weight of 40 kg or more.

[0042] In some embodiments, subjects treated according to the methods disclosed herein have a history of a documented diagnosis of EoG by endoscopic biopsy, as demonstrated by intraepithelial eosinophilic infiltration from at least two, three, four, or five distinct regions of the stomach. In some embodiments, subjects have a baseline eosinophil count ≥ 30 eos / hpf in at least five distinct regions of the stomach. "Eosinophil count," as used herein, refers to the number of eosinophils contained within one high-magnification field (hpf), e.g., 400x. In the embodiments described above, the subjects have an average eosinophil count of ≥35 eos / hpf, ≥40 eos / hpf, ≥45 eos / hpf, ≥50 eos / hpf, ≥55 eos / hpf, ≥60 eos / hpf, ≥65 eos / hpf, ≥70 eos / hpf, ≥75 eos / hpf, ≥80 eos / hpf, ≥85 eos / hpf, or ≥90 eos / hpf.

[0043] In some embodiments, subjects treated according to the methods disclosed herein have a history of a documented diagnosis of EoD by endoscopic biopsy, as demonstrated by intraepithelial eosinophilic infiltration from at least two, three, four, or five distinct regions of the small intestine. In some embodiments, subjects have a baseline eosinophil count ≥30 eos / hpf in at least three distinct regions of the small intestine. In some embodiments, subjects have a mean eosinophil count ≥35 eos / hpf, ≥40 eos / hpf, ≥45 eos / hpf, ≥50 eos / hpf, ≥55 eos / hpf, ≥60 eos / hpf, ≥65 eos / hpf, ≥70 eos / hpf, ≥75 eos / hpf, ≥80 eos / hpf, ≥85 eos / hpf, or ≥90 eos / hpf.

[0044] In some embodiments, subjects treated according to the methods disclosed herein have a history of one or more symptoms of EGE, EoG, or EoD, including but not limited to nausea, early satiety, vomiting, flatulence, abdominal pain, abdominal cramps, loss of appetite, diarrhea, and weight loss. In some embodiments, subjects have a history of one or more symptoms of EGE 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 50 weeks, or longer. In some embodiments, subjects have a history of one or more symptoms of EGE, EoG, or EoD for at least 6 months, at least 1 year, at least 2 years, or longer.

[0045] In some embodiments, subjects treated according to the methods disclosed herein have a history of prior treatment with one or more standard therapies for EGE, including but not limited to dietary modifications (e.g., elimination diets), systemic corticosteroids, swallowing topical corticosteroids (e.g., oral beclomethasone, budesonide, or fluticasone), antihistamines, or immunomodulators. In some embodiments, subjects treated are unresponsive, poorly responsive, intolerant, or resistant to one or more current standard therapies for EGE, EoG, or EoD. In some embodiments, subjects treated have contraindications to one or more standard therapies.

[0046] In some embodiments, the subject being treated is taking a stable dose of systemic corticosteroids or topical corticosteroids for maintenance therapy. In some embodiments, the subject being treated is taking a stable dose of PPIs. In some embodiments, the subject being treated is taking a stable dose of leukotriene inhibitors. In some embodiments, the subject being treated is following a stable food elimination diet.

[0047] In some embodiments, the subject being treated has or has had at least one comorbidity. In some embodiments, the subject being treated has or has had a concomitant type 2 inflammatory condition. As used herein, “type 2 inflammatory condition” means T helper 2 (T H 2) A disease, disorder, or condition related to an mediated immune response (Gandhi, et al., Nat Rev Drug Discov., 2016, 15(1):35-50). Non-limiting examples of type 2 inflammatory conditions include asthma, chronic sinusitis, allergic rhinitis, allergic fungal rhinitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), upper and lower respiratory tract diseases, eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), atopic conjunctivitis, atopic dermatitis, vasculitis, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic sinusitis with nasal polyps (CRSwNP), aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (e.g., NSAID-exacerbated respiratory disease or NSAID-ERD), perennial allergic rhinitis (PAR), chronic eosinophilic pneumonia (CEP), and exercise-induced bronchospasm. In some embodiments, the subject has a concomitant atopic disease or condition selected from the group consisting of food allergy, atopic dermatitis, asthma, chronic sinusitis, allergic rhinitis, or allergic conjunctivitis. In some embodiments, the subject has a concomitant atopic disease or condition other than eosinophilic esophagitis.

[0048] In some embodiments, the subject being treated is an allergen-sensitive subject, for example, a subject with a food allergy or oral allergy syndrome. For example, in some embodiments, the subject may exhibit one of the following characteristics: (a) prone to developing an allergic reaction or response upon exposure to one or more allergens, (b) previously exhibited an allergic reaction or response to one or more allergens, (c) have a known history of allergies, and / or (d) exhibit signs or symptoms of an allergic reaction or anaphylaxis. As used herein, terms such as “allergic response,” “allergic reaction,” and “allergic symptoms” include one or more signs or symptoms selected from the group consisting of urticaria (e.g., hive), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinusitis, watery eyes, wheezing, bronchospasm, decreased maximum expiratory flow (PEF), gastrointestinal disturbances, flushing, lip swelling, tongue swelling, decreased blood pressure, anaphylaxis, and organ damage / failure. “Allergic response,” “allergic reaction,” and “allergic symptoms” also include immunological responses and reactions such as increased IgE production, increased allergen-specific immunoglobulin production, and / or eosinophilia. In some embodiments, allergens are contained in or derived from foods such as dairy products (e.g., milk), eggs, wheat, soy, corn, rye, fish, shellfish, peanuts, and tree nuts. In some embodiments, the allergen is contained in or derived from non-food items such as dust (including, for example, house dust mites), pollen, insect toxins (for example, venom from bees, wasps, mosquitoes, etc.), mold, animal dander, latex, pharmaceuticals, drugs, ragweed, grasses, or birch.

[0049] In some embodiments, the subjects to be treated are selected based on exhibiting one or more inclusion criteria disclosed in Example 2. In some embodiments, the subjects to be treated are further selected based on not exhibiting one or more exclusion criteria disclosed in Example 2.

[0050] Interleukin-4 receptor antagonist In some embodiments, the methods of the present disclosure involve administering to a subject requiring it (e.g., a subject having EGE, EoG, or EoD) a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist or an IL-4R antagonist. As used herein, an "IL-4R antagonist" (also referred 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 to inhibit or attenuate the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. The type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and a γc chain. The type 2 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptors interact with and are stimulated by IL-4, while type 2 IL-4 receptors interact with and are stimulated by both IL-4 and IL-13. Therefore, IL-4R antagonists that can be used in the methods of the present disclosure may function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4-mediated and IL-13-mediated signaling. Thus, IL-4R antagonists of the present disclosure may prevent interaction between IL-4 and / or IL-13 and type 1 or type 2 receptors.

[0051] Non-limiting examples of the IL-4R antagonist category include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor-bodies" (e.g., engineered molecules containing ligand-binding domains of IL-4R components), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0052] Anti-IL-4Rα antibody and its antigen-binding fragment In certain exemplary embodiments of this disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment. The term “antibody,” as used herein, includes immunoglobulin molecules and their multimers (e.g., IgM) comprising four polypeptide chains interconnected by disulfide bonds (two heavy (H) chains and two light (L) chains). In a typical antibody, each heavy chain contains a heavy chain variable region (HCVR or V) as herein defined. H It includes the heavy chain constant region (abbreviated as C). The heavy chain constant region consists of three domains: C H 1. C H 2, and C H Includes 3. Each light chain has a light chain variable region (LCVR or V in this specification). L It includes the light chain steady region (abbreviated as C). The light chain steady region consists of one domain (C L Includes 1). V H Region and V L The region can be further subdivided into a highly variable region called the complementarity-determining region (CDR) and a more conserved region called the framework region (FR). H and V L It consists of three CDRs and four FRs, which are arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-IL-4R antibody (or its antigen-binding moiety) are identical to the human germline sequence. In some embodiments, one or more FRs of the anti-IL-4R antibody (or its antigen-binding moiety) are naturally or artificially modified.

[0053] The term “antibody” also, as used herein, includes the antigen-binding fragment of a complete antibody molecule. As used herein, terms such as “antigen-binding portion” of an antibody and “antigen-binding fragment” of an antibody include any naturally occurring, enzymatically obtained, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies may be derived, for example, from a complete antibody molecule using any suitable standard technique, such as protein digestion or recombinant genetic engineering techniques including manipulation and expression of DNA encoding the variable domain and, optionally, the constant domain of the antibody. Such DNA is publicly known and / or readily available, for example, from commercial suppliers, DNA libraries (e.g., including phage antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated using chemical or molecular biological techniques, for example, to sequence one or more variable domains and / or constant domains into a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids.

[0054] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv(scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated complementarity-determining regions (CDRs), e.g., CDR3 peptides) or FR3-CDR3-FR4 restricted peptides. Other manipulated molecules, such as domain-specific antibodies, single-domain antibodies, domain deletion antibodies, chimeric antibodies, CDR graft antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small module immunotherapies (SMIPs), and shark IgNAR variable domains, are also included by the term “antigen-binding fragment” as used herein.

[0055] The antigen-binding fragment of an antibody typically contains at least one variable domain. The variable domain may be of any size or amino acid composition and generally contains at least one CDR adjacent to or within the framework sequence of one or more framework sequences. L V associated with the domain H In an antigen-binding fragment having a domain, the V H and V L Domains can be positioned in any preferred arrangement relative to each other. For example, a variable region may be a dimer, V H -V H , V H -V L , or V L -V L It may contain dimers. Alternatively, the antigen-binding fragment of the antibody may contain monomer V H or V L It may contain a domain.

[0056] In certain embodiments, the antigen-binding fragment of an antibody may contain 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 the antigen-binding fragment of an antibody of this disclosure include (i)V H -C H 1. (ii)V H -C H 2, (iii)V H -C H 3, (iv)V H -C H 1-C H 2. (v)V H -C H 1-C H 2-C H 3. (vi)V H -C H 2-C H 3. (vii)V H -C L (viii)V L -C H 1. (ix)V L -C H 2, (x)V L -C H 3. (xi)VL -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 Examples include: In any configuration of the variable domain and constant domain that includes any of the exemplary configurations listed above, the variable domain and constant domain may be directly linked to each other, or they may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that result in a mobile or semi-mobile linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragments of the antibodies of this disclosure may be linked to each other and / or to one or more monomers. H Domain or V L It may include a homodimer or heterodimer (or other polymer) of any of the aforementioned configurations of the variable domain and the constant domain, which are associated with the domain by non-covalent bonds (for example, by disulfide bonds).

[0057] The constant region of an antibody is crucial for its ability to fix complement and mediate cell-dependent cytotoxicity. Therefore, in some embodiments, antibody isotypes may be selected based on whether the antibody is desirable for mediating cytotoxicity.

[0058] The term “antibody” also, as used herein, includes multispecific (e.g., bispecific) antibodies. A multispecific antibody or antigen-binding fragment of an antibody typically comprises at least two distinct variable domains, each of which can specifically bind to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in association with the antibodies or antigen-binding fragments of the present disclosure using conventional methods available in the art. For example, in some embodiments, the methods of the present disclosure involve the use of a bispecific antibody in which one arm of the immunoglobulin is specific to IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific to a second therapeutic target or is conjugated to a therapeutic portion. Exemplary bispecificity formats that may be used in connection with this disclosure include, but are not limited to, scFv-based formats or diabody bispecificity formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadromas, knob-in-holes, common light chains (e.g., common light chains with knob-in-holes), CrossMab, CrossFab, SEED bodies, leucine zippers, duobodies, IgG1 / IgG2, dual-acting Fab(DAF)-IgG, and Mab 2 One example is the bispecific format (for an overview of the above format, see, for example, Klein et al. 2012, mAbs 4:6, 1-11 and the references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugations. For example, in this case, non-natural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates, which then self-assemble into a multimeric complex with a specified composition, titer, and geometric structure. (See, for example, Kazane, et al., J.Am.Chem.Soc., [Epub:Dec.4,2012]).

[0059] In some embodiments, the antibodies used in the methods of the present disclosure are human antibodies. As used herein, the term “human antibody” is intended to encompass antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of the present disclosure may also include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo), for example, in the CDR, particularly CDR3. However, as used herein, the term “human antibody” is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as mouse, are grafted onto a human framework sequence.

[0060] The antibodies used in the methods of this disclosure are recombinant human antibodies. The term “recombinant human antibody,” as used herein, is intended to include all human antibodies prepared, expressed, produced, or isolated by recombinant means, e.g., antibodies expressed using recombinant expression vectors transfected into host cells (as further described below), antibodies isolated from recombinant combinatorial human antibody libraries (as further described below), antibodies isolated from transgenic animals of human immunoglobulin genes (e.g., mice) (see, e.g., Taylor, et al., (1992) Nucl. Acids Res., 20:6287-6295), or antibodies prepared, expressed, produced, or isolated by any other means involving the conjugation of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if transgenic animals with respect to the human Ig sequence are used, in vivo somatic mutagenesis), thereby regulating the recombinant antibody's V H and V L The amino acid sequence of the region is human germline V H and V LThese are sequences that are derived from and related to other sequences, but do not necessarily have to be naturally present in the in vivo human antibody germline repertoire.

[0061] An “isolated” antibody is an antibody that has been identified and separated from and / or recovered from at least one component of its natural environment. For example, an antibody separated or removed from at least one component of an organism, or from a tissue or cell in which antibodies are naturally present or naturally produced, is an “isolated antibody.” Isolated antibodies also include in situ antibodies within recombinant cells. 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 substantially contain no other cellular material and / or chemical substances.

[0062] According to certain embodiments, the antibody used in the method of the present disclosure specifically binds to IL-4Rα. The term "specifically binds," as used herein, means that the antibody or its antigen-binding fragment forms a relatively stable complex with the antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. In some embodiments, antibodies that "specifically bind" to IL-4Rα have equilibrium dissociation constants (K) less than approximately 1000 nM, less than approximately 500 nM, less than 300 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 90 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, less than approximately 50 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 1 nM, less than approximately 0.5 nM, less than approximately 0.25 nM, less than approximately 0.1 nM, or less than approximately 0.05 nM when measured by surface plasmon resonance assay (e.g., BIAcore®, Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). D) binds to IL-4Rα or a portion thereof. In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) can 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 to human IL-4Rα exhibits cross-reactivity to other antigens, e.g., IL-4Rα molecules from other (non-human) species.

[0063] In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) containing any of the amino acid sequences of the anti-IL-4R antibody described herein by reference, U.S. Patent No. 7,608,693. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment comprising a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0064] In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, LGS, and SEQ ID NO: 8, respectively, and further comprises an HCVR having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 1 (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity), and an LCVR having at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 2 (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity). In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises an HCVR containing SEQ ID NO: 1 and an LCVR containing SEQ ID NO: 2.

[0065] In some embodiments, the anti-IL-4R antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain containing the amino acid sequence of SEQ ID NO: 10.

[0066] An exemplary antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10 is a fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present disclosure involve the use of dupilumab. As used herein, “dupilumab” also includes bioequivalents of dupilumab. As used herein with respect to dupilumab, the term “bioequivalent” refers to an anti-IL-4R antibody or IL-4R-binding protein or fragment thereof that, when administered under similar experimental conditions at the same molar dose, either as a single or repeated dose, exhibits no significant difference in the rate and / or extent of absorption compared to dupilumab. In some embodiments, the term refers to an antigen-binding protein that binds to IL-4R and has no clinically significant difference in safety, purity, and / or potency compared to dupilumab.

[0067] Other anti-IL-4Rα antibodies that may be used in connection with the methods disclosed herein include, for example, AMG317 (Corren, et al., 2010, Am J Respir Crit Care Med., 181(8):788-796) or MEDI Examples include antibodies known in the art, referred to as 9314, or any of the anti-IL-4Rα antibodies described in U.S. Patent Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, 8,877,189, 10,774,141, or International Patent Publication Nos. WO2020 / 096381, WO2020 / 182197, WO2020 / 239134, WO2021 / 213329, WO2022 / 052974, WO2022 / 136669, or WO2022 / 136675 (the contents of each of these are incorporated herein by reference).

[0068] In some embodiments, the anti-IL-4Rα antibody or its antigen-binding fragment for use in the methods of the present disclosure comprises one or more CDR, HCVR, and / or LCVR sequences listed in Table 1 below.

[0069] In some embodiments, the anti-IL-4Rα antibody is (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-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) ), HCVR containing the amino acid sequence of 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: 1 5 (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),The antibody includes an LCVR containing the amino acid sequence of 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 includes an HCVR containing the amino acid sequence of SEQ ID NO: 64 (SCB-VH-91), and an LCVR containing 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).

[0070] In some embodiments, the anti-IL-4Rα antibody includes an amino acid sequence pair 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 / 82 (MEDI-8-VH / MEDI-8-VL), SEQ ID NOs. 83 / 84 (MEDI-9-VH / MEDI-9-VL), SEQ ID NOs. 85 / 86 (MEDI-10-VH / MEDI-10-VL), SEQ ID NOs. 87 / 88 (MEDI-11-VH / MEDI-11 / VL), SEQ ID NOs. 89 / 90 (MEDI-12-VH / MEDI-12-VL), SEQ ID NOs. 91 / 92 (MEDI-13-VH / MEDI-13-VL), SEQ ID NOs. 93 / 94 (MEDI-14-VH / MEDI-14- VL), SEQ ID NOs. 95 / 96 (MEDI-15-VH / MEDI-15-VL), SEQ ID NOs. 97 / 98 (MEDI-16-VH / MEDI-16 / VL), SEQ ID NOs. 99 / 100 (MEDI-17-VH / MEDI-17-VL), SEQ ID NOs. 101 / 102 (MEDI-18-VH / MEDI-18-VL), SEQ ID NOs. 103 / 104 (MEDI-19-VH / MEDI-19-VL), SEQ ID NOs. 105 / 106 (MEDI-20-VH / MEDI-20-VL), SEQ ID NOs. 107 / 108 (MEDI-21-VH / MEDI-21-VL), Sequence IDs 109 / 110 (MEDI-22-VH / MEDI-22-VL), 111 / 112 (MEDI-23-VH / MEDI-23-VL), 113 / 114 (MEDI-24-VH / MEDI-24-VL), 115 / 116 (MEDI-25-VH / MEDI-25-VL), 117 / 118 (MEDI-26-VH / MEDI-26-VL), 119 / 120 (MEDI-27-VH / MEDI-27-VL), 121 / 122 (MEDI-28-VH / MEDI-28-VL),SEQ ID NOs: 123 / 124 (MEDI-29-VH / MEDI-29-VL), 125 / 126 (MEDI-30-VH / MEDI-30-VL), 127 / 128 (MEDI-31-VH / MEDI-31-VL), 129 / 130 (MEDI-32-VH / MEDI-32-VL), 131 / 132 (MEDI-33-VH / MEDI-33-VL), 133 / 134 (MEDI-34-VH / MEDI-34-VL), 135 / 136 (MEDI-35-VH / MEDI-35-VL), 137 / 138 (MEDI-36- VH / MEDI-36-VL), SEQ ID NOs. 139 / 140 (MEDI-37-VH / MEDI-37-VL), SEQ ID NOs. 141 / 142 (MEDI-38-VH / MEDI-38-VL), SEQ ID NOs. 143 / 144 (MEDI-39-VH / MEDI-39-VL), SEQ ID NOs. 145 / 146 (MEDI-40-VH / MEDI-40-VL), SEQ ID NOs. 147 / 148 (MEDI-41-VH / MEDI-41-VL), SEQ ID NOs. 149 / 150 (MEDI-42-VH / MEDI-42-VL), and SEQ ID NOs. 151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).

[0071] In some embodiments, the anti-IL-4Rα antibody is (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 HCVRs containing the amino acid sequences of (i) AJOU-10-VH, AJOU-69-VH, AJOU-70-VH, AJOU-71-VH, AJOU-72-VH, or AJOU-83-VH, and (ii) AJOU-33-VL, AJOU-34-VL, SEQ ID NOs: 170 (AJOU-35-VL), 171 (AJOU-36-VL), 172 (AJOU-37-VL), 173 (AJOU-38-VL), 174 (AJOU-39-VL), 175 (AJOU-40-VL), 176 (AJOU-41-VL), 177 (AJOU-42-VL), 178 (AJOU-77-VL), 179 (AJ Contains LCVRs that include the amino acid sequence of OU-78-VL), SEQ ID NO: 180 (AJOU-79-VL), SEQ ID NO: 181 (AJOU-80-VL), SEQ ID NO: 182 (AJOU-86-VL), 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).

[0072] In some embodiments, the anti-IL-4Rα antibody is (i) 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) (ii) an HCVR containing the amino acid sequence of (ii) 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).

[0073] In some embodiments, the anti-IL-4Rα antibody is (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 (ST SA-C27-82-58-VH), 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 (S HCVR containing the amino acid sequence TSA-C27-Y2-Y2-VH), and (ii) SEQ ID NOs. 226 (STSA-C27-VL), SEQ ID NOs. 227 (STSA-C27-6-33-VL), SEQ ID NOs. 228 (STSA-C27-7-33-VL), SEQ ID NOs. 229 (STSA-C27-24-56-VL), SEQ ID NOs. 230 (STSA-C27-47-56-VL), SEQ ID NOs. 231 (STSA-C27-33-33-VL), SEQ ID NOs. 232 (STSA-C27-56-56-VL), SEQ ID NOs. 233 (STSA-C27-78-78-VL) ), SEQ ID NO: 234 (STSA-C27-82-58-VL), SEQ ID NO: 235 (STSA-C27-54-54-VL), 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),Alternatively, it may contain LCVR with the amino acid sequence of SEQ ID NO: 243 (STSA-C27-Y2-Y2-VL).

[0074] In some embodiments, the anti-IL-4Rα antibody is (i) SEQ ID NO: 244 (Y0188-1 VH), SEQ ID NO: 245 (Y0188-2 VH), SEQ ID NO: 246 (Y0188-3 VH), SEQ ID NO: 247 (Y0188-4 VH), SEQ ID NO: 248 (Y0188-6 VH), SEQ ID NO: 249 (Y0188-8 VH), SEQ ID NO: 250 (Y0188-9 VH), SEQ ID NO: 251 (Y0188-10 VH), SEQ ID NO: 252 (Y0188-14 VH), SEQ ID NO: 253 (HV3-15-14 VH), SEQ ID NO: 254 (HV3-48-14 VH), SEQ ID NO: 255 (HV3-73*2-14 VH), SEQ ID NO: 256 (HV3-72-14 VH), SEQ ID NO: 257 (Y01-14 HCVR containing the amino acid sequence of (VH), SEQ ID NO: 258 (162-14 VH), or SEQ ID NO: 259 (VH73-14 VH), and (ii) SEQ ID NO: 260 (Y0188-1 VL), SEQ ID NO: 261 (Y0188-2 VL), SEQ ID NO: 262 (Y0188-3 VL), SEQ ID NO: 263 (Y0188-4 VL), SEQ ID NO: 264 (Y0188-6 VL), SEQ ID NO: 265 (Y0188-8 VL), SEQ ID NO: 266 (Y0188-9 VL), SEQ ID NO: 267 (Y0188-10 VL), SEQ ID NO: 268 (Y0188-14 VL), SEQ ID NO: 269 (Y01-14 VL), SEQ ID NO: 270 (164-14 VL), SEQ ID NO: 271 (KV4-14 Includes LCVRs containing the amino acid sequences of VL, SEQ ID NO: 272 (KV1-27-14 VL), SEQ ID NO: 273 (KV1-9-14 VL), SEQ ID NO: 274 (KV1-NL1-14 VL), or SEQ ID NO: 275 (KV1D-43-14 VL).

[0075] In some embodiments, the anti-IL-4Rα antibodies used in the methods disclosed herein may have pH-dependent binding properties. For example, the anti-IL-4Rα antibodies for use disclosed herein may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, the anti-IL-4Rα antibodies for use disclosed herein may exhibit enhanced binding to the 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, 5.20, 5.15, 5.1, 5.05, 5.0, or less. As used herein, the term “neutral pH” means a pH of about 7.0 to about 7.4. The term "neutral pH" includes pH values ​​of approximately 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0076] In certain cases, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" indicates a decrease in antibody binding to IL-4Rα at acidic pH. D K value and antibody binding to IL-4Rα at neutral pH D It is expressed as a ratio to a value (and vice versa). For example, an antibody or its antigen-binding fragment is an acidic / neutral potassium (K) with an antibody or antigen-binding fragment of approximately 3.0 or higher. D Where a ratio is given, for the purposes of this disclosure, it may be considered to indicate "reduced binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K for the antibody or antigen-binding fragment of this disclosure D The ratio can be approximately 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or higher.

[0077] Antibodies with pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. Furthermore, antibodies with pH-dependent properties can be obtained by modifying the antigen-binding domain at the amino acid level. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues, antibodies with reduced antigen binding at acidic pH compared to neutral pH can be obtained.

[0078] Preparation of human antibodies Methods for producing human antibodies in transgenic mice are known in the art. Any of these known methods can be used in connection with the present disclosure to produce human antibodies that specifically bind to IL-4R.

[0079] Using VELOCIMMUNE® technology (see, for example, US6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies, a high-affinity chimeric antibody against IL-4R is initially isolated, possessing both a human variable region and a mouse constant region. VELOCIMMUNE® technology involves the creation of transgenic mice having a genome containing human heavy and light chain variable regions functionally ligated to an endogenous mouse constant region locus, so that the mice produce antibodies containing both human variable and mouse constant regions in response to antigen stimulation. The DNA encoding the heavy and light chain variable regions of the antibody is isolated and functionally ligated to the DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing a fully human antibody.

[0080] Generally, VELOCIMMUNE® mice are exposed to the target antigen, and lymphocytes (such as B cells) are collected from mice that express antibodies. Lymphocytes may be fused with myeloma cell lines to create immortalized hybridoma cell lines, and such hybridoma cell lines are selected and identified to produce hybridoma cell lines that produce antibodies specific to the target antigen. DNA encoding the variable regions of the heavy and light chains may be isolated and ligated to the constant regions of the desired isotypes of the heavy and light chains. Such antibody proteins may be produced in cells such as CHO cells. Alternatively, antigen-specific chimeric antibodies or DNA encoding the variable domains of the light and heavy chains may be directly isolated from antigen-specific lymphocytes.

[0081] First, a high-affinity chimeric antibody having a human variable region and a mouse constant region is isolated. The antibody is characterized and selected for desired features, including affinity, selectivity, and epitopes, using standard methods known to those skilled in the art. The mouse constant region is replaced with a desired human constant region to produce a fully human antibody of this disclosure, e.g., wild-type or modified IgG1 or IgG4. The selected constant region may vary depending on the specific application, but the high-affinity antigen-binding and target-specific properties reside in the variable region.

[0082] Generally, antibodies that can be used in the methods of this disclosure exhibit high affinity as described above when measured by binding to an antigen immobilized on either a solid or solution phase. The mouse constant region is replaced with a desired human constant region to produce the fully human antibody of this disclosure. The selected constant region may vary depending on the specific application, but the high affinity antigen-binding and target specificity properties reside in the variable region.

[0083] In one embodiment, a human antibody or its antigen-binding fragment, which specifically binds to IL-4R and can be used in the manner disclosed herein, comprises three heavy-chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy-chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1, and three light-chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light-chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary standard methods that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Under general conditions, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia methods. See, for example, 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.

[0084] Pharmaceutical compositions and kits In one embodiment, the present disclosure provides a method comprising administering an IL-4R antagonist to a target, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained within a pharmaceutical composition comprising one or more pharmaceutically acceptable vehicles, carriers, and / or excipients. Various pharmaceutically acceptable carriers and excipients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.

[0085] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, such as injection or bolus injection, by absorption through the epithelium or mucocutaneous lining (e.g., oral mucosa, rectal and intestinal mucosa), and may be administered together with other bioactive substances. In some embodiments, the pharmaceutical compositions described herein are administered intravenously. In some embodiments, the pharmaceutical compositions described herein are administered subcutaneously.

[0086] In some embodiments, the pharmaceutical composition includes injectable preparations, such as dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection and drip infusion. These injectable preparations can be prepared by known methods. For example, an injectable preparation may be prepared by dissolving, suspending, or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injection. Examples of aqueous media for injection include physiological saline, isotonic solutions containing glucose and other adjuvants, which may be used in combination with suitable solubilizers, such as alcohol (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. Examples of oily media include sesame oil and soybean oil, which may be used in combination with solubilizers, such as benzylbenzoic acid and benzyl alcohol. Thus, the injectable preparation can be filled into a suitable ampoule.

[0087] The dose of antibody administered to a subject according to the method of this disclosure may vary depending on the subject's age and size, symptoms, condition, and route of administration. The dose is usually calculated based on body weight or body surface area. The frequency and duration of treatment may be adjusted depending on the severity of the condition. Effective doses and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies may be determined empirically. For example, the subject's progress may be monitored by periodic assessments, and the dose may be adjusted accordingly. Furthermore, interspecies scaling of doses can be performed using methods well known in the art (e.g., Mordenti, et al., 1991, Pharmaceut. Res., 8:1351). Specific exemplary doses of anti-IL-4R antibodies that may be used in connection with this disclosure, and administration regimens containing them, are disclosed elsewhere herein.

[0088] In some embodiments, the IL-4R antagonist or pharmaceutical composition of this disclosure is contained in a container. Thus, in another embodiment, a container containing the IL-4R antagonist or pharmaceutical composition disclosed herein is provided. For example, in some embodiments, the pharmaceutical composition is contained in a container selected from the group consisting of glass vials, syringes, pen-type delivery devices, and autoinjectors.

[0089] In some embodiments, the pharmaceutical compositions of the Disclosure are delivered subcutaneously or intravenously, for example, using a standard needle and syringe. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, a pen-type delivery device or auto-injector is used to deliver the pharmaceutical compositions of the Disclosure (for example, for subcutaneous delivery). The pen-type delivery device may be reusable or disposable. Typically, reusable pen-type delivery devices utilize a replaceable cartridge containing the pharmaceutical composition. Once the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen-type delivery device can then be reused. In disposable pen-type delivery devices, there is no replaceable cartridge. Rather, disposable pen-type delivery devices are manufactured with the pharmaceutical composition pre-filled, which is contained in a reservoir within the device. Once the pharmaceutical composition has been dispensed and the reservoir is empty, the entire device is discarded.

[0090] Examples of suitable pen-type delivery devices and auto-injector delivery devices include 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®, and OPTIPEN Examples of disposable pen-type delivery devices used for subcutaneous delivery of the pharmaceutical compositions of this disclosure include, but are not limited to, STARLET® and OPTICLIK® (sanofi-aventis, Frankfurt, Germany).

[0091] In some embodiments, the pharmaceutical composition is delivered using a controlled-release system. In one embodiment, a pump may be used (see Langer, op. cit., Sefton, 1987, CRC Crit.Ref.Biomed.Eng.14:201). In another embodiment, a polymer material may be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Press, Boca Raton, Florida). In yet another embodiment, the controlled-release system may be positioned near the target of the composition, thereby requiring only a portion of the systemic dose (see, for example, Goodson, 1984, Medical Applications of Controlled Release (op. cit.), vol.2, pp.115-138). Other controlled-release systems are described in the overview by Langer, 1990, Science, 249:1527-1533. For example, other delivery systems such as liposome encapsulation, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432) are known and can be used to administer pharmaceutical compositions.

[0092] In some embodiments, the pharmaceutical composition containing an anti-IL-4R antibody is administered using a drug delivery device, which 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 classified into multi-dose container systems and single-dose (partial or full-dose) container systems. The container may be replaceable or a one-piece, non-replaceable container.

[0093] As further described in ISO 11608-1:2014(E), a multi-dose container system may include a needle-based injection device with replaceable containers. In such a system, each container holds a multi-dose, and its size may be fixed or variable (pre-set by the user). Another multi-dose container system may include a needle-based injection device with a single, non-replaceable container. In such a system, each container holds a multi-dose, and its size may be fixed or variable (pre-set by the user).

[0094] As further described in ISO 11608-1:2014(E), a single-dose container system may include a needle-based injection device with replaceable containers. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (total discharge). In a further example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partial discharge). As also described in ISO 11608-1:2014(E), a single-dose container system may include a needle-based injection device with a single, non-replaceable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (total discharge). In a further example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partial discharge).

[0095] An exemplary sleeve-operated auto-injector for manual needle insertion is described in International Publication WO2015 / 004052. Feedback mechanisms for audibly signaling the end of administration are described in International Publications WO2016 / 193346 and WO2016 / 193348. An exemplary needle safety mechanism after using an auto-injector is described in International Publication WO2016 / 193352. An exemplary needle cap removal mechanism for a syringe auto-injector is described in International Publication WO2016 / 193353. An exemplary support mechanism for supporting the axial position of a syringe is described in International Publication WO2016 / 193355.

[0096] In some embodiments, the pharmaceutical compositions for use described herein are prepared into dosage forms in unit doses adjusted to the dose of the active ingredient. Examples of such dosage forms in unit doses include tablets, pills, capsules, injections (ampoules), and suppositories.

[0097] Exemplary pharmaceutical compositions containing an anti-IL-4R antibody that may be used in connection with this disclosure are disclosed, for example, in U.S. Patent No. 8,945,559.

[0098] In another embodiment, a kit comprising an IL-4R antagonist or pharmaceutical composition disclosed herein is provided. In some embodiments, the kit comprises an anti-IL-4R antibody, or a pharmaceutical composition comprising an anti-IL-4R antibody, and instructions for its use in the treatment of eosinophilic gastroenteritis in a subject. In some embodiments, the instructions for use include administering the anti-IL-4R antibody or pharmaceutical composition in amounts, frequencies, and / or durations disclosed elsewhere herein.

[0099] Dosage and administration In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered to a subject (e.g., a subject having EGE, EoG, or EoD) in a therapeutically effective dose according to the method of this disclosure. As used herein with respect to IL-4R antagonists, the term “therapeutic dose” means the amount of IL-4R antagonist that results in one or more of the following: (a) reduction in the severity or duration of one or more symptoms of eosinophilic gastroenteritis (e.g., EoG and / or EoD); (b) a decrease in the number of eosinophils in a region of the gastrointestinal tract (e.g., stomach or small intestine); (c) improvement in one or more anatomical, endoscopic, or histological features of the gastrointestinal tract (e.g., stomach or small intestine); (d) normalization of one or more EGE-related biomarkers or gene expression signatures; and / or (e) a reduction in the use or need for concomitant or rescue treatment with another drug (e.g., a reduction or elimination of the use of systemic and / or topical corticosteroids).

[0100] For anti-IL-4R antibodies, the effective therapeutic dose is approximately 0.05 mg to 600 mg, 50 mg to 600 mg, 50 mg to 300 mg, or 100 mg to 300 mg, for example, approximately 0.05 mg, 0.1 mg, 1.0 mg, 1.5 mg, 2.0 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, and 24 mg. This may be 0 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, or approximately 600 mg of anti-IL-4R antibody. In some embodiments, the therapeutically effective dose is approximately 50 mg to 600 mg, or approximately 100 mg to 600 mg, or approximately 50 mg to 400 mg. In certain embodiments, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 300 mg of anti-IL-4R antibody is administered to the target.

[0101] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in individual doses may be expressed in milligrams of antibody per kilogram of body weight of the subject (i.e., mg / kg). For example, an IL-4R antagonist may be administered to a subject in doses ranging from approximately 0.0001 to approximately 10 mg / kg of body weight, for example, from approximately 1 mg / kg to approximately 10 mg / kg, from approximately 2 mg / kg to approximately 9 mg / kg, or from approximately 3 mg / kg to approximately 8 mg / kg. In some embodiments, an IL-4R antagonist may be administered to a subject in doses of approximately 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.

[0102] In certain embodiments, the methods disclosed herein include administering an IL-4R antagonist to a target at a frequency of administration of approximately four times per week, twice per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or at a frequency less frequent than that whichever is less frequent. In some embodiments, the methods disclosed herein include administering an IL-4R antagonist to a target once per week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody disclosed herein) is administered once weekly (QW), every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W) in amounts ranging from approximately 50 mg to approximately 600 mg, for example, approximately 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg.

[0103] In some embodiments, multiple doses of IL-4R antagonist are administered to a subject over a specified time period. In some embodiments, the method of the present disclosure includes administering multiple doses of IL-4R antagonist to a subject sequentially. As used herein, “administered sequentially” means that each dose of IL-4R antagonist is administered to the subject at different times, for example, on different days divided by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the method of the present disclosure includes administering a single initial dose of IL-4R antagonist, followed by one or more secondary doses of IL-4R antagonist, and optionally one or more subsequent tertiary doses of IL-4R antagonist, to a patient sequentially.

[0104] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the chronological order of administration of the IL-4R antagonist. Therefore, the “initial dose” is the dose administered at the start of the treatment regimen (also called the “loading dose”), the “secondary dose” is the dose administered after the initial dose, and the “tertiary dose” is the dose administered after the secondary dose. While the initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, they may generally differ from one another in terms of administration frequency. However, in certain embodiments, the amounts of IL-4R antagonist contained in the initial, secondary, and / or tertiary doses may vary from one another during the course of treatment (e.g., adjusted upward or downward as needed). In some embodiments, one or more doses (e.g., two, three, four, or five) are administered as a “loading dose” at the beginning of the treatment regimen, followed by subsequent doses (e.g., “maintenance doses”) administered at a lower frequency. In some embodiments, the initial or loading dose and one or more secondary or maintenance doses each contain an equal amount of IL-4R antagonist. In other embodiments, the initial dose contains a first amount of IL-4R antagonist, and one or more secondary doses each contain a second amount of IL-4R antagonist. For example, the first amount of IL-4R antagonist may be 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times, or more, the second amount of IL-4R antagonist. In some embodiments, one or more maintenance doses of IL-4R antagonist are administered without a loading dose.

[0105] In some embodiments, the loading dose is a “divided dose” administered as two or more doses given on separate days (e.g., two, three, four, or five doses). In some embodiments, the loading dose is administered as a divided dose, where the two or more doses are given at intervals of at least about one week. In some embodiments, the loading dose is administered as a divided dose, where the two or more doses are given at intervals of about one, two, three, or four weeks. In some embodiments, the loading dose is divided evenly over two or more doses (e.g., half of the loading dose is given as the first part and the other half as the second part). In some embodiments, the loading dose is divided unevenly over two or more doses (e.g., more than half of the loading dose is given as the first part and less than half as the second part).

[0106] In some embodiments, each of the secondary and / or tertiary doses is administered 1 to 14 weeks after the immediately preceding dose (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 weeks or more). The term "immediately preceding dose," as used herein, means the dose of the IL-4R antagonist administered to the patient before a series of subsequent doses without an intervening dose in a series of multiple doses.

[0107] The methods of this disclosure may include administering any number of secondary and / or tertiary doses of an IL-4R antagonist to a patient. For example, in one particular embodiment, only a single secondary dose is administered to the patient. In another embodiment, two or more secondary doses (e.g., two, three, four, five, six, seven, eight, or more) are administered to the patient. Similarly, in one particular embodiment, only a single tertiary dose is administered to the patient. In another embodiment, two or more tertiary doses (e.g., two, three, four, five, six, seven, eight, or more) are administered to the patient.

[0108] In some embodiments involving multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient one, two, three, or four weeks after the previous dose. Similarly, in some embodiments involving multiple tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient one, two, three, or four weeks after the previous dose. Alternatively, the frequency with which secondary and / or tertiary doses are administered to the patient may vary across the treatment regimen. The administration frequency may also be adjusted by the physician during the course of treatment according to the individual patient's needs after clinical examinations.

[0109] In some embodiments, for subjects with eosinophilic gastroenteritis (e.g., EoG and / or EoD), the therapeutically effective dose of an IL-4R antagonist (e.g., anti-IL-4R antibody) includes 300 mg administered weekly (QW). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, e.g., 600 mg, is administered.

[0110] In some embodiments, for subjects with eosinophilic gastroenteritis (e.g., EoG and / or EoD), the therapeutically effective dose of an IL-4R antagonist (e.g., anti-IL-4R antibody) includes 300 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, e.g., 600 mg, is administered.

[0111] Therapeutic dosage form In another embodiment, the Disclosure provides therapeutic formulations of IL-4R antagonists (e.g., anti-IL-4R antibodies or their antigen-binding fragments) for use in treating subjects having eosinophilic gastroenteritis (e.g., EoG and / or EoD) as disclosed herein. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment having one or more CDR, HCVR, and / or LCVR sequences listed in Table 1. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or its antigen-binding fragment (e.g., dupilumab) having an HCDR of HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCDR of LCVR containing the amino acid sequence of SEQ ID NO: 2.

[0112] In some embodiments, the therapeutic dose is 300 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody) administered weekly (QW).

[0113] In some embodiments, the therapeutic dose is 300 mg of an IL-4R antagonist (e.g., an anti-IL-4R antibody), administered every two weeks (Q2W).

[0114] EGE-related parameters In some embodiments, the therapeutic methods disclosed herein result in improvement of one or more evaluation items or EGE-related parameters used to assess the presence or severity of EGE (e.g., EoG with or without EoD) in a subject. Examples of EGE-related parameters include, but are not limited to, (a) changes (e.g., decreases) in eosinophil count (e.g., gastric eosinophil count or duodenal eosinophil count), (b) changes in the severity and / or degree of histological features in the gastrointestinal tract (e.g., stomach or small intestine) as measured, for example using EoGHSS or EoDHSS, or (c) one or more gastrointestinal characteristics as measured, for example using EG-REFS or ED-REFS. (d) changes in the levels of one or more EGE-related biomarkers or changes in the EGE gene expression signature (e.g., normalization), (e) changes in the frequency and / or intensity of symptoms (e.g., reduction) as measured using, for example, the EoG / EoD Symptom Questionnaire (EoG / EoD-SQ), Patient's General Impression of Change (PGI-C), Patient's General Impression of Severity (PGI-S), Clinician's General Impression of Change (CGI-C), Clinician's General Impression of Severity (CGI-S), EoG / EoD Quality of Life Questionnaire (EoG / EoD QoL), or the European Quality of Life 5-Perspective 5-Point Scale (EQ-5D-5L). Methods for evaluating these and other EGE-related parameters are described in the Examples section below.

[0115] To determine whether EGE-related parameters have "improved," the parameters are quantified at baseline (e.g., before initiation of treatment with an IL-4R antagonist) and at one or more time points after administration of the IL-4R antagonist. For example, EGE-related parameters may be measured on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85, or week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or thereafter, after the initial treatment with the pharmaceutical composition of this disclosure. The difference between the parameter value at a specific point in time after the start of treatment and the parameter value at baseline is used to determine whether the EGE-related parameter has improved.

[0116] In some embodiments, treatment of the target with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement (e.g., a decrease) in the maximum gastric eosinophil count or the maximum duodenal eosinophil count. "Maximum eosinophil count" refers to the number of eosinophils contained in one high-magnification field (hpf).

[0117] In some embodiments, treatment with an IL-4R antagonist results in a reduction of the maximum gastric eosinophil count compared to baseline (e.g., the maximum number of subjects before the start of treatment). In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to baseline. In some embodiments, treatment with an IL-4R antagonist reduces the maximum gastric eosinophil count to less than 30 eos / hpf, for example, ≤20 eos / hpf, ≤15 eos / hpf, ≤10 eos / hpf, or ≤6 eos / hpf. In some embodiments, treatment with an IL-4R antagonist reduces the maximum gastric eosinophil count to ≤6 eos / hpf, ≤5 eos / hpf, ≤4 eos / hpf, ≤3 eos / hpf, ≤2 eos / hpf, or ≤1 eos / hpf. In some embodiments, treatment with an IL-4R antagonist results in histological remission of the disease. In some embodiments, the change in maximum gastric eosinophil count is measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of the IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist.

[0118] In some embodiments, treatment with an IL-4R antagonist results in a reduction of the maximum duodenal eosinophil count compared to baseline (e.g., the maximum number of subjects before the start of treatment). In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the maximum duodenal eosinophil count compared to baseline. In some embodiments, treatment with an IL-4R antagonist reduces the maximum duodenal eosinophil count to less than 30 eos / hpf, for example, ≤20 eos / hpf, ≤15 eos / hpf, ≤10 eos / hpf, or ≤6 eos / hpf. In some embodiments, treatment with an IL-4R antagonist reduces the maximum duodenal eosinophil count to ≤6 eos / hpf, ≤5 eos / hpf, ≤4 eos / hpf, ≤3 eos / hpf, ≤2 eos / hpf, or ≤1 eos / hpf. In some embodiments, treatment with an IL-4R antagonist results in histological remission of the disease. In some embodiments, the change in maximum duodenal eosinophil count is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or thereafter after administration of the IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist.

[0119] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of one or more histological features of the EGE (e.g., EoG and / or EoD). In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of the EoG score (EoGHSS) of a histological scoring system. In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of the EoD score (EoDHSS) of a histological scoring system.

[0120] The EoGHSS score assesses 11 features of gastric tissue: lamina propria eosinophilic sheet-like infiltration, periglandular collar, eosinophils in the superficial epithelium, eosinophilic adenitis, eosinophilic abscess, eosinophils in the muscularis mucosa and submucosa, lamina propria fibrosis, lamina propria smooth muscle thickening, reactive epithelial changes, acute inflammation, and superficial erosion / ulceration. In some embodiments, each feature is assigned a score from 0 to 3 (0 = normal, 3 = maximum change), and the total score is the sum of the feature scores divided by the maximum possible score. In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the EoGHSS score compared to baseline (e.g., the subject's EoGHSS score before the start of treatment). In some embodiments, changes in the EoGHSS score are measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of the IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist.

[0121] The EoDHSS score assesses 11 features of duodenal tissue: lamina propria eosinophilic sheet-like infiltration, pericryptial annular collar, eosinophils in superficial epithelium, eosinophilic cryptitis, subcryptal eosinophil aggregation, subcryptal lymphoplasmacytic inflammation, eosinophilic crypt abscess, eosinophils in muscularis mucosa / submucosa, villous atrophy, crypt elongation, reactive epithelial changes, acute inflammatory cells, superficial erosion / ulceration, and intraepithelial lymphocytosis. In some embodiments, each feature is assigned a score of 0 to 3 (0=normal, 3=maximum change), and the total score is the sum of feature scores divided by the maximum possible score. In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the EoDHSS score compared to baseline (e.g., the subject's EoDHSS score before the start of treatment). In some embodiments, changes in the EoDHSS score are measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of the IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist.

[0122] In some embodiments, treatment of the target with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of one or more endoscopic features of EGE, such as inflammatory or remodeling features in the stomach or duodenum. In some embodiments, treatment of the target with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement of the EG-REFS score (for EoG patients), ED-REFS score (for EoD patients), or EoE-EREFS score (for patients with comorbid EoE).

[0123] The EoG Endoscopic Reference Score (EG-REFS) is an endoscopic assessment system developed specifically to evaluate eosinophilic gastritis and completed by an endoscopist. It is used in therapeutic trials and captures particle size (0-2 scale), erosion / ulcer (0-6), elevated lesions (0-2), erythema (0-2), easy bleeding / bleeding (0-2), as well as folds of the gastric fundus, body, and pyloric sinuses (0-1). Pyloric stenosis (0-1) is also captured. The maximum value for the EG-REF total score is 46. In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the EG-REFS score compared to baseline (e.g., the subject's EG-REFS score before the start of treatment). In some embodiments, changes in the EG-REFS score are measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of an IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with an IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in an improvement in one or more EG-REFS subscores.

[0124] The EoD Endoscopic Reference Score (ED-REFS) is an endoscopic assessment system developed specifically to evaluate eosinophilic duodenitis and completed by an endoscopist. It is used in therapeutic trials and captures particle size (0–2 scale), erythema (0–2), bleeding / bleeding (0–2), ulceration (0–4), ecchymal delamination (0–2), and stricture (0–2). The maximum value for the ED-REF total score is 14. In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the ED-REFS score compared to baseline (e.g., the subject's ED-REFS score before the start of treatment). In some embodiments, changes in the ED-REFS score are measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, and 113 after administration of the IL-4R antagonist, or thereafter, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist. In some embodiments, treatment with the IL-4R antagonist results in an improvement in one or more ED-REFS subscores.

[0125] EoE-EREFS (Edema, Crinoid Sulcus, Exudate, Longitudinal Sulcus, Stenosis) is a validated scoring system for disease inflammatory and remodeling features used to measure the inflammatory and remodeling features of EoE esophageal mucosa identified endoscopically (Hirano, et al., Gut, 2013, 62:489-495). In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more EoE-EREFS score compared to baseline (e.g., the subject's EoE-EREFS score before the start of treatment). In some embodiments, changes in the EoE-EREFS score are measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of an IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with an IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in an improvement in one or more EoE-EREFS subscores.

[0126] In some embodiments, treatment of a target with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in the normalization of the normalized enrichment score (NES) calculated for one or more EGE-related biomarkers, eosinophilic gastritis diagnostic panel (EGDP) gene signatures, type 2 inflammatory gene signatures, and / or EGE-related genes (e.g., EoG-related genes or EoD-related genes). In some embodiments, treatment of a target with an IL-4R antagonist suppresses the NES calculated for the EGDP gene signature, type 2 inflammatory gene signature, and / or EGE-related or type 2 inflammatory gene set. As used herein, the term “EGE-related biomarker” refers to a biological response, cell type, parameter, protein, polypeptide, enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or other biomolecule that is present or detectable in EGE patients at levels or amounts different (e.g., greater or less) than the levels or amounts of a marker present or detectable in non-EGE patients. Exemplary EGE-related biomarkers include, but are not limited to, gastric or duodenal eosinophils, cytokines / chemokines (CCL11, CCL18, CCL24, CCL26, IL13RA2, and IL5), eosinophilia (CLC), cell adhesion (CDH26), antimicrobial defense (KLK7, DEFB1), epithelial-related processes (MUC4), fibrosis (BMP3 and COL2A1), ion transport (SLC26A7), neuronal sensory activity (GABRA1, GLDN, NPY, and TAC1), and gastric-related processes (ATP4A and SST). The term “EGE gene signature” refers to the differential gene expression profile of gastric biopsies from EGE (e.g., EoG with or without EoD) patients compared to healthy controls, and is also referred to as the “EGE disease transcriptome” (Caldwell, et al., J Allergy Clin Med, 2014, 134:1114-1124). In some embodiments, the EGE gene signature is a differential gene expression profile associated with EoG, and is also referred to herein as the “EoG disease transcriptome” or “EoG gene signature”.In some embodiments, the EGE gene signature is a smaller set of genes, such as the EGDP panel (Shoda, et al., J Allergy Clin Med, 2020, 145:255-269). The “type 2 inflammation gene signature” refers to the transcriptome of a set of genes associated with type 2 inflammation. Exemplary type 2 inflammation-associated genes include, but are not limited to, CCL26, ALOX15, CCR3, and IL1RL1. An exemplary gene list of type 2 inflammation gene signatures is shown in WO2021 / 237110, which is incorporated herein by reference. The normalized enrichment score (NES) reflects the extent to which the activity levels of a set of transcripts are overrepresented at the ends (upper or lower) of the overall ranked list of transcripts in the sample, and is normalized to account for the number of transcripts in the set (Subramanian, et al., Proc Natl Acad Sci USA, 2005, 102:15545-50) (Barbie, et al., Nature, 2009, 462:108-112).

[0127] In some embodiments, EGE-related biomarkers, EGE gene signatures, type 2 inflammatory gene signatures, and / or NES are measured using tissue samples derived from the subject (e.g., gastric or duodenal biopsy samples). In some embodiments, treatment of the subject with an IL-4R antagonist results in the normalization of one or more EGE-related biomarkers, EGE gene signatures, type 2 inflammatory gene signatures, and / or NES compared to baseline (e.g., the subject's expression levels of EGE-related biomarkers, EGE gene signatures, or NES before the start of treatment) when measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of the IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist. In some embodiments, treatment of a subject with an IL-4R antagonist suppresses the NES of one or more EGE-related biomarkers, EGE gene signatures, or type 2 inflammatory gene signatures compared to baseline (e.g., the subject's NES before the start of treatment) when measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of an IL-4R inhibitor, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with an IL-4R antagonist.

[0128] In some embodiments, treatment of the target with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in the alleviation of one or more other signs or symptoms of EGE (e.g., EoG and / or EoD), or an improvement in health-related quality of life.

[0129] In some embodiments, the treatment results in an improvement in the EoG / EoD Symptom Questionnaire score. The EoG / EoD-SQ is a novel PRO metric designed to be collected daily and developed to assess EoG symptoms (with or without EoD) reported by adult and adolescent participants. The EoG / EoD-SQ assesses nine symptoms of EoG (with or without EoD): stomach pain, stomach cramps, nausea, heartburn, flatulence, early satiety, loss of appetite, vomiting, and diarrhea. The severity of stomach pain, stomach cramps, nausea, heartburn, flatulence, early satiety, and loss of appetite is assessed using an 11-point numerical rating scale (NRS, 0-10), while for vomiting and diarrhea, the frequency of episodes is assessed. A higher score indicates a higher symptom burden. The severity scores reported by participants for each symptom of the Total Symptom Score (TSS) (stomach pain, stomach cramps, nausea, flatulence, early satiety, loss of appetite; each reported on a scale of 0 to 10) are summed daily using eDiary data (maximum daily score of 60). The TSS is then calculated by averaging the daily sum scores over all days using eDiary data over a 7-day period. The maximum TSS is 60. Heartburn is excluded from the TSS because it may be misinterpreted as esophageal dysfunction, while the other symptoms are localized to the stomach / small intestine (site of eosinophilic inflammation in EoG [with or without EoD]). In some embodiments, subjects have a baseline EoG / EoD-SQ TSS of 20 or higher prior to the initiation of treatment, e.g., a baseline TSS of at least 25, 30, 35, or 40. In some embodiments, subjects have a baseline mean severity score of 4 or higher for at least two components of the EoG / EoD-SQ TSS (i.e., two or more of the components: stomach pain, stomach cramps, nausea, flatulence, early satiety, and loss of appetite) before the initiation of treatment. In some embodiments, subjects have a baseline mean severity score of 4 or higher for at least two, at least four, at least five, or all six components of the EoG / EoD-SQ TSS.In some embodiments, subjects have a baseline mean severity score of 5 or greater for at least two, at least four, at least five, or all six components of the EoG / EoD-SQ TSS. In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or greater in the EoG / EoD-SQ score compared to baseline. In some embodiments, the change in the EoG / EoD-SQ score is measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of the IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in a reduction in the number of days with one or more EGE signs or the total number of segments within a day (e.g., night, morning, afternoon, evening) as measured by EoG / EoD-SQ. In some embodiments, treatment with an IL-4R antagonist results in an improvement in one or more signs / symptoms as measured by EoG / EoD-SQ.

[0130] In some embodiments, the treatment results in an improvement in the PGI-C score. The patient's overall impression of change (PGI-C) is a 10-item PRO metric that uses a 7-point response scale (from "very good" to "very bad") to assess the participant's impression of the overall change (improvement or worsening) in EoG symptoms (with or without EoD) since the start of the study treatment, and the change in individual EoG / EoD symptoms. In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the PGI-C score compared to baseline. In some embodiments, the change in PGi-C score is measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of an IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with an IL-4R antagonist.

[0131] In some embodiments, the treatment results in an improvement in the PGI-S score. The Patient's Overall Impression of Severity (PGI-S) is a 10-item PRO metric that uses a 5-point response scale (from "none" to "very severe") to assess the participant's impression of the overall severity of EoG symptoms (with or without EoD) over the past 7 days, and the severity of individual EoG / EoD symptoms. In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the PGI-S score compared to baseline. In some embodiments, changes in the PGI-S score are measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of an IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with an IL-4R antagonist.

[0132] In some embodiments, the treatment results in an improvement in the CGI-C score. The Clinician's Overall Impression of Change (CGI-C) is a single-item observer-reported outcome metric that assesses the investigator's / clinician's impression of the overall change (improvement or deterioration) in the participant's EoG (with or without EoD) since the start of the study treatment, using a 7-point response scale (from "greatly improved" to "greatly worsened"). In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the CGI-C score compared to baseline. In some embodiments, changes in the CGI-C score are measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of an IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with an IL-4R antagonist.

[0133] In some embodiments, the treatment results in an improvement in the CGI-S score. The Clinician General Impression of Severity (CGI-S) is a single-item observer-reported outcome metric that assesses the investigator / clinician's impression of the overall severity of a participant's End-of-G (with or without EoD), based on the participant's assessment on the questionnaire completion day, using a four-point response scale (from “mild” to “severe”). In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the CGI-S score compared to baseline. In some embodiments, changes in the CGI-S score are measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of an IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with an IL-4R antagonist.

[0134] In some embodiments, the treatment results in an improvement in the EoG / EoD Quality of Life (EoG / EoD QoL) score. The EoG / EoD QoL is a disease-specific metric for health-related QoL in EoG patients (with or without EoD) developed by the sponsor. The EoG / EoD QoL measures the impact of EoG (with or without EoD) on emotional, social, functional, work and education, and sleep. Participants rate the degree of impact over the past 7 days using a 5-point scale (ranging, where appropriate, from “not affected at all” to “very affected,” or from “never affected” to “always affected.” In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the EoG / EoD QoL score compared to baseline. In some embodiments, changes in EoG / EoD QoL scores are measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of an IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with an IL-4R antagonist.

[0135] In some embodiments, the treatment results in an improvement in the European Quality of Life 5-Perspective 5-Point Scale (EQ-5D-5L) score. EQ-5D-5L is a standardized questionnaire used to assess health status (Brooks, 1996) (Rabin, et al., Value Health, 2014, 17:70-76). It consists of a descriptive system and an EQ visual analog scale (EQ VAS). The descriptive system includes five perspectives: mobility, self-care, routine activities, pain / discomfort, and anxiety / depression. For each perspective, participants select one of five levels (no problem, minor problem, moderate problem, severe problem, and severe problem). The EQ VAS records participants' self-reported health status on a vertical visual analog scale, with assessment items labeled "best possible health" and "worst possible health." In some embodiments, treatment with an IL-4R antagonist results in an improvement of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more in the EQ-5D-5L score compared to baseline. In some embodiments, the change in the EQ-5D-5L score is measured at 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 days or thereafter after administration of the IL-4R antagonist, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist.

[0136] Combination therapy In some embodiments, the methods of the present disclosure involve administering an IL-4R antagonist according to the present disclosure (e.g., an anti-IL-4R antibody) to a subject (e.g., a subject having EGE) in combination with one or more additional therapeutic agents. As used herein, the expression “in combination with” means that the additional therapeutic agent is administered before, after, or concurrently with the pharmaceutical composition comprising the IL-4R antagonist. The term “in combination with” also includes sequential or concomitant administration of the IL-4R antagonist and the second therapeutic agent or therapy.

[0137] For example, when administered "before" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 72 hours, 60 hours, 48 ​​hours, 36 hours, 24 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes before the administration of the pharmaceutical composition containing the IL-4R antagonist. When administered "after" a pharmaceutical composition containing an IL-4R antagonist, the additional therapeutic agent may be administered approximately 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, or 72 hours after the administration of the pharmaceutical composition containing the IL-4R antagonist. "Concurrent" administration or administration with a pharmaceutical composition containing an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within approximately 10 minutes of (before, after, or simultaneously with) the administration of the pharmaceutical composition containing an IL-4R antagonist, or that it is administered to the subject as a single combination formulation containing both the additional therapeutic agent and the IL-4R antagonist.

[0138] In some embodiments, the second therapeutic agent or therapy is an IL-1β inhibitor, an IL-5 or IL-5R inhibitor (e.g., an anti-IL-5 or anti-IL-5R antibody such as benralizumab, mepolizumab, or reslizumab), an IL-9 inhibitor, an IL-13 inhibitor (e.g., an anti-IL-13 antibody such as tralokinumab, RPC4046, or QAX576), an IL-17 inhibitor, an IL-25 inhibitor, a TNFα inhibitor (e.g., an anti-TNFα antibody such as infliximab or adalimumab), an eotaxin-3 inhibitor, an IgE inhibitor (e.g., an anti-IL-5 or anti-IL-5R antibody such as omalizumab), These include anti-IgE antibodies, TSLP inhibitors (e.g., anti-TSLP antibodies such as tezeperumab), CRTH2 inhibitors, Siglec-8 inhibitors, prostaglandin D2 inhibitors, integrin inhibitors (e.g., integrin α4β7 inhibitors such as vedolizumab), eotaxin inhibitors, immunosuppressants, topical corticosteroids, oral corticosteroids, systemic corticosteroids, inhaled corticosteroids, glucocorticoids, PPIs, decongestants, antihistamines, leukotriene inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), allergen elimination, or dietary management. In some embodiments, IL-4R antagonists are used in combination with dietary management. In some embodiments, IL-4R antagonists are used in combination with PPIs, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole. In some embodiments, the IL-4R antagonist is used in combination with a topical corticosteroid for swallowing, such as budesonide or fluticasone. In some embodiments, the IL-4R antagonist is used in combination with a systemic corticosteroid, such as prednisone or prednisolone.

[0139] In some embodiments, administration of an IL-4R antagonist reduces dependence on or the need to use concomitant therapy (e.g., systemic corticosteroids or swallowing topical corticosteroids). In some embodiments, administration of an IL-4R antagonist in combination with a second therapy reduces the amount of the second therapy used by the patient by at least 20%, at least 30%, at least 40%, or at least 50% compared to the amount used by the subject before treatment with the IL-4R antagonist. In some embodiments, administration of an IL-4R antagonist eliminates the need for the second therapy.

[0140] In some embodiments, the method of the present disclosure comprises administering to a subject (e.g., a subject having EGE, EoG, or EoD) a combination therapy comprising (i) an IL-4R antagonist according to the present disclosure (e.g., an anti-IL-4R antibody) and (ii) a systemic corticosteroid or a swallowing topical corticosteroid. In some embodiments, the combination therapy comprises an IL-4R antagonist according to the present disclosure (e.g., an anti-IL-4R antibody) and a systemic corticosteroid (e.g., prednisone or prednisolone). In some embodiments, the combination therapy comprises an IL-4R antagonist according to the present disclosure (e.g., an anti-IL-4R antibody) and a swallowing topical corticosteroid (e.g., budesonide or fluticasone). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21

Example

[0141] The following examples are provided to give a complete disclosure and description of the methods and compositions of this disclosure to those skilled in the art, and are not intended to limit the scope that inventors consider to be their own invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantity, temperature, etc.), but some experimental error and deviation should be taken into consideration. Unless otherwise indicated, parts are parts by weight, molecular weight is the average molecular weight, temperature is Celsius, and pressure is atmospheric pressure or close to it.

[0142] Example 1: Effect of IL-4R inhibition in a mouse model of eosinophilic gastritis In vivo experiments were conducted to evaluate the effect of prophylactic blockade of IL-4Rα in a mouse model of eosinophilic gastritis induced by overexpression of mouse interleukin-25 (mIL-25). Overexpression of mIL-25 induces eosinophilia and type 2-driven pathology in gastric tissue. Therefore, a mouse model of eosinophilia, including eosinophilic gastritis, was generated using mIL-25 overexpression.

[0143] mIL-25 overexpression was induced using hydrodynamic delivery (HDD) of 25 μg of plasmid DNA. Mice were administered either mIL-25 or a vector control via HDD on day 0. Blockade of IL-4Rα in this mouse model was mediated using the antibody REGN1103 against mouse IL-4Rα, administered via subcutaneous (SC) injection on days -4, 1, and 3. REGN1103 is a monoclonal antibody specific to mouse IL-4Rα, possessing binding and functional properties similar to dupilumab in humans. REGN1103 has the HCVR sequence of SEQ ID NO: 276 and the LCVR sequence of SEQ ID NO: 277. Mice were sacrificed on day 8 (i.e., 8 days after induction of mIL-25 overexpression and 5 days after the last antibody administration), and pathological conditions associated with mIL-25 overexpression in gastric tissue were assayed by flow cytometry, determination of eotaxin mRNA levels, and histology.

[0144] Flow cytometry: To enable flow cytometry analysis of circulating immune cells versus tissue-infiltrating cells in the lungs, mice were intravenously injected with BV650 anti-CD45 five minutes before sacrifice to selectively label immune cells still in the vascular system, while cells infiltrating gastric cells were not labeled. Dissected gastric tissue was then stained with a mixture of antibodies containing the same clone of anti-CD45 antibody injected before sacrifice, but conjugated to a different fluorophore (BV786 anti-CD45). This ex vivo CD45 stain preferentially labels cells present in the gastric tissue that were protected from the in vivo injected CD45 antibody.

[0145] Longitudinal sections of gastric tissue were removed and placed in ice-cold enzyme digestion solution (0.6% FBS, 0.5 mg / ml collagenase D, 0.1 mg / ml DNase I, and 1 mg / ml dispase II in HBSS without calcium and magnesium). The gastric tissue was cut into small pieces with scissors and transferred to a conical tube with additional enzyme digestion solution, and incubated at 37°C for 45 minutes with shaking. After incubation, the sample was dissociated, filtered through a 70 μm mesh, collected, and pelletized by centrifugation at 4°C. The supernatant was removed, and the sample cells were resuspended in Dulbecco's phosphate-buffered saline (DPBS) and stained.

[0146] Cells were stained with Live / Dead Fixable Dead Cell Stain in DPBS to allow for the exclusion of dead cells. Cells were incubated with anti-mouse CD16 / CD32 (Fc shield), followed by incubation with an antibody cocktail of APC anti-CD11c, BV421 anti-Siglec-F, BV786 anti-CD45, PE anti-CD200R3, and APC-eFluor CD117 monoclonal antibodies. Samples were acquired using an LSR Fortessa X20 or FACSymphony cell analyzer with an HTS attachment. Eosinophils were analyzed as intact cells, singlets, live (low LIVE / DEAD viability dye signal), CD45+ (BV786), and CDC11. lo-int Siglec F hiThis was defined as follows. Data analysis was performed using FlowJo v10 software.

[0147] Real-time PCR analysis: Tissues were homogenized, and chloroform was used for phase separation. The aqueous phase containing total RNA was purified using the MagMAX™-96 for Microarrays Total RNA Isolation Kit according to the manufacturer's specifications. Genomic DNA was removed using an RNase-Free DNase set. β-actin was used as a housekeeping gene. Gene expression was normalized to Actb (β-actin).

[0148] Histological and pathological scoring: Gastric tissue sections were collected at autopsy and treated for hematoxylin and eosin staining. After staining, whole slide images of the tissue sections were evaluated blindly by a certified veterinary pathologist. The following histological features of the stomach were scored using a semi-quantitative evaluation system (0 - no lesion, 1 - very slight lesion, 2 - mild lesion, 3 - moderate lesion, 4 - severe lesion): orthokeratotic hyperkeratosis, squamous epithelial thickening in non-glandular stomachs, squamous epithelial vacuolation, and cytoplasmic inclusions in squamous epithelium, mucosal cell hypertrophy / thickening in glandular stomachs, mixed cell type inflammation (mononuclear cells, neutrophils, and eosinophils), edema, and gastric myometrium thickening / hypertrophy. The overall pathological score was determined by summing the scores of the individual histological features, with a maximum score of 36.

[0149] Statistical Analysis: All data are presented as group mean ± standard deviation (SD). In experiments showing eosinophils as the frequency of CD45+ cells, normality was tested using the Shapiro-Wilk test, p-values ​​were determined using Brown-Forsythe and Welch analysis of variance (ANOVA) tests, and multiple comparisons were performed using Dunnett's T3 multiple comparison test. In experiments showing the levels of Ccl11 and Ccl24 mRNA in gastric tissue, normality was tested using the Shapiro-Wilk test, p-values ​​were determined using the Kruskal-Wallis test, and multiple comparisons were performed using Dun's multiple comparison test. For disease state scoring, statistical analysis of the data variance was performed using one-way ANOVA followed by Tukey's true significance (HSD) test. P-values ​​less than 0.5 were considered statistically significant, and statistical analysis was performed using GraphPad Prism software.

[0150] result The effect of REGN1103 on the frequency of eosinophils as a percentage of CD45+ cells in gastric tissue of a mouse model of eosinophilic gastritis was measured. Overexpression of mouse IL-25 significantly increased the frequency of eosinophils, and administration of 25 mg / kg of REGN1103 to IL-25-overexpressing mice significantly reduced the frequency of eosinophils in gastric tissue compared to administration of isotype control antibody (Figure 1). Furthermore, administration of REGN1103 to IL-25-overexpressing mice significantly reduced the expression of Ccl11 and Ccl24 mRNA in gastric tissue compared to mice administered with isotype control antibody or a control without antibody, and REGN1103 reduced Ccl11 and Ccl24 mRNA in gastric tissue of mIL-25-overexpressing mice to a level indistinguishable from mice administered with a vector control via HDD (Figures 2A and 2B). Stained sections of gastric tissue were evaluated to determine the severity of the disease. Mice overexpressing IL-25 and administered either an isotype control antibody or a control without the antibody showed significantly higher mean disease scores compared to IL-25 overexpressing mice administered REGN1103 (Figures 3A and 3B). Mice that did not express exogenous IL-25 and were administered a control without the antibody showed no lesions.

[0151] In summary, administration of 25 mg / kg of REGN1103 via SC injection at days 4, 1, and 3 in gastric tissue of a mouse model of eosinophilic gastritis induced a statistically significant reduction in eosinophil frequency, Ccl11 and Ccl24 mRNA levels, and lesion development.

[0152] Example 2: A clinical trial investigating the efficacy and safety of dupilumab in adult and adolescent patients with eosinophilic gastritis, with or without eosinophilic duodenitis. This example is a phase 2 / 3 randomized, three-part trial investigating the efficacy and safety of dupilumab in adult and adolescent participants with eosinophilic gastritis (EoG) with or without eosinophilic duodenitis (EoD). Parts A (Phase 2) and B (Phase 3) are 24-week randomized, double-blind, placebo-controlled trial periods, and Part C is a 28-week extended active treatment period, enrolling participants from Parts A and B (i.e., approximately 52 weeks of total exposure).

[0153] In Part A, the primary objectives are to determine the treatment effect of dupilumab treatment compared to placebo in adult and adolescent participants with or without EoG after 24 weeks of treatment, as assessed by histological metrics, and to inform / confirm the final sample size for Part B.

[0154] In Part B, the primary objective is to demonstrate the efficacy of dupilumab treatment compared to placebo in adult and adolescent participants with or without EoG after 24 weeks of treatment, as assessed by histological and clinical metrics.

[0155] In Part C, the primary objective is to evaluate the safety and efficacy of dupilumab treatment in adult and adolescent participants with or without EoG (with or without EoG) post-treatment EoG for up to 52 weeks, as assessed by histological and clinical metrics.

[0156] The secondary objectives of this examination are as follows: • Determine the treatment effect of dupilumab treatment compared to placebo in adult and adolescent participants, based on clinically assessed EoG (with or without EoG) after 24 weeks of treatment, as measured by clinical metrics (Part A only). • To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up to 52 weeks in adult and adolescent participants with or without endovascular regulation (EoG). To characterize the trough concentration of functional dupilumab over time after dupilumab administration in adult and adolescent participants with or without EoG. • To evaluate the efficacy of dupilumab against transcriptome signatures associated with EoG (with or without EoG) and type 2 inflammation.

[0157] In total, approximately 279 participants will be registered for this test.

[0158] In Part A, approximately 54 adult and adolescent participants will be randomized in a 1:1 ratio to receive either dupilumab 300 mg once weekly (QW) or a matching placebo subcutaneously (SC). At the end of the double-blind treatment visits in Part A (week 24), eligible participants may enter an extended 28-week active treatment period (Part C). All participants in Part A will receive active treatment with dupilumab 300 mg QW during Part C. During Part C, participants from Part A will maintain blinding to their Part A treatment assignments.

[0159] In Part B, approximately 225 adult and adolescent participants will be randomized in a 1:1:1 ratio to receive either dupilumab 300 mg quarterly, dupilumab 300 mg every two weeks (Q2W), or a matching placebo via a single-component (SC) regimen. The re-estimation of the Part B sample size will be evaluated, which may result in adjustments to the Part B sample size. At the end of the double-blind treatment visits in Part B (week 24), eligible participants may enter an extended 28-week active treatment period (Part C). During Part C, participants from Part B will maintain blinding to their Part B treatment assignments and Part C treatment regimens.

[0160] Participants from Part B who were randomized to placebo during the double-blind treatment period will be re-randomized in a 1:1 ratio to either dupilumab 300 mg QW or dupilumab 300 mg Q2W during Part C. All other participants will maintain the same dupilumab dose regimen to which they were randomized during the double-blind treatment period. Participants randomized to dupilumab 300 mg Q2W (Part B or Part C) will also receive a Q2W dose of matched placebo alternately with dupilumab in Part C to match injection frequency with other groups for regimen-blinding purposes.

[0161] Selection Criteria: The main selection criteria for Parts A and B include the following: • Males or females aged 12 or older. (Note: Youth participants will only be registered at testing facilities in countries / regions authorized by local regulatory authorities and the EC). • A documented endoscopic biopsy supporting the pathological diagnosis of EoG, taken at least three months prior to screening. (Note: Sufficient documentation supporting the pathological diagnosis of EoG is required.) • Screening endoscopic biopsy (serving as a baseline) showing eosinophilic infiltration (≥30 eos / hpf in at least 5 distinct hpfs within the stomach) for the diagnosis of EoG, determined by central histological evaluation of biopsies collected during screening endoscopy, in the absence of other significant causes of gastric eosinophilia (e.g., parasitic infections, malignant tumors). • At least 11 days of the 14-day EoG / EoD-SQ eDiary data entries were completed in the two weeks prior to baseline visit. • A history of at least two episodes of EoG symptoms per week (e.g., stomach pain, stomach cramps, nausea, flatulence, early satiety, loss of appetite) in the 8 weeks prior to screening (as reported by participants). • Mean TSS of 20 or higher, calculated using data collected weekly via EoG / EoD-SQ eDiary over the two weeks prior to baseline. • Mean weekly severity score of 4 or higher (on a scale of 0-10) over the two weeks prior to baseline for at least two of the following six symptoms: gastric cramps, stomach pain, nausea, flatulence, early satiety, loss of appetite.

[0162] Exclusion Criteria: The main exclusion criteria for Parts A and B include the following: • Weight less than 40kg • Past participation in dupilumab clinical trials, or past or present treatment with dupilumab • Helicobacter pylori infection • Any esophageal stricture that cannot be passed by a standard diagnostic upper endoscope during screening, or any significant esophageal stricture requiring dilation. • Achalasia, Crohn's disease, eosinophilic colitis, ulcerative colitis, celiac disease, and a history of gastric or duodenal surgery • Gastric eosinophilia and, if applicable, duodenal eosinophilia or other causes of the following conditions: eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) or eosinophilic syndrome • In the opinion of the principal investigator, a history of bleeding disorders, esophageal or gastric varices, etc., would put participants at excessive risk of serious complications from endoscopic procedures. • Initiation or modification of an elimination diet regime, or reintroduction of previously eliminated foods, within the four weeks prior to screening. Participants on an elimination diet must maintain the same diet throughout the entire study. • Receiving enteral (tube) or parenteral nutrition at the time of screening. • Treatment with topical corticosteroids for swallowing (with or without EoD) within 8 weeks prior to baseline, not for the treatment of EoG and / or EoE.

[0163] Study Procedure: The dosing regimen for this study is as follows:

[0164] Part A: 24-week double-blind treatment period • Dupilumab 300 mg administered via QW SC • Placebo QW SC administration containing the same formulation as dupilumab but without the active substance.

[0165] Part B: 24-week double-blind treatment period • Dupilumab 300 mg administered via QW SC • Dupilumab 300mg administered via Q2W SC For participants randomized to receive dupilumab 300 mg Q2W, matching placebo SC injections will be administered alternately with dupilumab administration to ensure the same injection frequency (QW) for both groups, in order to blind the regimen. • Placebo QW SC administration containing the same formulation as dupilumab but without the active substance.

[0166] Part C: Extended active treatment period of 28 weeks • All participants from Part A will receive dupilumab 300 mg via QW SC during Part C. All participants from Part B will receive a 300 mg dose of dupilumab via short-term infusion (SC) during Part C, either quarterly (QW) or quarterly (Q2W). For participants randomized to receive dupilumab 300 mg Q2W, matching placebo SC injections will be administered alternately with dupilumab administration to ensure the same injection frequency (QW) for both groups, in order to blind the regimen.

[0167] Part A randomization will also be stratified by the use of systemic corticosteroids or STCs at randomization (with or without EoD) (with vs. without), and by organ involvement at baseline (stomach only vs. stomach and duodenum). Part B randomization will be stratified by region (Japan vs. other countries), age (18 years or older vs. 12 years or older but under 18), the use of systemic corticosteroids or STCs for EoG (with or without EoD) at randomization (with vs. without), and by organ involvement at baseline (stomach only vs. stomach and duodenum). Participants from Japanese study sites will not be further stratified by the other three stratification factors (age, use of systemic or STCs, and organ involvement at baseline).

[0168] Primary and secondary endpoints: The primary endpoint for Part A of the study was the proportion of participants (i.e., histological respondents) who achieved a maximum gastric eosinophil count of ≤6 eos / hpf at week 24.

[0169] The two primary endpoints for Part B of the study were the proportion of participants (i.e., histological respondents) who achieved a maximum gastric eosinophil count of ≤6 eos / hpf at week 24, and the absolute change in EoG / EoD-SQ TSS from baseline to week 24.

[0170] The secondary efficacy endpoints for Parts A, B, and C of the study are as follows: • Percentage of participants who achieved both a maximum gastric eosinophil count of ≤6 eos / hpf and a maximum duodenal eosinophil count of ≤15 eos / hpf at week 24 (assessed for participants with involvement in both gastric and duodenal eosinophilia). • Percentage of participants who achieved a maximum duodenal eosinophil count of ≤15 eos / hpf at week 24 (assessed for participants with duodenal involvement) • Absolute change in EoG / EoD-SQ TSS from baseline to week 24 (Part A only [Second primary outcome measure of Part B]) • Percentage change in EoG / EoD-SQ TSS from baseline to week 24 • Percentage change in maximum gastric tissue eosinophil count (eos / hpf) from baseline to week 24 • Percentage of participants who achieved a maximum gastric tissue eosinophil count <30 eos / hpf at week 24 • Percentage change in maximum duodenal eosinophil count (eos / hpf) from baseline to week 24 (assessed only for participants with duodenal involvement) • Percentage of participants who achieved a maximum duodenal eosinophil count <30 eos / hpf at week 24 (evaluated only for participants with duodenal involvement) • Absolute change in EoG score using the EoG Histological Scoring System (EoGHSS) from baseline to week 24. • Change from baseline in the frequency of diarrheal episodes at week 24 (assessed only for participants who experienced diarrhea at baseline) • Change from baseline in the frequency of vomiting episodes at week 24 (assessed only for participants who experienced vomiting at baseline) • Changes in the normalized concentrated score (NES) of the type 2 inflammatory transcriptome signature (assessed using gastric tissue) from baseline to week 24. • Changes in NES from baseline to 24 weeks in the type 2 inflammatory transcriptome signature (assessed from duodenal tissue of EoD participants) • Changes in NE from baseline to 24 weeks in the EoG disease signature (EGDP) transcriptome signature (evaluated in gastric tissue), and • The percentage of participants who received rescue treatment or therapy during a 24-week placebo-controlled treatment period.

[0171] The present invention is not limited in scope by the specific embodiments described herein. In fact, 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 the accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A method for treating, preventing, or improving at least one symptom of eosinophilic gastroenteritis, comprising administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to a subject having eosinophilic gastroenteritis.

2. The method according to claim 1, wherein the subject has eosinophilic gastritis (EoG) accompanied by eosinophilic duodenitis (EoD).

3. The method according to claim 1, wherein the subject has eosinophilic gastritis (EoG) without eosinophilic duodenitis (EoD).

4. The method according to claim 1, wherein the subject has eosinophilic duodenitis (EoD) without eosinophilic gastritis (EoG).

5. The method according to any one of claims 1 to 4, wherein the subject has previously been treated with a systemic corticosteroid or a local corticosteroid for swallowing.

6. The method according to any one of claims 1 to 5, wherein the subject is unresponsive, has an insufficient response, or is intolerant to treatment with systemic corticosteroids or local corticosteroids for swallowing, or is contraindicated for treatment with standard therapy.

7. A method for reducing the use of systemic corticosteroids or local corticosteroids for swallowing in a subject with eosinophilic gastroenteritis, comprising administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist.

8. The method according to claim 7, wherein the subject has eosinophilic gastritis (EoG) accompanied by eosinophilic duodenitis (EoD).

9. The method according to claim 7, wherein the subject has eosinophilic gastritis (EoG) without eosinophilic duodenitis (EoD).

10. The method according to claim 7, wherein the subject has eosinophilic duodenitis (EoD) without eosinophilic gastritis (EoG).

11. The method according to any one of claims 7 to 10, wherein at the start of treatment with the IL-4R antagonist, the subject is taking a stable dose of maintenance therapy systemic corticosteroids or swallowing topical corticosteroids.

12. The method according to any one of claims 1 to 11, wherein the subject is 12 years of age or older.

13. The method according to any one of claims 1 to 12, wherein the subject is an adult.

14. The method according to any one of claims 1 to 13, wherein the subject has a co-occurring atopic disease.

15. The method according to claim 14, wherein the co-occurring atopic disease is food allergy, atopic dermatitis, asthma, chronic sinusitis, allergic rhinitis, or allergic conjunctivitis.

16. The subject, before the commencement of treatment with the IL-4R antagonist, (i) Having an eosinophil count ≥ 30 eos / hpf as measured by endoscopic biopsy in at least five distinct regions of the stomach, (ii) When measured by endoscopic biopsy in at least three distinct regions of the small intestine, the eosinophil count is ≥ 30 eos / hpf, (iii) When measured using the EoG / EoD Symptom Questionnaire (EoG / EoD-SQ), the patient has a baseline total symptom score (TSS) of 20 or higher. (iv) Having a baseline mean severity score of 4 or higher per week for at least two components of the EoG / EoD-SQ for at least two weeks, wherein the components are selected from the group consisting of stomach pain, stomach cramps, nausea, flatulence, early satiety, and loss of appetite, and / or (v) The method according to any one of claims 1 to 15, wherein the patient has a history of at least two EoG symptom episodes per week for at least eight weeks, wherein the symptoms are selected from the group consisting of stomach pain, stomach cramps, nausea, flatulence, early satiety, and loss of appetite.

17. The method according to any one of claims 1 to 16, wherein the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment.

18. The method according to any one of claims 1 to 17, wherein the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

19. The method according to any one of claims 1 to 18, wherein the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

20. The method according to any one of claims 1 to 19, wherein the IL-4R antagonist is an anti-IL-4R antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

21. The method according to any one of claims 1 to 20, wherein the IL-4R antagonist is dupilumab.

22. The method according to any one of claims 1 to 21, wherein the IL-4R antagonist is administered in a dose of about 50 mg to about 600 mg.

23. The method according to any one of claims 1 to 22, wherein the IL-4R antagonist is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

24. The method according to claim 22 or 23, wherein the IL-4R antagonist is administered in a dose of approximately 300 mg in a quarterly dose.

25. The method according to claim 22 or 23, wherein the IL-4R antagonist is administered in a dose of approximately 300 mg in Q2W.

26. The method according to any one of claims 1 to 25, wherein the IL-4R antagonist is administered subcutaneously.

27. The method according to any one of claims 1 to 26, wherein the IL-4R antagonist is administered in combination with a second therapeutic agent or therapy.

28. A method for treating eosinophilic gastroenteritis in a subject, comprising administering to the subject a combination therapy comprising (i) an interleukin-4 receptor (IL-4R) antagonist and (ii) a systemic corticosteroid or a local corticosteroid administered by swallowing.

29. The method according to claim 28, wherein the combination therapy comprises an IL-4R antagonist and a systemic corticosteroid.

30. The method according to claim 29, wherein the systemic corticosteroid is prednisone or prednisolone.

31. The method according to claim 28, wherein the combination therapy comprises an IL-4R antagonist and a local corticosteroid for swallowing.

32. The method according to claim 31, wherein the local corticosteroid for swallowing is budesonide or fluticasone.

33. The method according to any one of claims 28 to 32, wherein the subject has eosinophilic gastritis (EoG) accompanied by eosinophilic duodenitis (EoD).

34. The method according to any one of claims 28 to 32, wherein the subject has eosinophilic gastritis (EoG) without eosinophilic duodenitis (EoD).

35. The method according to any one of claims 28 to 32, wherein the subject has eosinophilic duodenitis (EoD) without eosinophilic gastritis (EoG).

36. The method according to any one of claims 28 to 35, wherein the subject is 12 years of age or older.

37. The method according to any one of claims 28 to 36, wherein the subject is an adult.

38. The method according to any one of claims 28 to 37, wherein the subject has a co-occurring atopic disease.

39. The method according to claim 38, wherein the co-occurring atopic disease is food allergy, atopic dermatitis, asthma, chronic sinusitis, allergic rhinitis, or allergic conjunctivitis.

40. The subject treated by the aforementioned combination therapy is (i) Having an eosinophil count ≥ 30 eos / hpf as measured by endoscopic biopsy in at least five distinct regions of the stomach, (ii) When measured by endoscopic biopsy in at least three distinct regions of the small intestine, the eosinophil count is ≥ 30 eos / hpf, (iii) When measured using the EoG / EoD Symptom Questionnaire (EoG / EoD-SQ), the patient has a baseline total symptom score (TSS) of 20 or higher. (iv) Having a baseline mean severity score of 4 or higher per week for at least two components of the EoG / EoD-SQ for at least two weeks, wherein the components are selected from the group consisting of stomach pain, stomach cramps, nausea, flatulence, early satiety, and loss of appetite, and / or (v) The method according to any one of claims 28 to 39, wherein the patient has a history of at least two EoG symptom episodes per week for at least eight weeks, wherein the symptoms are selected from the group consisting of stomach pain, stomach cramps, nausea, flatulence, early satiety, and loss of appetite.

41. The method according to any one of claims 28 to 40, wherein the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment.

42. The method according to any one of claims 28 to 41, wherein the IL-4R antagonist is an anti-IL-4R antibody or its antigen-binding fragment comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3, HCDR2 comprises the amino acid sequence of SEQ ID NO: 4, HCDR3 comprises the amino acid sequence of SEQ ID NO: 5, LCDR1 comprises the amino acid sequence of SEQ ID NO: 6, LCDR2 comprises the amino acid sequence of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

43. The method according to any one of claims 28 to 42, wherein the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:

2.

44. The method according to any one of claims 28 to 43, wherein the IL-4R antagonist is an anti-IL-4R antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO:

10.

45. The method according to any one of claims 28 to 44, wherein the IL-4R antagonist is dupilumab.

46. The method according to any one of claims 28 to 45, wherein the IL-4R antagonist is administered in a dose of about 50 mg to about 600 mg.

47. The method according to any one of claims 28 to 46, wherein the IL-4R antagonist is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

48. The method according to claim 46 or 47, wherein the IL-4R antagonist is administered in a dose of approximately 300 mg in a quarterly dose.

49. The method according to claim 46 or 47, wherein the IL-4R antagonist is administered in a dose of approximately 300 mg in Q2W.

50. The method according to any one of claims 28 to 49, wherein the IL-4R antagonist is administered subcutaneously.

51. The method according to any one of claims 1 to 50, wherein the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen-type delivery device, and an auto-injector.

52. The method according to claim 51, wherein the IL-4R antagonist is contained in a pre-filled syringe.

53. The method according to claim 52, wherein the pre-filled syringe is a single-dose pre-filled syringe.

54. The method according to claim 51, wherein the IL-4R antagonist is contained in the autoinjector.

55. The method according to claim 51, wherein the IL-4R antagonist is contained in a pen-type delivery device.

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