Methods of treating pediatric eosinophilic esophagitis by administering IL-4R antagonist

Abstract

Methods for treating eosinophilic esophagitis in a pediatric subject are provided. In one aspect, the method comprises administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or antigen-binding fragment thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a PCT international patent application filed on July 7, 2023, which claims priority to and the benefit of U.S. Provisional Application No. 63 / 359,577 filed on July 8, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0002] Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by esophageal dysfunction and eosinophilic inflammation of the esophagus, and is thought to be triggered by an abnormal type 2 immune response to food allergens (Furuta et al., J Allergy Clin Immunol, 2017, 139: 1131-1134; Liacouras et al., J Allergy Clin Immunol, 2011, 128: 3-20.e6). Although eosinophilic esophagitis is considered a rare disease, its global prevalence is currently estimated to be 22.7 per 100,000 people (Arias et al., Aliment Pharmaco Ther, 2016, 43: 3-15), and appears to be on the rise (Dellon, Gastroenterology Clinics of North America, 2014, 43: 201-218). Eosinophilic esophagitis has been reported in all age groups; however, most cases occur in children and adults under the age of 50. Children under the age of 18 comprise approximately 30% of the EoE patient population (see, e.g., Dellon et al., Clinical Gastroenterology and Hepatology, 2014, 12:589-596).

[0003] The main clinical manifestations of EoE in adults and children over 10 years old are dysphagia and food impaction (Lucendo et al., United European Gastroenterol J, 2017, 5: 335-358). The clinical features of young children are essentially non-specific and vary greatly depending on the patient's age and the patient's ability to describe prominent symptoms. Infants and young children are more likely to experience difficulty eating, vomiting or regurgitation, and may lead to stunted growth, while school-age children experience abdominal pain and heartburn symptoms (Iuliano et al., Acta Biomed, 2018, 89: 20-26). Older children with EoE symptoms may also change their diet and eating behavior by taking small bites, chewing thoroughly, eating slowly, drinking large amounts of liquids, and avoiding food sticking, which is highly suggestive of dysphagia because this is an eating behavior reported in adults to try to prevent esophageal food impaction. Same as above. These symptoms lead to substantial impairment of quality of life (see, e.g., DeBrosse et al., J Allergy Clin Immunol, 2011, 128: 132-138). Endoscopic findings are associated with inflammation in the esophagus and are composed of fixed or temporary concentric rings, longitudinal grooves, white patches, reduced mucosal vascularity, fragile or wrinkled mucosa, and stenosis. Grooves and white patches may be the most common findings in children, while rings are uncommon in children (Singla and Moawad, Clin Transl Gastroenterol, 2016, 7: e155). Some patients (particularly pediatric patients) may have a normal-looking esophagus but still have histologically active EoE (Wechsler et al., Clin Gastroenterol Hepatol, 2018, 16: 1056-1063).

[0004] The current standard treatment for EoE includes dietary adjustments (e.g., food elimination diets), as well as off-label proton pump inhibitors (PPIs), off-label use of oral topical corticosteroids, and esophageal dilation. However, the standard treatment for EoE is limited by variable response rates, recurrence after cessation of therapy, and adverse effects on quality of life. Esophageal dilation is commonly used to alleviate the symptoms of dysphagia caused by esophageal stenosis, but because stenosis is uncommon in children, esophageal dilation is uncommon for children with EoE compared to adults with EoE (Chehade et al., J Allergy Clin Immunol Pract, 2018, 6: 1534-1544.e5). In addition, emergency endoscopy for prolonged and / or painful food impaction and esophageal dilation for relieving stenosis are associated with the risk of severe esophageal damage and do not change the underlying pathogenesis or progression of the disease. Diets that exclude specific foods can be effective in a significant percentage of patients; however, 30% to 40% of patients are unable to achieve disease remission through dietary modification (Nhu et al., Curr Treat Options Gastroenterol, 2019, 17:48-62). Proton pump inhibitors can achieve histological remission in approximately 50% of EoE patients (Lucendo et al., United European Gastroenterol J, 2017, 5:335-358), with the remainder of patients experiencing no response. Clinical trials have reported that oral topical corticosteroids can induce partial clinical responses and histological remission; however, their effects are inconsistent, may be associated with local fungal infections, and there is a risk of growth inhibition and hypothalamic-pituitary-adrenal axis suppression after systemic absorption (Golekoh et al., J Pediatr, 2016, 170:240-245), limiting their use to short-term. Therefore, there is still a high unmet medical need for safe and effective therapies for the treatment of EoE in children. Summary of the Invention

[0005] In one aspect, methods are provided for treating, preventing, or ameliorating at least one symptom of eosinophilic esophagitis (EoE) in a pediatric subject <12 years of age. In some embodiments, the method comprises administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to the subject. In some embodiments, the IL-4R antagonist specifically binds to IL-4 and / or IL-13. In some embodiments, the IL-4R antagonist specifically binds to IL-4Rα (e.g., human IL-4Rα).

[0006] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof 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.

[0007] In some embodiments, the subject is ≥ 1 year old and < 12 years old. In some embodiments, the subject weighs ≥ 5 kg. In some embodiments, the subject weighs < 60 kg.

[0008] In some embodiments, the subject is <12 years old and weighs ≥5 kg to <15 kg. In some embodiments, the subject is <12 years old and weighs ≥15 kg to <30 kg. In some embodiments, the subject is <12 years old and weighs ≥30 kg to <60 kg. In some embodiments, the subject is <12 years old and weighs ≥40 kg.

[0009] In some embodiments, the subject is ≥1 year old and weighs ≥5 kg to <15 kg. In some embodiments, the subject is ≥1 year old and weighs ≥15 kg to <30 kg. In some embodiments, the subject is ≥1 year old and weighs ≥30 kg to <60 kg. In some embodiments, the subject is ≥1 year old and weighs ≥40 kg.

[0010] In some embodiments, prior to initiation of IL-4R antagonist treatment, the subject has a peak intraepithelial eosinophil infiltration cell count of ≥ 15 eos / hpf as measured by endoscopic biopsy in at least two of the proximal, mid, and distal esophageal regions.

[0011] In some embodiments, the subject has been previously treated with oral topical corticosteroids and / or proton pump inhibitors (PPIs). In some embodiments, the subject has no response, insufficient response, or intolerance to oral topical corticosteroids and / or PPIs, or the standard of care treatment is a contraindication. In some embodiments, the subject suffers from an associated atopic disease. In some embodiments, the associated atopic disease is food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis.

[0012] In some embodiments, prior to initiation of treatment, the subject's: baseline peak intraepithelial eosinophil count ≥70eos / hpf; baseline mean intraepithelial eosinophil count ≥50eos / hpf; A baseline EoE Endoscopy Reference Score (EoE-EREFS) of at least 6; and / or Baseline serum total IgE level of at least 400 IU / L.

[0013] In some embodiments, the subject is selected based on not displaying one or more exclusion criteria selected from: (a) Weight <5kg; (b) body weight ≥60 kg; (c) Suffering from eosinophilic gastroenteritis, hypereosinophilic syndrome or Churg-Strauss syndrome; (d) history of Crohn's disease, ulcerative colitis, celiac disease, or previous esophageal surgery; (e) esophageal strictures that cannot be passed through standard diagnostic upper gastrointestinal endoscopy or esophageal strictures that require dilation; (f) received oral topical corticosteroids within the previous 8 weeks; (g) previously received subcutaneous immunotherapy (SCIT) unless treated at a stable maintenance dose for at least 1 year; (h) previous treatment with sublingual immunotherapy (SLIT), epicutaneous immunotherapy (EPIT), or oral immunotherapy (OIT); (i) receiving systemic immunosuppressive or immunomodulatory drug treatment within the previous 3 months; (j) starting or changing a food elimination diet within the previous 6 weeks; (k) starting, stopping, or changing the dosing regimen of a PPI, leukotriene inhibitor, nasal corticosteroid, or inhaled corticosteroid within the previous 8 weeks; (l) received live (attenuated) vaccine treatment within the previous 4 weeks; (m) have active Helicobacter pylori infection, helminth infection, active parasitic infection, or chronic or acute infection requiring treatment with systemic antibiotics, antiviral agents, or antifungal agents; (n) Suffering from known or suspected immunodeficiency disorder; (o) have liver disease; and (p) Platelet level <100×10 3 / μL, neutrophil level ≤1.5×10 3 / μL, or estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m2 .

[0014] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab.

[0015] In some embodiments, the IL-4R antagonist is administered at a dose of about 50 mg to about 600 mg. In some embodiments, the IL-4R antagonist is administered weekly or biweekly at a dose of about 100 mg to about 300 mg. In some embodiments, the IL-4R antagonist is administered subcutaneously.

[0016] In some embodiments, the subject weighs ≥ 5 kg, wherein For subjects weighing ≥5 kg to <15 kg, the IL-4R antagonist is administered at a dose of about 100 mg Q2W, about 200 mg Q3W, or about 200 mg Q4W; For subjects weighing ≥15 kg to <30 kg, the IL-4R antagonist is administered at a dose of about 200 mg Q2W or about 300 mg Q4W; For subjects weighing ≥30 kg to <60 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W or about 200 mg Q2W; and / or For subjects weighing ≥60 kg, the IL-4R antagonist is administered at a dose of about 300 mg QW or about 300 mg Q2W.

[0017] In some embodiments, the subject weighs ≥ 5 kg, wherein For subjects weighing ≥5 kg to <15 kg, the IL-4R antagonist is administered at a dose of about 100 mg Q2W or about 200 mg Q3W; For subjects weighing ≥15 kg to <30 kg, the IL-4R antagonist is administered at a dose of approximately 200 mg Q2W; For subjects weighing ≥30 kg to <60 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W; and / or For subjects weighing ≥60 kg, the IL-4R antagonist is administered at a dose of approximately 300 mg QW.

[0018] In some embodiments, the subject weighs ≥ 5 kg, wherein For subjects weighing ≥5 kg to <15 kg, the IL-4R antagonist is administered at a dose of approximately 200 mg Q3W; For subjects weighing ≥15 kg to <30 kg, the IL-4R antagonist is administered at a dose of approximately 200 mg Q2W; For subjects weighing ≥30 kg to <40 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W; and / or For subjects weighing ≥40 kg, the IL-4R antagonist is administered at a dose of approximately 300 mg QW.

[0019] In some embodiments, the subject weighs ≥5 kg to <15 kg. In some embodiments, the subject weighs ≥5 kg to <15 kg, and the IL-4R antagonist is administered at a dose of about 100 mg Q2W. In some embodiments, the subject weighs ≥5 kg to <15 kg, and the IL-4R antagonist is administered at a dose of about 200 mg Q3W. In some embodiments, the subject weighs ≥5 kg to <15 kg, and the IL-4R antagonist is administered at a dose of about 200 mg Q4W.

[0020] In some embodiments, the subject weighs ≥15 kg to <30 kg. In some embodiments, the subject weighs ≥15 kg to <30 kg, and the IL-4R antagonist is administered at a dose of about 200 mg Q2W. In some embodiments, the subject weighs ≥15 kg to <30 kg, and the IL-4R antagonist is administered at a dose of about 300 mg Q4W.

[0021] In some embodiments, the subject weighs ≥30 kg to <60 kg. In some embodiments, the subject weighs ≥30 kg to <60 kg, and the IL-4R antagonist is administered at a dose of about 300 mg Q2W. In some embodiments, the subject weighs ≥30 kg to <60 kg, and the IL-4R antagonist is administered at a dose of about 200 mg Q2W.

[0022] In some embodiments, the subject weighs ≥60 kg. In some embodiments, the subject weighs ≥60 kg, and the IL-4R antagonist is administered at a dose of about 300 mg QW. In some embodiments, the subject weighs ≥60 kg, and the IL-4R antagonist is administered at a dose of about 300 mg Q2W.

[0023] In some embodiments, the subject weighs ≥ 40 kg. In some embodiments, the subject weighs ≥ 40 kg, and the IL-4R antagonist is administered at a dose of about 300 mg QW.

[0024] In some embodiments, the IL-4R antagonist is administered in combination with a second therapeutic agent or therapy. In some embodiments, the second therapeutic agent or therapy is an IL-1β inhibitor, an IL-5 inhibitor, an IL-9 inhibitor, an IL-13 inhibitor, an IL-17 inhibitor, an IL-25 inhibitor, a TNFα inhibitor, an eotaxin-3 inhibitor, an IgE inhibitor, a prostaglandin D2 inhibitor, an immunosuppressant, a topical corticosteroid, an oral corticosteroid, a systemic corticosteroid, an inhaled corticosteroid, a glucocorticoid, a PPI, a decongestant, an antihistamine, a nonsteroidal anti-inflammatory drug (NSAID), an esophageal dilation, a feeding tube, allergen removal, or dietary management. In some embodiments, the second therapeutic agent or therapy is dietary management. In some embodiments, the second therapeutic agent or therapy is a PPI.

[0025] In some embodiments, treatment with the IL-4R antagonist for at least 16 weeks results in: a decrease in peak esophageal intraepithelial eosinophil count; a reduction in the severity and / or extent of disease as measured by the Eosinophilic Esophagitis-Histology Scoring System (EoE-HSS); Improvement in esophageal anatomy as measured by the Eosinophilic Esophagitis-Endoscopy Reference Score (EoE-EREFS); Increase in weight for age percentile; and / or Reduction in normalized enrichment score (NES) of genes in the type 2 inflammation group and / or EoE diagnostic group.

[0026] In some embodiments, treatment with the IL-4R antagonist for 16 weeks results in a peak esophageal intraepithelial eosinophil count of ≤6 eos / hpf, and / or a reduction in peak esophageal intraepithelial eosinophil count of at least 75%.

[0027] In some embodiments, the IL-4R antagonist is contained in a container selected from the group consisting of a vial, a syringe, a prefilled syringe, a pen delivery device, and an autoinjector. In some embodiments, the IL-4R antagonist is contained in a prefilled syringe. In some embodiments, the prefilled syringe is a single-dose prefilled syringe. In some embodiments, the IL-4R antagonist is contained in an autoinjector. In some embodiments, the IL-4R antagonist is contained in a pen delivery device.

[0028] In another aspect, the present disclosure provides pharmaceutical compositions comprising an IL-4R antagonist for treating, preventing, or ameliorating at least one symptom of EoE in pediatric subjects <12 years of age (e.g., subjects ≥1 year and <12 years of age) or pediatric or adolescent subjects with a baseline weight <40 kg (e.g., baseline weight ≥5 kg and <40 kg). In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof comprising a HCDR1 comprising, or consisting of, the amino acid sequence of SEQ ID NO:3, a HCDR2 comprising, or consisting of, the amino acid sequence of SEQ ID NO:4, a HCDR3 comprising, or consisting of, the amino acid sequence of SEQ ID NO:5, a LCDR1 comprising, or consisting of, the amino acid sequence of SEQ ID NO:6, a LCDR2 comprising, or consisting of, the amino acid sequence of LGS, and a LCDR3 comprising, or consisting of, the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:1 and a LCVR comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab. In some embodiments, the pharmaceutical composition is formulated to administer about 50 mg to about 600 mg of the IL-4R antagonist per dose, e.g., about 100 mg, about 200 mg, or about 300 mg.

[0029] In another aspect, the present invention provides for use of an IL-4R antagonist in the preparation of a medicament for treating, preventing, or ameliorating at least one symptom of EoE in a pediatric subject <12 years of age (e.g., a subject ≥1 year and <12 years of age) or a pediatric or adolescent subject with a baseline weight <40 kg (e.g., a baseline weight ≥5 kg and <40 kg). In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof comprising a HCDR1 comprising, or consisting of, the amino acid sequence of SEQ ID NO:3, a HCDR2 comprising, or consisting of, the amino acid sequence of SEQ ID NO:4, a HCDR3 comprising, or consisting of, the amino acid sequence of SEQ ID NO:5, a LCDR1 comprising, or consisting of, the amino acid sequence of SEQ ID NO:6, a LCDR2 comprising, or consisting of, the amino acid sequence of LGS, and a LCDR3 comprising, or consisting of, the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO:1 and a LCVR comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab. In some embodiments, the drug is formulated to administer about 50 mg to about 600 mg of the IL-4R antagonist per dose, such as about 100 mg, about 200 mg, or about 300 mg.

[0030] In another aspect, the present disclosure provides a therapeutic dosage form comprising a pharmaceutical composition of an IL-4R antagonist for treating, preventing, or ameliorating at least one symptom of EoE in a pediatric subject <12 years of age (e.g., a subject ≥1 year and <12 years of age) or a pediatric or adolescent subject with a baseline weight <40 kg (e.g., a baseline weight ≥5 kg and <40 kg). In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof comprising a HCDR1 comprising, or consisting of, the amino acid sequence of SEQ ID NO:3, a HCDR2 comprising, or consisting of, the amino acid sequence of SEQ ID NO:4, a HCDR3 comprising, or consisting of, the amino acid sequence of SEQ ID NO:5, a LCDR1 comprising, or consisting of, the amino acid sequence of SEQ ID NO:6, a LCDR2 comprising, or consisting of, the amino acid sequence of LGS, and a LCDR3 comprising, or consisting of, the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab. In some embodiments, the therapeutic dosage form is formulated to administer about 50 mg to about 600 mg of the IL-4R antagonist per dose, e.g., about 100 mg, about 200 mg, or about 300 mg.

[0031] In another aspect, the present disclosure provides kits comprising an IL-4R antagonist, a pharmaceutical composition comprising an IL-4R antagonist, or a medicament comprising an IL-4R antagonist for treating, preventing, or ameliorating at least one symptom of EoE in a pediatric subject <12 years of age (e.g., a subject ≥1 year and <12 years of age) or a pediatric or adolescent subject <40 kg at baseline (e.g., a subject with a baseline weight ≥5 kg and <40 kg). In some embodiments, the kit further comprises a label or instructions for use.

[0032] Other embodiments will become apparent upon reading the following detailed description. DETAILED DESCRIPTION definition

[0033] Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, as these methods and conditions may vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting, as the scope of the present invention will be limited only by the appended claims.

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0035] As used herein, the term "about," when used to refer to a specific recited value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0036] As used herein, the terms "treat" and "treating" and the like refer to alleviating the symptoms, temporarily or permanently eliminating the cause of the symptoms, or preventing or slowing down the occurrence of the disorder or condition.

[0037] "Eosinophilic esophagitis" or "EoE" refers to an inflammatory disease characterized by abnormal eosinophilic inflammation in the esophagus and esophageal dysfunction. The main symptoms of EoE include, but are not limited to, chest and abdominal pain, dysphagia, heartburn, food refusal, vomiting, food impaction, and failure to thrive. The histopathological features of EoE are related to inflammation in the esophagus and may include fixed or transient concentric rings, longitudinal grooves, white patches, reduced mucosal vascularity, fragile or wrinkled mucosa, and strictures. Grooves and white patches are more common in children, while rings are more common in adults than in children. EoE is usually diagnosed by esophageal endoscopy and biopsy, followed by microscopic and biochemical analysis of the esophageal mucosal lining. The current consensus recommendation for the diagnosis of EoE is a peak esophageal intraepithelial eosinophil count ≥15eos / hpf.

[0038] As used herein, the term "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms or signs of eosinophilic esophagitis, and / or a human or non-human animal that has been diagnosed with eosinophilic esophagitis. In certain embodiments, the term includes subjects that exhibit elevated levels of one or more EoE-associated biomarkers (described elsewhere herein) and / or subjects that have a gene expression profile associated with EoE ("EoE disease transcriptome"). For example, in some embodiments, a subject treated according to the methods of the present disclosure is a subject that has elevated levels of IgE, serum TARC, and / or eotaxin-3, a subject that has a gene expression profile consistent with a disclosed EoE gene expression marker (Dellon et al., Clin Transl Gastroenterol, 2017, 8(2):e74), or a subject that has altered expression levels of one or more genes of a disclosed EoE gene expression marker. As used herein, the terms "subject" and "patient" are used interchangeably.

[0039] The term "patient in need thereof" may also include, for example, patients who exhibit (or have exhibited) one or more EoE indicators prior to treatment, such as, for example, esophageal overexpression of proinflammatory mediators such as mast cells, esophageal eosinophil infiltration, esophageal wall thickening, dysphagia, food impaction, and chest and abdominal pain and / or elevated levels of EoE-associated 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).

[0040] The term "eosinophil infiltration" refers to the presence of eosinophils in an organ or tissue of a subject, including the blood, esophagus, stomach, duodenum, and ileum. In the context of the present disclosure, the term "eosinophil infiltration" refers to the presence of eosinophils in the mucosal lining of the gastrointestinal tract, including but not limited to the esophagus and stomach. For example, eosinophil infiltration is analyzed in an esophageal tissue biopsy of a subject with EoE. According to some embodiments, "eosinophil infiltration" refers to the presence of ≥15 eosinophils per high-power field in two or more areas of the esophagus or the proximal, middle, and distal regions of the esophagus. The term "high power field" refers to a standard total magnification of 400× for a microscope used to observe eosinophils in tissue (e.g., from the esophagus of a subject). Thus, in some embodiments, a "subject in need thereof" is a subject who demonstrates the presence of ≥15 eosinophils ("eosinophils") per high power field ("hpf") in the esophagus, e.g., in two or more regions of the proximal, middle, and distal regions of the esophagus. In certain embodiments, "eosinophil infiltration" includes infiltration of tissue by leukocytes, e.g., lymphocytes, neutrophils, and mast cells. Infiltration of leukocytes into, e.g., esophageal tissue can be detected by cell surface markers, e.g., eosinophil-specific markers (e.g., CD11c Low / Neg 、SiglecF + 、F4 / 80 + 、EMR1 + 、Siglec8 + and MBP2 + ), 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 + ).

[0041] In some embodiments, the subject does not respond, responds insufficiently, or is intolerant to treatment with a standard of care therapy (e.g., oral topical corticosteroids or PPIs). As used herein, a subject who is "non-responsive" to treatment is one whose disease symptoms do not improve, do not significantly improve, or worsen after a defined period of time with standard of care treatment, e.g., as measured using an EoE-related parameter as disclosed herein (e.g., as measured by esophageal intraepithelial eosinophil count, changes in severity and / or extent of histological features in the esophagus, or changes in one or more esophageal characteristics as measured by EoE-EREFS). As used herein, a subject who is "inadequately responsive" to a treatment is one whose disease symptoms may partially improve after treatment with the standard of care, but not to a level indicative of disease control, or one whose disease symptoms initially improve but who is unable to achieve stable, long-term disease control, e.g., as measured using an EoE-associated parameter as disclosed herein (e.g., as measured by esophageal intraepithelial eosinophil count, changes in severity and / or extent of histological features in the esophagus, or changes in one or more esophageal characteristics as measured by the EoE-EREFS). As used herein, a subject who is "intolerant" to a treatment is one who cannot tolerate the side effects of the treatment, e.g., at a therapeutic dose or subtherapeutic dose.

[0042] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, typical methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety. Treatment

[0043] In one aspect, a method for treating, preventing, or ameliorating one or more symptoms of eosinophilic esophagitis (EoE) in a subject is provided. In some embodiments, the subject is a pediatric or adolescent subject <18 years of age. In some embodiments, the subject is a pediatric subject <12 years of age. In some embodiments, the subject is ≥1 year old to <12 years of age. In some embodiments, the subject is ≥1 year old and <4 years old. In some embodiments, the subject is ≥1 year old and <5 years old. In some embodiments, the subject is ≥2 years old and <8 years old. In some embodiments, the subject is ≥5 years old and <12 years old. In some embodiments, the subject is ≥8 years old and <12 years old.

[0044] In some embodiments, the subject being treated according to the methods disclosed herein has a history of EoE diagnosis documented by endoscopic biopsy, as evidenced by intraepithelial eosinophil infiltration from at least one esophageal region. In some embodiments, the subject's baseline peak eosinophil count is ≥15eos / hpf. As used herein, "peak esophageal intraepithelial eosinophil count" refers to the number of eosinophils contained within one high-power field (hpf), for example, at 400×. In some embodiments, the subject's intraepithelial eosinophil infiltration peak cell count is ≥15eos / hpf as measured by endoscopic biopsy in at least two or all three of the proximal esophageal, mid-esophageal, and distal esophageal regions. In some embodiments, the subject has a mean peak esophageal intraepithelial eosinophil count of ≥20eos / hpf, ≥25eos / hpf, ≥30eos / hpf, ≥35eos / hpf, ≥40eos / hpf, ≥45eos / hpf, ≥50eos / hpf, ≥55eos / hpf, ≥60eos / hpf, ≥65eos / hpf, ≥70eos / hpf, ≥75eos / hpf, ≥80eos / hpf, ≥85eos / hpf, or ≥90eos / hpf.

[0045] In some embodiments, the subject treated according to the methods disclosed herein has a history of one or more symptoms of EoE, such as, but not limited to, abdominal pain, chest pain, acid reflux, food regurgitation, dysphagia, vomiting, food impaction, difficulty eating, food refusal, or failure to thrive. In some embodiments, the subject has a history of one or more symptoms of EoE 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, the subject has a history of one or more symptoms of EoE for at least 6 months, at least 1 year, at least 2 years, or longer. In some embodiments, the subject's weight is below the average percentile for their age.

[0046] In some embodiments, the subject treated according to the methods disclosed herein has a history of prior treatment with one or more standard of care therapies for EoE, such as, but not limited to, dietary changes (e.g., a food elimination diet), swallowed topical corticosteroids, glucocorticoids, proton pump inhibitor (PPI) therapy (e.g., a high-dose PPI regimen), or esophageal dilation. In some embodiments, the subject to be treated is a subject who is unresponsive, inadequately responsive, intolerant, or tolerant to one or more current standard of care therapies for EoE. In some embodiments, the subject to be treated has a contraindication to one or more standard of care therapies.

[0047] In some embodiments, the subject to be treated has a baseline weight of ≥5 kg. In some embodiments, the subject to be treated has a baseline weight of <60 kg. In some embodiments, the subject to be treated has a baseline weight of ≥5 kg and <60 kg. In some embodiments, the subject to be treated has a baseline weight of ≥5 kg and <15 kg. In some embodiments, the subject to be treated has a baseline weight of ≥15 kg and <30 kg. In some embodiments, the subject to be treated has a baseline weight of ≥30 kg and <60 kg.

[0048] In some embodiments, the subject to be treated is a pediatric or adolescent patient with a baseline weight <40 kg. In some embodiments, the subject to be treated has a baseline weight ≥5 kg and <40 kg.

[0049] In some embodiments, the subject to be treated has altered levels of one or more EoE biomarkers or has a gene signature profile of EoE-related genes that is indicative of or consistent with a published gene signature profile of an EoE patient. EoE-related biomarkers and gene expression panels for diagnosing EoE are described in the art, for example, in Sherrill et al., Genes Immun, 2014, 15(6):361-369; Dellon et al., Clin Transl Gastroenterol, 2017, 8(2):e74; and U.S. Patent Publication No. 2017 / 0067111. In some embodiments, the subject has elevated levels of eotaxin-3, serum TARC, and / or total IgE. In some embodiments, the subject to be treated has elevated levels of one or more EoE-associated genes, such as TNFAIP6, LRRC31, SLC26A4-AS1, ALOX15, CCL26, TGM6, NRXN1, PMCH, SLC26A4, CXCL1, CCR3, TREML2, POSTN, LURAP1L, or CXCL6. In some embodiments, the subject to be treated has decreased levels of one or more EoE-associated genes, such as CRTAC1, BC107108, SFTA2, C2orf16, KRTAP3-2, PLNIPRP3, CIDEA, FLG, SLC8A1-AS1, SPINK5, SPINK7, SPINK8, DPCR1, MUC22, CRISP2, DSG1, GYS2, or CRISP3.

[0050] In some embodiments, the subject to be treated has or has had at least one comorbidity. In some embodiments, the comorbidity is asthma, atopic dermatitis, hand and food eczema, allergic rhinitis, oral allergy syndrome, or food allergy (e.g., peanut allergy).

[0051] In some embodiments, the subject to be treated has or has had a concomitant type 2 inflammatory condition. As used herein, a "type 2 inflammatory condition" is a disease, disorder, or condition associated with a T helper cell 2 (TH2)-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 rhinosinusitis, allergic rhinitis, allergic fungal sinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), unified airway disease, eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), gastroesophageal reflux disease (GERD), atopic conjunctivitis, atopic dermatitis, vasculitis, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis 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 food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis.

[0052] In some embodiments, the subject to be treated is a subject susceptible to allergens, for example, a subject with food allergy or oral allergy syndrome. For example, in some embodiments, the subject may exhibit one of the following characteristics: (a) prone to allergic reactions or responses when exposed to one or more allergens; (b) previously exhibited an allergic response or reaction to one or more allergens; (c) has a known history of allergies; and / or (d) exhibits signs or symptoms of an allergic response or anaphylaxis. As used herein, the phrases "allergic response," "allergic reaction," "allergic symptoms," and the like include one or more signs or symptoms selected from wheals (e.g., hives), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinusitis, watery eyes, wheezing, bronchospasm, decreased peak expiratory flow (PEF), gastrointestinal distress, flushing, swollen lips, swollen tongue, decreased blood pressure, anaphylaxis, and organ dysfunction / failure. "Allergic response," "allergic reaction," "allergic symptoms," and the like also include immune responses and reactions, such as increased IgE production, increased production of allergen-specific immunoglobulins, and / or eosinophilia. In certain embodiments, the subject is allergic to an allergen associated with EoE or to an allergen that predisposes and / or predisposes the subject to the development of EoE. In some embodiments, the allergen is contained in or derived from a food, such as dairy products (e.g., cow's milk), eggs, wheat, soy, corn, rye, fish, shellfish, peanuts, tree nuts. In some embodiments, the allergen is contained in or derived from a non-food item, such as dust (e.g., containing dust mites), pollen, insect venom (e.g., venom of bees, wasps, mosquitoes, etc.), mold, animal dander, latex, medication, drug, ragweed, grass, or birch.

[0053] In some embodiments, the subjects to be treated are selected based on displaying one or more of the inclusion criteria disclosed in Example 1. In some embodiments, the subjects to be treated are further selected based on not displaying one or more of the exclusion criteria disclosed in Example 1. Interleukin-4 receptor antagonists

[0054] In some embodiments, the methods of the present disclosure include administering an interleukin-4 receptor (IL-4R) antagonist or a pharmaceutical composition comprising an IL-4R antagonist to a subject in need thereof (e.g., a subject <12 years of age with EoE, or a subject ≥1 year and <12 years of age with EoE). As used herein, an "IL-4R antagonist" (also referred to herein as an "IL-4R inhibitor," "IL-4R blocker," or "IL-4Rα antagonist") is any agent that binds to or interacts with IL-4Rα or IL-4R ligand and inhibits or attenuates the normal biological signaling function of type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. Type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and a γc chain. Type 2 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. The type 1 IL-4 receptor interacts with and is stimulated by IL-4, while the type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, the IL-4R antagonists useful in the methods of the present disclosure may function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4 and IL-13-mediated signaling. The IL-4R antagonists of the present disclosure may thus prevent the interaction of IL-4 and / or IL-13 with either the type 1 or type 2 receptors.

[0055] Non-limiting examples of classes of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor-bodies" (e.g., engineered molecules comprising the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13. Anti-IL-4Rα antibodies and antigen-binding fragments thereof

[0056] In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. As used herein, the term "antibody" includes immunoglobulin molecules comprising four polypeptide chains interconnected by disulfide bonds, two heavy chains (H) and two light chains (L), as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H ) and heavy chain constant region. The heavy chain constant region contains three domains, C H 1. C H 2 and C H3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and the light chain constant region. The light chain constant region contains a domain (C L 1). V H and V L The V region can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). H and V L It consists of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences. In some embodiments, one or more FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) are naturally or artificially modified.

[0057] As used herein, the term "antibody" also includes the antigen-binding fragment of a full antibody molecule. "Antigen-binding portion thereof" of the term antibody used herein, "antigen-binding fragment" of the term antibody etc. include any naturally occurring, enzymatically obtainable, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen-binding fragment of an antibody can use any suitable standard technique, such as obtained from, for example, a full antibody molecule by proteolytic digestion or obtained by recombinant genetic engineering techniques involving operation and expression of the DNA encoding antibody variable domains and alternatively constant domains. Such DNA is known and / or can be easily obtained from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. This DNA can be sequenced, and by chemical methods or by using molecular biology techniques, for example, to arrange one or more variable domains and / or constant domains into suitable configuration or to introduce codons, produce cysteine ​​residues, modify, add or delete amino acid etc.

[0058] 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., an isolated complementarity-determining region (CDR), such as a CDR3 peptide) or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed by the term "antigen-binding fragment" as used herein.

[0059] The antigen-binding fragment of an antibody will typically contain at least one variable domain. The variable domain can be of any size or amino acid composition and generally contains at least one CDR that is adjacent to or in frame with one or more framework sequences. L Domain-associated V H In the antigen-binding fragment of the structural domain, V H and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be dimeric and contain V H -V H 、V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may contain a monomer V H or V L domain.

[0060] 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 fragments of the antibodies of the present 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-CH 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) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L . In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly connected to each other, or may be connected by a complete or partial hinge or linker region. The hinge region may be composed of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which results in a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. In addition, the antigen-binding fragments of the antibodies of the present disclosure may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above, which are non-covalently bound to each other and / or to one or more monomeric V H or V L The domains are non-covalently associated (e.g., via disulfide bonds).

[0061] The constant region of an antibody is very important for the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Therefore, in some embodiments, the isotype of an antibody can be selected based on whether the antibody is required to mediate cytotoxicity.

[0062] As used herein, the term "antibody" also includes multispecific (e.g., bispecific) antibodies. A multispecific antibody or an antigen-binding fragment of an antibody generally comprises at least two different variable domains, each of which is capable of specifically binding to a separate antigen or binding to a different epitope on the same antigen. Conventional techniques available in the art can be used to adjust any multispecific antibody format for use with the antibodies or antigen-binding fragments of the present disclosure. For example, in some embodiments, the methods of the present disclosure include the use of bispecific antibodies in which one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present disclosure include, but are not limited to, e.g., scFv-based bispecific formats or diabody bispecific formats, IgG-scFv fusions, dual variable domains (DVD)-Ig, tetramers, knob-into-hole, common light chain (e.g., common light chain with knob-into-hole, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, Duobody, IgG1 / IgG2, dual-action Fab (DAF)-IgG, and Mab 2 Bispecific formats (see, e.g., Klein et al., 2012, mAbs, 4:6, 1-11, and references cited therein for a review of the aforementioned formats). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, for example, where unnatural amino acids with orthogonal chemical reactivities are used to generate site-specific antibody-oligonucleotide conjugates, which then self-assemble into multimeric complexes with defined composition, valency, and geometry. (See, e.g., Kazane, et al., J. Am. Chem. Soc., [Epub: Dec. 4, 2012])

[0063] In some embodiments, the antibody used in the method of the present disclosure is a human antibody. The term "human antibody" as used herein is intended to include antibodies with variable regions and constant regions derived from human germline immunoglobulin sequences. Nevertheless, human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (for example, mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutations in vivo), for example, in CDR, particularly in CDR3. However, the term "human antibody" as used herein is not intended to include antibodies wherein the CDR sequences derived from another mammalian species (for example, mouse) germline have been transplanted to human framework sequences.

[0064] The antibody used in the method of the present disclosure can be a recombinant human antibody. The term "recombinant human antibody" as used herein is intended to include all human antibodies prepared, expressed, produced or separated by a recombinant method, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies separated from a recombinant, combined human antibody library (described further below), antibodies separated from an animal (e.g., mouse) transgenic for human immunoglobulin genes (see, e.g., Taylor, et al. (1992) Nucl. Acids Res., 20: 6287-6295) or antibodies prepared, expressed, produced or separated by any other means involving splicing 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, the recombinant human antibodies are subjected to in vitro mutagenesis (or, when using human Ig sequence transgenic animals, somatic cell mutagenesis is performed in vivo), so that the V H and V L The amino acid sequence of the region is such a sequence that, although derived from human germline V H and V L sequences that are related to, but may not naturally occur in the human antibody germline repertoire in vivo.

[0065] An "isolated antibody" refers to an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally occurs or is naturally produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ within a recombinant cell. An isolated antibody is an antibody that has been subjected to at least one purification or separation step. According to certain embodiments, the isolated antibody may be substantially free of other cellular material and / or chemicals.

[0066] According to certain embodiments, the antibodies used in the methods of the present disclosure specifically bind to IL-4Rα. As used herein, the term "specifically binds" refers to the formation of a relatively stable complex between the antibody or its antigen-binding fragment and 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, surface plasmon resonance, and the like. In some embodiments, an antibody that "specifically binds" to IL-4Rα has an equilibrium dissociation constant (K) when bound to IL-4Rα or a portion thereof. D) less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 0.5 nM, less than about 0.25 nM, less than about 0.1 nM, or less than about 0.05 nM, as measured in a surface plasmon resonance assay (e.g., BIAcore TM , Biacore Life Sciences, a division of GE Healthcare, Piscataway, NJ). In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) may also specifically bind to another antigen, such as 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, such as IL-4Rα molecules from other (non-human) species.

[0067] In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-IL-4R antibodies described in U.S. Patent No. 7,608,693, which is incorporated herein by reference. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (HCDR) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity determining region (LCDR) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof, which comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence of LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0068] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 3, 4, 5, 6, 7, and 8, respectively, and further comprises a HCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 1 and a LCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO: 1 and a LCVR comprising SEQ ID NO: 2.

[0069] In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0070] An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 is a fully human anti-IL-4R antibody, referred to as dupilumab. According to certain exemplary embodiments, the methods of the present disclosure include the use of dupilumab. As used herein, "duplumab" also includes bioequivalents of dupilumab. The term "bioequivalent" as used herein with respect to dupilumab refers to an anti-IL-4R antibody or IL-4R binding protein or fragment thereof that is a pharmaceutical equivalent or pharmaceutical substitute and that has an absorption rate and / or extent that is not significantly different from that of dupilumab when administered at the same molar dose (single or multiple doses) under similar experimental conditions. In some embodiments, the term refers to an antigen-binding protein that binds to IL-4R and has no clinically meaningful differences in safety, purity, and / or potency from that of dupilumab.

[0071] Other anti-IL-4Rα antibodies that can be used in the context of the disclosed methods include, for example, antibodies referred to and known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796) or MEDI 9314, or U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, U.S. Patent No. 8,877,189, U.S. Patent No. 10,774,141, or International Patent Publication Nos. WO2020 / 096381, WO2020 / 182197, WO2020 / 239134, WO Any anti-IL-4Rα antibody described in WO2021 / 213329, WO2022 / 052974, WO2022 / 136669, or WO2022 / 136675, the contents of each of which are incorporated herein by reference.

[0072] In some embodiments, an anti-IL-4Rα antibody or antigen-binding fragment thereof for use in the methods of the present disclosure comprises one or more CDR, HCVR, and / or LCVR sequences listed in Table 7 below.

[0073] In some embodiments, the anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO: 32 (SCB-VH-59), SEQ ID NO: 33 (SCB-VH-60), SEQ ID NO: 34 (SCB-VH-61), SEQ ID NO: 35 (SCB-VH-62), SEQ ID NO: 36 (SCB-VH-63), SEQ ID NO: 37 (SCB-VH-64), SEQ ID NO: 38 (SCB-VH-65), SEQ ID NO: 39 (SCB-VH-66), SEQ ID NO: 40 (SCB-VH-67), SEQ ID NO: 41 (SCB-VH-68), SEQ ID NO: 42 (SCB-VH-69), SEQ ID NO: 43 (SCB-VH-70), SEQ ID NO: 44 (SCB-VH-71), SEQ ID NO: 45 (SCB-VH-72), SEQ ID NO: 46 (SCB-VH-73), SEQ ID NO: 47 (SCB-VH-74), SEQ ID NO: 48 (SCB-VH-75), SEQ ID NO: 49 (SCB-VH-80), SEQ ID NO: 50 (SCB-VH-81), SEQ ID NO: 51 (SCB-VH-82), SEQ ID NO: 52 (SCB-VH-83), SEQ ID NO: 53 (SCB-VH-84), SEQ ID NO: 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), SEQID NO: 51 (SCB-VH-78), SEQ ID NO: 52 (SCB-VH-79), SEQ ID NO: 53 (SCB-VH-80), SEQ ID NO: 54 (SCB-VH-81), SEQ ID NO: 55 (SCB-VH-82), SEQ ID NO: 56 (SCB-VH-83), SEQ ID NO: 57 (SCB-VH-84), SEQ ID NO: 58 (SCB-VH-85), SEQ ID NO: 59 (SCB-VH-86), SEQ ID NO:60(SCB-VH-87), SEQ ID NO:61(SCB-VH-88), SEQ ID NO:62(SCB-VH-89), SEQ ID NO:63(SCB-VH-90), SEQ ID NO:64(SCB-VH-91), SEQ ID NO:65(SCB-VH-92) or SEQ ID NO:66(SCB-VH-93);and (ii) an LCVR comprising the following amino acid sequence: SEQ ID NO: 12 (SCB-VL-39), SEQ ID NO: 13 (SCB-VL-40), SEQ ID NO: 14 (SCB-VL-41), SEQ ID NO: 15 (SCB-VL-42), SEQ ID NO: 16 (SCB-VL-43), SEQ ID NO: 17 (SCB-VL-44), SEQ ID NO: 18 (SCB-VL-45), SEQ ID NO: 19 (SCB-VL-46), SEQ ID NO: 20 (SCB-VL-47), SEQ ID NO: 21 (SCB-VL-48), SEQ ID NO: 22 (SCB-VL-49), SEQ ID NO: 23 (SCB-VL-50), SEQ ID NO: 24 (SCB-VL-51), SEQ ID NO: 25 (SCB-VL-52), SEQ ID NO: 26 (SCB-VL-53), SEQ ID NO: 27 (SCB-VL-54), SEQ ID NO: 28 (SCB-VL-55), SEQ ID NO: 29 (SCB-VL-56), SEQ ID NO: 30 (SCB-VL-37), SEQ ID NO: 31 (SCB-VL-38), SEQ ID NO: 32 (SCB-VL-39), SEQ ID NO: 26 (SCB-VL-53), SEQ ID NO: 27 (SCB-VL-54), SEQ ID NO: 28 (SCB-VL-55), SEQ ID NO: 29 (SCB-VL-56), SEQ ID NO: 30 (SCB-VL-57), or SEQ ID NO: 31 (SCB-VL-58). In some embodiments, the anti-IL-4Rα antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 64 (SCB-VH-91) and a LCVR comprising the amino acid sequence of SEQ ID NO: 17 (SCB-VL-44), SEQ ID NO: 27 (SCB-VL-54), or SEQ ID NO: 28 (SCB-VL-55).

[0074] In some embodiments, the anti-IL-4Rα antibody comprises an amino acid sequence pair selected from the group consisting of: SEQ ID NO: 67 / 68 (MEDI-1-VH / MEDI-1-VL); SEQ ID NO: 69 / 70 (MEDI-2-VH / MEDI-2-VL); SEQ ID NO: 71 / 72 (MEDI-3-VH / MEDI-3-VL); SEQ ID NO: 73 / 74 (MEDI-4-VH / MEDI-4-VL); SEQ ID NO: 75 / 76 (MEDI-5-VH / MEDI-5-VL); SEQ ID NO: 77 / 78 (MEDI-6-VH / MEDI-6 / VL); SEQ ID NO: 79 / 80 (MEDI-7-VH / MEDI-7-VL); SEQ ID NO: 81 / 82 (MEDI-8-VH / MEDI-8-VL); SEQ ID NO: 83 / 84 (MEDI-9-VH / MEDI-9-VL); NO: 83 / 84 (MEDI-9-VH / MEDI-9-VL); SEQ ID NO: 85 / 86 (MEDI-10-VH / MEDI-10-VL); SEQ ID NO: 87 / 88 (MEDI-11-VH / MEDI-11 / VL); SEQ ID NO: 89 / 90 (MEDI-12-VH / MEDI-12-VL); SEQ ID NO: ID NO:91 / 92(MEDI-13-VH / MEDI-13-VL); SEQ ID NO:93 / 94(MEDI-14-VH / MEDI-14-VL); SEQ ID NO:95 / 96(MEDI-15-VH / MEDI-15-VL); SEQ ID NO:97 / 98(MEDI-16-VH / MEDI-16 / VL); SEQ ID NO:99 / 100(MEDI-17-VH / MEDI-17-VL); SEQ ID NO:101 / 102(MEDI-18-VH / MEDI-18-VL); SEQ ID NO:103 / 104(MEDI-19-VH / MEDI-19-VL); SEQ ID NO:105 / 106(MEDI-20-VH / MEDI-20-VL); SEQ ID NO:107 / 108(MEDI-21-VH / MEDI-21-VL); SEQ ID NO:109 / 110(MEDI-22-VH / MEDI-22-VL); SEQ ID NO:111 / 112(MEDI-23-VH / MEDI-23-VL); SEQ ID NO:113 / 114(MEDI-24-VH / MEDI-24-VL);SEQ ID NO: 115 / 116 (MEDI-25-VH / MEDI-25-VL); SEQ ID NO: 117 / 118 (MEDI-26-VH / MEDI-26-VL); SEQ ID NO: 119 / 120 (MEDI-27-VH / MEDI-27-VL); SEQ ID NO: 121 / 122 (MEDI-28-VH / MEDI-28-VL); SEQ ID NO: 123 / 124 (MEDI-29-VH / MEDI-29-VL); SEQ ID NO: 125 / 126 (MEDI-30-VH / MEDI-30-VL); SEQ ID NO: 127 / 128 (MEDI-31-VH / MEDI-31-VL); SEQ ID NO: 129 / 130 (MEDI-32-VH / MEDI-32-VL); SEQ ID NO: 131 / 132 (MEDI-33-VH / MEDI-33-VL); SEQ ID NO: 133 / 134 (MEDI-34-VH / MEDI-34-VL); SEQ ID NO: 135 / 136 (MEDI-35-VH / MEDI-35-VL); SEQ ID NO: 137 / 138 (MEDI-36-VH / MEDI-36-VL); SEQ ID NO: 139 / 140 (MEDI-37-VH / MEDI-37-VL); SEQ ID NO: 141 / 142 (MEDI-38-VH / MEDI-38-VL); SEQ ID NO: 143 / 144 (MEDI-39-VH / MEDI-39-VL); SEQ ID NO: 145 / 146 (MEDI-40-VH / MEDI-40-VL); SEQ ID NO: 147 / 148 (MEDI-41-VH / MEDI-41-VL); SEQ ID NO: 149 / 150 (MEDI-42-VH / MEDI-42-VL); and SEQ ID NO: 151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).;

[0075] In some embodiments, the anti-IL-4Rα antibody comprises (i) a HCVR comprising an amino acid sequence of: SEQ ID NO:153 (AJOU-1-VH), SEQ ID NO:154 (AJOU-2-VH), SEQ ID NO:155 (AJOU-3-VH), SEQ ID NO:156 (AJOU-4-VH), SEQ ID NO:157 (AJOU-5-VH), SEQ ID NO:158 (AJOU-6-VH), SEQ ID NO:159 (AJOU-7-VH), SEQ ID NO:160 (AJOU-8-VH), SEQ ID NO:161 (AJOU-9-VH), SEQ ID NO:162 (AJOU-10-VH), SEQ ID NO:163 (AJOU-69-VH), SEQ ID NO:164 (AJOU-70-VH), SEQ ID NO:165 (AJOU-71-VH), SEQ ID NO:166 (AJOU-72-VH), or SEQ ID NO:167 (AJOU-83-VH); and (ii) a LCVR comprising an amino acid sequence of: SEQ ID NO:168 (AJOU-33-VL), SEQ ID NO:169 (AJOU-34-VL), SEQ ID NO:170 (AJOU-35-VL), SEQ ID NO:171 (AJOU-36-VL), SEQ ID NO:172 (AJOU-37-VL), SEQ ID NO:173 (AJOU-38-VL), SEQ ID NO:174 (AJOU-39-VL), SEQ ID NO:175 (AJOU-40-VL), SEQ ID NO:176 (AJOU-41-VL), SEQ ID NO:177 (AJOU-42-VL), SEQ ID NO:178 (AJOU-77-VL), SEQ ID NO:179 (AJOU-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).

[0076] In some embodiments, the anti-IL-4Rα antibody comprises (i) a HCVR comprising the amino acid sequence of SEQ ID NO: 188 (REGN-VH-3), SEQ ID NO: 189 (REGN-VH-19), SEQ ID NO: 190 (REGN-VH-35), SEQ ID NO: 191 (REGN-VH-51), SEQ ID NO: 192 (REGN-VH-67), SEQ ID NO: 193 (REGN-VH-83), SEQ ID NO: 194 (REGN-VH-99), SEQ ID NO: 195 (REGN-VH-115), SEQ ID NO: 196 (REGN-VH-147), or SEQ ID NO: 197 (REGN-VH-163); and (ii) a LCVR comprising the amino acid sequence of SEQ ID NO: SEQ ID NO: 198 (REGN-VL-11), SEQ ID NO: 199 (REGN-VH-20), SEQ ID NO: 210 (REGN-VH-21), SEQ ID NO: 211 (REGN-VH-22), SEQ ID NO: 212 (REGN-VH-23), SEQ ID NO: 213 (REGN-VH-24), SEQ ID NO: 214 (REGN-VH-25), SEQ ID NO: 215 (REGN-VH-26), SEQ ID NO: 216 (REGN-VH-27), SEQ ID NO: 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).

[0077] In some embodiments, the anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO: 208 (STSA-C27-VH), SEQ ID NO: 209 (STSA-C27-6-33-VH), SEQ ID NO: 210 (STSA-C27-7-33-VH), SEQ ID NO: 211 (STSA-C27-24-56-VH), SEQ ID NO: 212 (STSA-C27-47-56-VH), SEQ ID NO: 213 (STSA-C27-33-33-VH), SEQ ID NO: 214 (STSA-C27-56-56-VH), SEQ ID NO: 215 (STSA-C27-78-78-VH), SEQ ID NO: 216 (STSA-C27-82-58-VH), SEQ ID NO: 217 (STSA-C27-92-92-VH), SEQ ID NO: 218 (STSA-C27-94-94-VH), SEQ ID NO: 219 (STSA-C27-100-100-VH), SEQ ID NO: 220 (STSA-C27-101-102-VH), SEQ ID NO: 221 (STSA-C27-102-103-VH), SEQ ID NO: NO: 217 (STSA-C27-54-54-VH), SEQ ID NO: 218 (STSA-C27-36-36-VH), SEQ ID NO: 219 (STSA-C27-53-53-VH), SEQ ID NO: 220 (STSA-C27-67-67-VH), SEQ ID NO:221(STSA-C27-55-55-VH), SEQ ID NO:222(STSA-C27-59-59-VH), SEQ ID NO:223(STSA-C27-58-58-VH), SEQ ID NO:224(STSA-C27-52-52-VH) or SEQ ID NO:225(STSA-C27-Y2-Y2-VH);and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO: 226 (STSA-C27-VL), SEQ ID NO: 227 (STSA-C27-6-33-VL), SEQ ID NO: 228 (STSA-C27-7-33-VL), SEQ ID NO: 229 (STSA-C27-24-56-VL), SEQ ID NO: 230 (STSA-C27-47-56-VL), SEQ ID NO: 231 (STSA-C27-33-33-VL), SEQ ID NO: 232 (STSA-C27-56-56-VL), SEQ ID NO: 233 (STSA-C27-78-78-VL), SEQ ID NO: 234 (STSA-C27-82-58-VL), SEQ ID NO: 235 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) or SEQ ID NO: 243 (STSA-C27-Y2-Y2-VL). ;

[0078] In some embodiments, the anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence of 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 (HV3-54-15 VH), SEQ ID NO: 256 (HV3-54-15 VH), SEQ ID NO: 257 (HV3-54-15 VH), SEQ ID NO: 258 (HV3-54-15 VH), SEQ ID NO: 259 (HV3-54-15 VH), SEQ ID NO: 260 (HV3-54-15 VH), SEQ ID NO: 261 (HV3-54-15 VH), SEQ ID NO: NO: 255 (HV3-73*2-14 VH), SEQ ID NO: 256 (HV3-72-14 VH), SEQ ID NO: 257 (Y01-14 VH), SEQ ID NO: 258 (I62-14 VH) or SEQ ID NO: 259 (VH73-14 VH); and (ii) an LCVR comprising the following amino acid sequence: 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: NO:267(Y0188-10 VL), SEQ ID NO:268(Y0188-14VL), SEQ ID NO:269(Y01-14 VL), SEQ ID NO:270(164-14VL), SEQ ID NO:271(KV4-14 VL), SEQ ID NO: 272 (KV1-27-14VL), SEQ ID NO: 273 (KV1-9-14VL), SEQ ID NO: 274 (KV1-NL1-14 VL) or SEQ ID NO: 275 (KV1D-43-14VL).

[0079] In some embodiments, the anti-IL-4Rα antibodies used in the methods of the present disclosure may have pH-dependent binding characteristics. For example, the anti-IL-4Rα antibodies used as disclosed herein may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, the anti-IL-4Rα antibodies used as disclosed herein may exhibit enhanced binding to their antigens at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values ​​less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or less. The term "neutral pH" as used herein refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

[0080] In some cases, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" is expressed as the K of the antibody binding to IL-4Rα at acidic pH. D The values ​​are comparable to the K values ​​of antibodies binding to IL-4Rα at neutral pH. D For example, if the antibody or antigen-binding fragment thereof exhibits an acidic / neutral K of about 3.0 or greater, D For the purposes of this disclosure, an antibody or antigen-binding fragment thereof may be considered to exhibit "reduced binding to IL-4Rα at acidic pH compared to neutral pH" if the ratio of acidic to neutral K is greater than 1. D The ratio may be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or more.

[0081] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening for a population of antibodies that have reduced (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. In addition, modifications of the antigen-binding domain at the amino acid level can produce antibodies with pH-dependent characteristics. For example, by replacing one or more amino acids in the antigen-binding domain (e.g., within the CDRs) with histidine residues, antibodies with reduced antigen binding at acidic pH compared to neutral pH can be obtained. Preparation of human antibodies

[0082] Methods for producing human antibodies in transgenic mice are known in the art. Any such known methods can be used in the context of the present disclosure to prepare human antibodies that specifically bind to human IL-4R.

[0083] Using VELOCIMMUNE TM High affinity chimeric antibodies to IL-4R having human variable regions and mouse constant regions are initially isolated using the IL-4R technology (see, e.g., US 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies. The technology involves generating transgenic mice whose genomes contain human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, such that the mice produce antibodies containing human variable regions and mouse constant regions in response to antigenic stimulation. DNA encoding the antibody heavy and light chain variable regions is isolated and operably linked to DNA encoding human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing fully human antibodies.

[0084] Typically, challenge with the target antigen Mice, and reclaim lymphocytes (such as B cells) from the mice expressing antibodies. Lymphocytes can be fused with myeloma cell lines to prepare immortal hybridoma cell lines, and screening and selecting such hybridoma cell lines to identify hybridoma cell lines that produce antibodies specific to the target antigen. The DNA encoding the heavy chain variable region and the light chain variable region can be separated and connected to the desired heavy chain and light chain isotype constant region. This antibody protein can be produced in cells such as CHO cells. Alternatively, the DNA encoding the variable region of antigen-specific chimeric antibodies or light chain and heavy chain can be directly separated from antigen-specific lymphocytes.

[0085] First, high-affinity chimeric antibodies with human variable regions and mouse constant regions are isolated. Using standard methods known to those skilled in the art, antibodies are characterized and selected for desired characteristics, including affinity, selectivity, epitopes, etc. The mouse constant region is replaced with the desired human constant region to generate fully human antibodies disclosed herein, such as wild-type or modified IgG1 or IgG4. Although the selected constant region can vary depending on the specific application, the high-affinity antigen binding and target specificity characteristics are present in the variable region.

[0086] Typically, antibodies useful in the disclosed methods have high affinity as described above when measured by binding to an antigen immobilized in solid phase or solution phase. Mouse constant regions are substituted with desired human constant regions to generate fully human antibodies disclosed herein. Although the selected constant region may vary depending on the specific application, the high affinity antigen binding and target specificity characteristics are present in the variable region.

[0087] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to an IL-4R and can be used in the methods disclosed herein comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1, and three light chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to determine CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani, et al., J. Mol. Biol., 273:927-948 (1997); and Martin, et al., Proc. Natl. Acad. Sci., USA 86:9268-9272 (1989). Public databases can also be used to identify CDR sequences in antibodies. Pharmaceutical compositions and kits

[0088] In one aspect, the present disclosure provides methods comprising administering an IL-4R antagonist to a subject, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained in a pharmaceutical composition comprising one or more pharmaceutically acceptable solvents, carriers, and / or excipients. Various pharmaceutically acceptable carriers and excipients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.

[0089] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other bioactive agents. In some embodiments, pharmaceutical compositions disclosed herein are administered intravenously. In some embodiments, pharmaceutical compositions disclosed herein are administered subcutaneously.

[0090] In some embodiments, the pharmaceutical composition includes an injectable preparation, such as a dosage form for intravenous, subcutaneous, intradermal and intramuscular injection, infusion, etc. These injectable preparations can be prepared by known methods. For example, the above-mentioned antibody or its salt can be dissolved, suspended or emulsified in a conventional sterile aqueous medium or oily medium for injection to prepare an injectable preparation. As an aqueous medium for injection, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, etc. can be used, which can be used in combination with suitable solubilizing agents such as alcohol (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As an oily medium, for example, sesame oil, soybean oil, etc. can be used, which can also be used in combination with solubilizing agents such as benzyl benzoate, benzyl alcohol, etc. The prepared injection is placed in a suitable ampoule.

[0091] The dosage of the antibody administered to a subject according to the methods of the present disclosure can vary depending on the subject's age and size, symptoms, condition, route of administration, and the like. Dosages are typically calculated based on body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. The effective dosage and regimen for administering a pharmaceutical composition comprising an anti-IL-4R antibody can be determined empirically; for example, the subject's progress can be monitored by regular assessments, and the dosage adjusted accordingly. In addition, cross-species dose scaling can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res., 8:1351). Specific exemplary dosages of anti-IL-4R antibodies useful in the context of the present disclosure and administration regimens thereof are disclosed elsewhere herein.

[0092] In some embodiments, an IL-4R antagonist or pharmaceutical composition disclosed herein is contained within a container. Thus, in another aspect, a container comprising an IL-4R antagonist or pharmaceutical composition disclosed herein is provided. For example, in some embodiments, the pharmaceutical composition is contained within a container selected from a glass vial, a syringe, a pen delivery device, and an autoinjector.

[0093] In some embodiments, the pharmaceutical composition of the present invention is delivered with a standard needle and syringe, for example, subcutaneously or intravenously. In some embodiments, the syringe is a prefilled syringe. In some embodiments, a pen-type delivery device or an automatic injector is used to deliver the pharmaceutical composition of the present invention (for example, for subcutaneous delivery). The pen-type delivery device can be reusable or disposable. Typically, a reusable pen-type drug delivery device uses a replaceable cartridge containing the pharmaceutical composition. Once all the pharmaceutical compositions in the cartridge have been administered and the cartridge becomes 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 a disposable pen-type delivery device, there is no replaceable cartridge. In contrast, the disposable pen-type delivery device is pre-filled with the pharmaceutical composition in the reservoir held in the device. Once the pharmaceutical composition in the reservoir is emptied, the entire device is discarded.

[0094] Examples of suitable pen delivery devices and autoinjector delivery devices include, but are not limited to, AUTOPEN TM (Owen Mumford, Woodstock, UK), DISETRONIC TM Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TM Pen (Eli Lilly and Co., Indianapolis, Indiana), NOVOPEN TM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (Novo Nordisk, Copenhagen, Denmark), BD TM Pen (Becton Dickinson, Franklin Lakes, New Jersey), OPTIPEN TM 、OPTIPEN PRO TM 、OPTIPEN STARLET TM and OPTICLIK TM (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen delivery devices for subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to, SOLOSTAR TM Pen (sanofi-aventis), FLEXPEN TM (Novo Nordisk) and KWIKPEN TM(Eli Lilly), SURECLICK TM Autoinjector (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA TM Pen (Abbott Labs, Abbott Park IL).

[0095] In some embodiments, a controlled release system is used to deliver the pharmaceutical composition. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14: 201). In another embodiment, a polymeric material can be used; see, Medical Applications of Controlled Release, Langer and Wise, eds., 1974, CRC Press., Boca Raton, Florida. In another embodiment, a controlled release system can be placed near the target of the composition, so only a portion of the systemic dose is required (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, Vol. 2, pp. 115-138). Other controlled release systems are discussed in the review of Langer, 1990, Science, 249: 1527-1533. Other delivery systems are known and can be used to administer the pharmaceutical composition, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant virus, receptor-mediated endocytosis (see, e.g., Wu, et al., 1987, J. Biol. Chem., 262:4429-4432).

[0096] In some embodiments, a pharmaceutical composition comprising an anti-IL-4R antibody is administered using a drug delivery device that is a needle-based injection system as described in Table 1, Section 5.2 of ISO 11608-1:2014(E). As described in ISO 11608-1:2014(E), needle-based injection systems can be broadly divided into multi-dose container systems and single-dose (partially or completely emptied) container systems. The container can be a replaceable container or an integrated, non-replaceable container.

[0097] As further described in ISO 11608-1:2014(E), a multi-dose container system may include a needle-based injection device with a replaceable container. In such a system, each container holds multiple doses, which may be fixed or variable in size (pre-set by the user). Another multi-dose container system may include a needle-based injection device with an integrated, non-replaceable container. In such a system, each container holds multiple doses, which may be fixed or variable in size (pre-set by the user).

[0098] As further described in ISO 11608-1:2014 (E), a single-dose container system may include a needle-based injection device with a replaceable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (complete emptying). In another example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partial emptying). Also as described in ISO 11608-1:2014 (E), a single-dose container system may include a needle-based injection device with an integrated non-replaceable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (complete emptying). In another example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partial emptying).

[0099] An exemplary sleeve-triggered auto-injector with manual needle insertion is described in International Publication WO 2015 / 004052. Exemplary audible end-of-dose feedback mechanisms are described in International Publications WO 2016 / 193346 and WO 2016 / 193348. An exemplary needle safety mechanism after use of an auto-injector is described in International Publication WO 2016 / 193352. An exemplary needle shield remover mechanism for a syringe auto-injector is described in International Publication WO 2016 / 193353. An exemplary support mechanism for supporting the axial position of a syringe is described in International Publication WO 2016 / 193355.

[0100] In some embodiments, the pharmaceutical compositions used as described herein are prepared into a unit dosage form suitable for the dosage of the active ingredient. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0101] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present disclosure are disclosed, for example, in U.S. Pat. No. 8,945,559.

[0102] In another aspect, kits comprising an IL-4R antagonist or pharmaceutical composition disclosed herein are provided. In some embodiments, the kit comprises an anti-IL-4R antibody or pharmaceutical composition comprising an anti-IL-4R antibody and instructions for use in treating eosinophilic esophagitis in a pediatric subject <12 years of age (e.g., a subject ≥1 and <12 years of age) or a pediatric or adolescent subject with a baseline weight <40 kg. In some embodiments, the instructions include administering the anti-IL-4R antibody or pharmaceutical composition in an amount, dosing frequency, and / or dosing duration as disclosed elsewhere herein. Dosage and administration

[0103] In some embodiments, according to the methods of the present disclosure, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered to a subject (e.g., a subject aged ≥1 to <12 years) in a therapeutically effective amount. As used herein, with respect to an IL-4R antagonist, the phrase "therapeutically effective amount" refers to an amount of an IL-4R antagonist that results in one or more of the following: (a) a decrease in the severity or duration of symptoms of eosinophilic esophagitis; (b) a decrease in the number of eosinophils in the esophagus; (c) an improvement in one or more anatomical, endoscopic, or histological features of the esophagus; (d) an increase in esophageal distensibility; (e) a decrease in the onset or intensity of dysphagia; (f) normalization of one or more EoE-associated biomarkers or gene expression markers; and / or (g) a reduction in the use or need for concomitant or rescue therapy with another agent (e.g., a reduction or elimination of the use of systemic and / or topical corticosteroids, PPIs, etc.).

[0104] In the case of an anti-IL-4R antibody, a therapeutically effective amount can be from about 0.05 mg to about 600 mg, about 50 mg to about 600 mg, about 50 mg to about 300 mg, or about 100 mg to about 300 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg , about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg or about 600 mg of an anti-IL-4R antibody. In some embodiments, the therapeutically effective amount is from about 50 mg to about 600 mg, or from about 100 mg to about 600 mg, from about 50 mg to about 400 mg, or from about 100 mg to about 300 mg. In certain embodiments, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 300 mg of the anti-IL-4R antibody is administered to the subject.

[0105] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in an individual dose can be expressed as milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to a subject at a dose of about 0.0001 to about 10 mg / kg of subject body weight, such as about 1 mg / kg to about 10 mg / kg, about 2 mg / kg to about 9 mg / kg, or about 3 mg / kg to about 8 mg / kg. In some embodiments, the IL-4R antagonist can be administered to a subject at a dose of about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg.

[0106] In some embodiments, the methods disclosed herein comprise administering an IL-4R antagonist to a subject at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently, as long as a therapeutic response is achieved. In some embodiments, the methods disclosed herein comprise administering an IL-4R antagonist to a subject once a 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 as disclosed herein) is administered in an amount of about 50 mg to about 600 mg, e.g., about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg, once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

[0107] In some embodiments, multiple doses of an IL-4R antagonist are administered to a subject over a defined time course. In some embodiments, the methods of the present disclosure comprise sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, "sequential administration" means administering each dose of an IL-4R antagonist to a subject at different time points, such as on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the methods of the present disclosure comprise sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of an IL-4R antagonist, optionally followed by one or more tertiary doses of an IL-4R antagonist.

[0108] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the temporal order in which the IL-4R antagonist is administered. Thus, the "initial dose" is the dose administered at the beginning of a treatment regimen (also referred to as a "loading dose"); the "secondary dose" is the dose administered after the initial dose; and the "tertiary dose" is the dose administered after the second dose. The initial, second, and third doses may all contain the same amount of IL-4R antagonist, but typically differ from one another in the frequency of administration. However, in certain embodiments, the amount of IL-4R antagonist contained in the initial, second, and / or third doses differs from one another (e.g., is adjusted upward or downward, as appropriate) during the course of treatment. In some embodiments, at the beginning of a treatment regimen, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered as "loading doses," followed by subsequent doses administered on a less frequent basis (e.g., "maintenance doses"). In some embodiments, the initial or loading dose and one or more second or maintenance doses each contain the same amount of IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of the IL-4R antagonist, and the one or more second doses each comprise a second amount of the IL-4R antagonist. For example, the first amount of the IL-4R antagonist can be 1.5×, 2×, 2.5×, 3×, 3.5×, 4×, or 5× or more of the second amount of the IL-4R antagonist. In some embodiments, one or more maintenance doses of the IL-4R antagonist are administered without a loading dose.

[0109] In some embodiments, the loading dose is a "split dose," which is administered as two or more doses (e.g., 2, 3, 4, or 5 doses) administered on different days. In some embodiments, the loading dose is administered as a split dose, wherein the two or more doses are administered at least about a week apart. In some embodiments, the loading dose is administered as a split dose, wherein the two or more doses are administered about 1 week, 2 weeks, 3 weeks, or 4 weeks apart. In some embodiments, the loading dose is divided evenly into two or more doses (e.g., half of the loading dose is administered as a first portion and half of the loading dose is administered as a second portion). In some embodiments, the loading dose is divided unevenly into two or more doses (e.g., more than half of the loading dose is administered as a first portion and less than half of the loading dose is administered as a second portion).

[0110] In some embodiments, each second and / or third dose is administered 1 to 14 weeks (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2, or longer) after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" refers to the dose of the IL-4R antagonist administered to the patient in a multiple administration sequence prior to the immediately next dose in the sequence, with no intervening doses therebetween.

[0111] The methods of the present disclosure may include administering any number of second and / or third doses of an IL-4R antagonist to a patient. For example, in certain embodiments, only a single second dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) second doses are administered to a patient. Similarly, in certain embodiments, only a single third dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) third doses are administered to a patient.

[0112] In some embodiments involving multiple second doses, each second dose is administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose. Similarly, in some embodiments 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 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose. Alternatively, the frequency with which the second and / or third doses are administered to the patient may vary over the course of the treatment regimen. The frequency of administration may also be adjusted by the physician during treatment based on the needs of the individual patient after clinical examination.

[0113] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥5 kg to <15 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 100 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 200 mg loading dose, is administered.

[0114] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥5 kg to <15 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every three weeks (Q3W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 400 mg loading dose, is administered.

[0115] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥5 kg to <15 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every four weeks (Q4W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 400 mg loading dose, is administered.

[0116] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥15 kg to <30 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 400 mg loading dose, is administered.

[0117] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥15 kg to <30 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every four weeks (Q4W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 400 mg loading dose, is administered.

[0118] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥30 kg to <40 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 600 mg loading dose, is administered.

[0119] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥30 kg to <40 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 400 mg loading dose, is administered.

[0120] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥ 40 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered weekly (QW). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 600 mg loading dose, is administered.

[0121] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥ 40 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 600 mg loading dose, is administered.

[0122] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥30 kg to <60 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 600 mg loading dose, is administered.

[0123] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥30 kg to <60 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 400 mg loading dose, is administered.

[0124] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥ 60 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered weekly (QW). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 600 mg loading dose, is administered.

[0125] In some embodiments, for a subject with eosinophilic esophagitis, if the subject weighs ≥ 60 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered. In some embodiments, a loading dose, such as a 600 mg loading dose, is administered. Therapeutic dosage form

[0126] In another aspect, the present disclosure provides therapeutic dosage forms of an IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) for treating a subject having eosinophilic esophagitis as disclosed herein.

[0127] In some embodiments, if the subject weighs ≥5 kg to <15 kg, the therapeutic dose is 100 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every two weeks (Q2W).

[0128] In some embodiments, if the subject weighs ≥5 kg to <15 kg, the therapeutic dose is 200 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every three weeks (Q3W).

[0129] In some embodiments, if the subject weighs ≥5 kg to <15 kg, the therapeutic dose is 200 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every four weeks (Q4W).

[0130] In some embodiments, if the subject weighs ≥15 kg to <30 kg, the therapeutic dose is 200 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every two weeks (Q2W).

[0131] In some embodiments, if the subject weighs ≥15 kg to <30 kg, the therapeutic dose is 300 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every four weeks (Q4W).

[0132] In some embodiments, if the subject weighs ≥30 kg to <40 kg, the therapeutic dose is 300 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every two weeks (Q2W).

[0133] In some embodiments, if the subject weighs ≥30 kg to <40 kg, the therapeutic dose is 200 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every two weeks (Q2W).

[0134] In some embodiments, if the subject weighs ≥40 kg, the therapeutic dose is 300 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered weekly (QW).

[0135] In some embodiments, if the subject weighs ≥40 kg, the therapeutic dose is 300 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every two weeks (Q2W).

[0136] In some embodiments, if the subject weighs ≥30 kg to <60 kg, the therapeutic dose is 300 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every two weeks (Q2W).

[0137] In some embodiments, if the subject weighs ≥30 kg to <60 kg, the therapeutic dose is 200 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every two weeks (Q2W).

[0138] In some embodiments, if the subject weighs ≥ 60 kg, the therapeutic dose is 300 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered weekly (QW).

[0139] In some embodiments, if the subject weighs ≥ 60 kg, the therapeutic dose is 300 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody), and is administered once every two weeks (Q2W). EoE-related parameters

[0140] In some embodiments, the treatment methods disclosed herein result in improvement in one or more endpoints or EoE-associated parameters used to assess the presence or severity of EoE in a subject. Examples of EoE-associated parameters include, but are not limited to: (a) a change (e.g., a decrease) in the esophageal intraepithelial eosinophil count; (b) a change in the severity and / or extent of histological features in the esophagus, e.g., as measured using the Eosinophilic Esophagitis Histological Scoring System (EoE-HSS); (c) a change in one or more esophageal characteristics, such as the absence, presence, or severity of edema, rings, exudates, grooves, and / or strictures, e.g., as measured using the EoE-EREFS; (d) a change (e.g., normalization) in the level of one or more EoE-associated biomarkers or an EoE gene expression signature; (e) a change (e.g., a decrease) in the frequency and / or intensity of dysphagia, e.g., as measured using the Dysphagia Symptom Questionnaire (DSQ), the Straumann Dysphagia Instrument (SDI), the Patient Global Impression of Change (PGIC), or the Patient Global Impression of Severity (PGIC). or (f) changes in the frequency and / or severity of other symptoms of EoE, e.g., as measured by the Pediatric EoE Signs / Symptoms Questionnaire (PESQ) Patient Version (PESQ-P) or Caregiver Version (PESQ-C), the Pediatric EoE Impact Scale (PEIS) Patient Version (PEIS-P) or Caregiver Version (PEIS-C), the Global Impression of Change (GIC) Patient Version (GIC-P), Caregiver Version (GIC-C), or Clinician Version (GIC-Clin), the Global Impression of Severity (GIS) Patient Version (GIS-P), Caregiver Version (GIS-C), or Clinician Version (GIS-Clin), or the Pediatric Esophagitis Symptom Score (PEESS). Methods for assessing these and other EoE-related parameters are described in the Examples section below and are also disclosed in WO 2019 / 028367 and WO 2021 / 237110, which are incorporated herein by reference.

[0141] To determine whether an EoE-associated parameter has "improved," the parameter is quantified at baseline (e.g., before initiation of treatment with the IL-4R antagonist) and at one or more time points after administration of the IL-4R antagonist. For example, EoE-associated parameters can 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 at the end of 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 more after initial treatment with a pharmaceutical composition of the present disclosure. The difference between the parameter value at a specific time point after the start of treatment and the parameter value at baseline was used to determine whether the EoE-related parameter had improved.

[0142] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement (e.g., a decrease) in the peak esophageal intraepithelial eosinophil count. "Peak esophageal intraepithelial eosinophil count" refers to the number of eosinophils contained within one high-power field (hpf). In some embodiments, treatment with an IL-4R antagonist results in a decrease in the peak esophageal intraepithelial eosinophil count relative to a baseline (e.g., the subject's peak count before treatment began). In some embodiments, treatment with an IL-4R antagonist results in a peak esophageal intraepithelial eosinophil count that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to a baseline. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the peak esophageal intraepithelial eosinophil count to less than 10 eos / hpf or less than 6 eos / hpf. In some embodiments, IL-4R antagonist treatment results in a reduction in peak esophageal intraepithelial eosinophil count to ≤6eos / hpf, ≤5eos / hpf, ≤4eos / hpf, ≤3eos / hpf, ≤2eos / hpf, or ≤1eos / hpf. In some embodiments, treatment with an IL-4R antagonist results in a histological disease remission as measured by a peak esophageal intraepithelial eosinophil count of ≤6eos / hpf. In some embodiments, the change in peak esophageal intraepithelial eosinophil count is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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 an IL-4R antagonist.

[0143] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in one or more histological features of EoE. In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in the EoE-HSS score. The EoE-HSS is a validated tool that generates separate severity (grade) and extent (stage) disease scores. The score measures eight histological features (parameters) of EoE from three different regions of the esophagus (proximal, mid, and distal) (Collins et al., Dis Esophagus, 2017, 30: 1-8). The eight parameters include: eosinophil density, basal hyperplasia, eosinophilic abscesses, eosinophilic surface stratification, enlarged intercellular spaces, surface epithelial changes, dyskeratotic cells, and lamina propria fibrosis. Each parameter (grade and stage) uses a scale of 0-3 (0 indicating minimal inflammation, normal). In some embodiments, treatment with an IL-4R antagonist results in a decrease in EoE-HSS score relative to baseline (e.g., the subject's EoE-HSS score before the start of treatment) by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the EoE-HSS composite score, grade score, and / or stage score. In some embodiments, the change in EoE-HSS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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.

[0144] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in one or more endoscopic features of EoE. In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in the EoE-EREFS score. EoE-EREFS (edema, rings, exudates, grooves, strictures) is a validated scoring system for disease inflammation and remodeling features that measures endoscopically identified esophageal mucosal inflammation and remodeling features of EoE (Hirano, et al., Gut, 2013, 62:489-495). The tool includes a total of 17 items related to the presence and severity of esophageal features. Specific esophageal characteristics included: rings (concentric rings around the esophagus – absent, mild, moderate, severe, not applicable); strictures (esophageal stricture – yes, no, not applicable); stricture diameter (if applicable); exudates (white spots – absent, mild, severe); grooves (vertical lines below the esophagus – absent, present); edema (loss of mucosal vascular markings – absent, present); crepe-paper esophagus (absent, present); and gross appearance, including all endoscopically identified EoE findings (ie, fixed rings, strictures, white exudates, grooves, edema, and crepe-paper mucosa). In addition, mucosal changes associated with gastroesophageal reflux disease were recorded using the Los Angeles erosion classification system (no erosion or LA classification A, B, C, D). In some embodiments, treatment with an IL-4R antagonist results in a decrease in EoE-EREFS score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline (e.g., the subject's EoE-EREFS score before the start of treatment). In some embodiments, the change in EoE-EREFS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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 an improvement in one or more EoE-EREFS subscores.

[0145] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in dysphagia symptoms. In some embodiments, treatment results in a change (e.g., a decrease) in the frequency and / or intensity of dysphagia in a subject, for example, as measured using the Dysphagia Symptom Questionnaire (DSQ), the Straumann Dysphagia Instrument (SDI), the Patient Global Impression of Change (PGIC), or the Patient Global Impression of Severity (PGIS). In some embodiments, treatment results in a decrease in the frequency of dysphagia episodes per week, for example, a decrease of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline (e.g., the average frequency of dysphagia episodes per week in the subject before treatment began). In some embodiments, treatment results in an improvement in the DSQ score or SDI. The DSQ is a validated PRO that has been used in clinical studies to measure the frequency and intensity of dysphagia. See, Hudgens, et al., J Patient Rep Outcomes, 2017, 1(1):3, doi:10.1186 / s41687-017-0006-5. The SDI is an unvalidated patient-reported outcome (PRO) that has been used in clinical studies to determine the frequency and intensity of dysphagia (Straumann, Gastroenterology, 2010, 139:1526-1537). In some embodiments, treatment with an IL-4R antagonist results in a decrease in DSQ score by at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more points relative to baseline. In some embodiments, treatment with an IL-4R antagonist results in a decrease in DSQ score or SDI score by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more relative to baseline. In some embodiments, the change in score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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 the IL-4R antagonist reduces dysphagia symptoms in the subject (e.g., as measured by a change in absolute DSQ score or a percentage decrease in DSQ or SDI score relative to the subject's baseline value) within about 4, 5, 6, 7, 8, 9, or 10 weeks of initiating treatment with the IL-4R antagonist.

[0146] In some embodiments, treatment of a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in normalization of one or more EoE-associated biomarkers, EoE gene signatures, type 2 inflammatory gene signatures, and / or a normalized enrichment score (NES) calculated for a panel of EoE-associated genes. In some embodiments, treatment of a subject with an IL-4R antagonist suppresses the EoE gene signature, type 2 inflammatory gene signature, and / or a NES calculated for a panel of EoE-associated or type 2 inflammatory genes. As used herein, the term "EoE-associated biomarker" refers to a biological reaction, cell type, parameter, protein, polypeptide, enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or other biomolecule that is present or detectable in an EoE patient at a level or amount that is different (e.g., greater than or less than) than a marker that is present or detectable in a non-EoE patient. In some embodiments, an EoE-associated biomarker is a gene associated with fibrosis, tissue remodeling, or epithelial barrier function. Exemplary EoE-associated biomarkers include, but are not limited to, e.g., esophageal eosinophils, eotaxin-3 (CCL26), periostin (POSTN), serum IgE (total and allergen-specific), serum IgG (total and allergen-specific), arachidonic acid 15-lipoxygenase (ALOX15), IL-13, IL-5, serum thymus and activation-regulated chemokine (TARC; CCL17), thymic stromal lymphopoietin (TSLP), serum eosinophilic cationic protein (ECP), collagen genes (e.g., COL4A3, COL4A4, COL4A6, COL8A2, COL14A1, and COL21A1), calpain 14, desmoglein-1 (DSG1), filaggrin (FLG), signal transducer and activator of transcription 6 (STAT6), serine peptidase inhibitor Kazal-type 5 (SPINK5), SPINK7, SPINK8, interleukin 4 receptor (IL-4R), eosinophil-related genes (such as CLC and SIGLEC8), anoctamin-1 (ANO1), cathepsin CC (CTSC), CC chemokine receptor 3 (CCR3), and eosinophil-derived neurotoxin (EDN). The term "EoE gene signature" refers to the differential gene expression profile of esophageal biopsies of EoE patients compared to healthy controls, and is also referred to as the "EoE disease transcriptome" (Sherrill, et al., Genes Immun, 2014, 15:361-369). In some embodiments, the EoE gene signature is a smaller set of genes from a published EoE disease transcriptome, such as the EoE diagnostic panel (EDP, clinically available EoGenius TM, Inform Diagnostics, USA). "Type 2 inflammatory gene signature" refers to a transcriptome of a group of genes associated with type 2 inflammation. Exemplary type 2 inflammation-related genes include, but are not limited to, CCL26, ALOX15, CCR3, and IL1RL1. An exemplary gene list of type 2 inflammatory gene signatures is shown in WO 2021 / 237110. The normalized enrichment score (NES) reflects the extent to which the activity level of a group of transcripts is overrepresented at the extremes (top or bottom) of the entire ranked list of transcripts within the sample and is normalized by taking into account the number of transcripts in the group (Subramanian, et al., Proc Natl Acad Sci USA, 2005, 102: 15545-50) (Barbie, et al., Nature, 2009, 462: 108-112).

[0147] In some embodiments, EoE-associated biomarkers, EoE gene signatures, Type 2 inflammatory gene signatures, and / or NES are determined using a tissue sample from the subject (e.g., an esophageal pinch biopsy sample from the proximal, mid, and / or distal regions). In some embodiments, treatment of a subject with an IL-4R antagonist results in normalization of one or more EoE-associated biomarkers, EoE gene signatures, Type 2 inflammatory gene signatures, and / or NES relative to baseline (e.g., the subject's expression level of an EoE-associated biomarker, EoE gene signature, or NES before starting treatment), e.g., as measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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 can suppress NES of one or more EoE-associated biomarkers, EoE gene signatures, or Type 2 inflammation gene signatures relative to baseline (e.g., the subject's NES before initiation of treatment), e.g., measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist.

[0148] In some embodiments, treating a subject with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in improvement in one or more other signs or symptoms of EoE or improvement in health-related quality of life.

[0149] In some embodiments, treatment results in an improvement in the PESQ score. The PESQ is available in a patient version (PESQ-P) for EoE patients aged 8-12 years and a caregiver version (PESQ-C) for caregivers of EoE patients aged 1-11 years. Both questionnaires measure the same concepts; the PESQ-P assesses the frequency, duration, and / or severity of symptoms, and the PESQ-C assesses the presence / absence of signs / symptoms. These symptoms include stomach pain, heartburn, acid reflux, regurgitation, vomiting, food refusal, difficulty swallowing, and food stuck in the throat. See, Kamat, et al., J Allergy Clin Immunol: In Practice, 2022, ISSN: 2213-2198. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the PESQ score relative to baseline of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the change in PESQ score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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 reduces the number of days with one or more signs of EoE or the total number of segments in a day (e.g., nighttime, morning, afternoon, evening) as measured by PESQ-P or PESQ-C. In some embodiments, treatment with an IL-4R antagonist improves one or more signs / symptoms measured by the PESQ.

[0150] In some embodiments, treatment results in an improvement in the PEIS score. The PEIS is available in a patient version (PEIS-P) that is intended to be completed independently by pediatric EoE patients aged 8-12 years, and a caregiver version (PEIS-C) that is intended for use by caregivers of EoE patients aged 1-11 years. The PEIS-P assesses the impact of EoE on the patient's health-related aspects over the past week, while the PEIS-C assesses the impact of EoE in pediatric patients on caregiver anxiety, social and occupational activities, daily living activities, and relationships over the past week. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the PEIS score relative to baseline of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more. In some embodiments, the change in PEIS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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.

[0151] In some embodiments, treatment results in an improvement in the GIC score. The GIC is a single outcome measure that includes a patient version (GIC-P), intended to be completed independently by pediatric EoE patients aged 8-12 years, a caregiver version (GIC-C), intended to be completed independently by caregivers of EoE patients aged 1-11 years, and a clinician version (GIC-Clin), intended to be completed independently by physicians for EoE patients aged 1-11 years. All measures are based on the same concept: the GIC-P assesses the patient's impression of the overall change (improvement or worsening) in his / her EoE condition since the start of study treatment, while the GIC-C and GIC-Clin assess the caregiver's or physician's impression of the overall change (improvement or worsening) in the pediatric patient's EoE condition since the start of study treatment, respectively. In some embodiments, treatment with an IL-4R antagonist results in an improvement (e.g., a decrease) in the GIC score relative to baseline of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more. In some embodiments, the change in GIC score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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.

[0152] In some embodiments, treatment results in an improvement in the GIS score. The GIS is a single outcome measure that includes a patient version (GIS-P), intended to be completed independently by pediatric EoE patients aged 8-12 years, a caregiver version (GIS-C), intended to be completed independently by caregivers of EoE patients aged 1-11 years, and a clinician version (GIS-Clin), intended to be completed independently by physicians for EoE patients aged 1-11 years. All measures are based on the same concept: the GIS-P assesses the patient's impression of the overall severity of his / her EoE condition over the past week, while the GIS-C and GIS-Clin assess the caregiver's or physician's impression of the overall severity of the pediatric patient's EoE condition over the past week, respectively. In some embodiments, treatment with an IL-4R antagonist results in an improvement (e.g., a decrease) in the GIS score relative to baseline of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the change in GIS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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.

[0153] In some embodiments, treatment results in an improvement in the PEESS score. The PEESSv2.0 is a caregiver-reported outcome measure that assesses the frequency and severity of EoE symptoms in pediatric patients (Franciosi, 2011). The PEESSv2.0 caregiver version consists of 20 items and has a one-month recall period. The total PEESSv2.0 score ranges from 0 to 100; higher scores indicate a greater symptom burden in pediatric EoE patients. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the PEESS score relative to baseline of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, treatment with an IL-4R antagonist results in a decrease in the PEESS score relative to baseline of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more points. In some embodiments, the change in PEESS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113, or later 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.

[0154] In some embodiments, treatment with an IL-4R antagonist results in improved weight gain relative to the patient's baseline weight, compared to a control (e.g., a patient receiving a placebo). In some embodiments, treatment with an IL-4R antagonist results in an increase in body weight of at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3% or more relative to baseline. In some embodiments, the change in body weight is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later 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. Combination therapy

[0155] In some embodiments, the methods of the present disclosure comprise administering to a subject (e.g., a subject ≥1 year old and <12 years old) an IL-4R antagonist according to the present disclosure (e.g., an anti-IL-4R antibody) in combination with one or more additional therapeutic agents. As used herein, the expression "in combination with" refers to administration of the additional therapeutic agent before, after, or simultaneously with the pharmaceutical composition comprising the IL-4R antagonist. The term "in combination with" also encompasses sequential or simultaneous administration of the IL-4R antagonist and the second therapeutic agent or therapy.

[0156] For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent can be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition comprising an IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition comprising an IL-4R antagonist. Administration "concurrently" or with a pharmaceutical composition comprising an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than about 10 minutes of (before, after, or simultaneously with) administration of the pharmaceutical composition comprising the IL-4R antagonist, or that the additional therapeutic agent is administered to the subject as a single combined dose formulation comprising the additional therapeutic agent and the IL-4R antagonist.

[0157] 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 eosinophil Chemokine-3 inhibitors, IgE inhibitors (e.g., anti-IgE antibodies such as omalizumab), TSLP inhibitors (e.g., anti-TSLP antibodies such as tezepelumab), 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, nonsteroidal anti-inflammatory drugs (NSAIDs), esophageal dilation, feeding tubes, allergen removal, or dietary management. In some embodiments, the IL-4R antagonist is used in combination with dietary management, allergen removal, or feeding tubes. In some embodiments, the IL-4R antagonist is used in combination with a corticosteroid (e.g., a topical corticosteroid that is swallowed). In some embodiments, an IL-4R antagonist is used in combination with a PPI (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

[0158] In some embodiments, administration of an IL-4R antagonist reduces dependence on or the need to use a concurrent therapy (e.g., a PPI, corticosteroids, glucocorticoids, or a feeding tube). In some embodiments, administration of an IL-4R antagonist in combination with a second therapy (e.g., a PPI, corticosteroids, glucocorticoids, or a feeding tube) 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 prior to treatment with the IL-4R antagonist. In some embodiments, administration of an IL-4R antagonist eliminates the need for a second therapy. Example

[0159] The following examples are presented to provide a complete disclosure and description of how to prepare and use the methods and compositions of the present disclosure to those of ordinary skill in the art and are not intended to limit the scope of the present invention as considered to be its disclosure. Efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is degrees Celsius, and pressure is at or near atmospheric pressure. Example 1: Clinical trial investigating the efficacy and safety of dupilumab in pediatric patients with eosinophilic esophagitis Study design and objectives

[0160] The study is a Phase 3, multicenter, randomized, three-part, double-blind, placebo-controlled study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and immunogenicity of dupilumab in pediatric patients (aged ≥1 year to <12 years) with active EoE. The study consists of a screening period of up to 85 days, a double-blind 16-week treatment period (Part A), an open-label 36-week extension treatment period (Part B), a 108-week open-label extension period (Part C), and a 12-week follow-up period. Dupilumab is a fully human anti-IL-4R antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NOs: 1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NOs: 3-8.

[0161] The primary objective of this study was to demonstrate the efficacy of dupilumab treatment compared with placebo in pediatric patients with active EoE, based on histologic improvement that met validated histologic criteria. Secondary objectives included: demonstrating the efficacy of dupilumab compared with placebo in pediatric patients with active EoE after 16 weeks of treatment, as assessed by endoscopic visual measurement of disease activity using the Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-EREFS) and histological abnormalities measured by the EoE Histology Scoring System (EoE-HSS); evaluating the safety, tolerability, and immunogenicity of dupilumab treatment for up to 16 weeks in pediatric patients with active EoE; evaluating the effect of dupilumab on transcriptomic signatures associated with EoE and type 2 inflammation; investigating the effect of dupilumab on type 2 inflammation gene expression signatures; assessing the concentration-time profile of functional dupilumab in serum in this population; evaluating the long-term efficacy of dupilumab treatment (up to 160 weeks); and evaluating the effects of dupilumab treatment on the expression of type 2 inflammation genes during the extended active phase of the study. The objectives were to evaluate the effects of dupilumab treatment on changes in body weight and growth during the initial phase (up to 160 weeks) and the open-label extension phase; to assess the long-term safety, tolerability, and immunogenicity of dupilumab treatment; and to assess the effects of dupilumab treatment on the signs and symptoms of EoE.

[0162] The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guidelines, and applicable regulatory requirements. The protocol was reviewed and approved by the institutional review boards / ethics committees at all sites. Written informed consent was obtained from parents or legal guardians for all patients. Patient population

[0163] The study included pediatric patients (aged ≥1 year to <12 years at the screening visit) with active EoE.

[0164] Inclusion criteriaPatients were required to meet the following criteria to be eligible for inclusion in the study: (1) male or female, aged ≥1 to <12 years; (2) confirmed EoE by endoscopic biopsy prior to screening, with the diagnosis showing intraepithelial eosinophilic infiltration (peak eosinophil count ≥15eos / hpf) in at least 1 esophageal region (400×), performed after receiving at least 8 weeks of PPI therapy. If the patient discontinued PPI therapy, the biopsy had to be performed within 2 weeks of the date of discontinuation of therapy. If there was no previous (documented) endoscopic biopsy meeting these criteria (or a previous biopsy was unavailable), patients who met the other clinical and laboratory eligibility criteria were to receive at least 8 weeks of PPI therapy during the screening period before their baseline endoscopy / biopsy. (3) Baseline endoscopic biopsy with central readings showing intraepithelial eosinophilic infiltration (peak eosinophil count ≥15eos / hpf) in at least 2 of the 3 biopsied esophageal regions (proximal, mid, or distal); (4) History of symptoms attributed to EoE (e.g., abdominal pain, chest pain, acid reflux, food regurgitation, dysphagia, vomiting, or food refusal) determined by the investigator in the month prior to screening (reported by the patient or caregiver); (5) Patients aged ≥8 years to <12 years, and all patients' caregivers or legal guardians must be able to understand and complete the study requirements and study-related questionnaires. At least 8 of the 14-day PESQ-C electronic diary should be completed prior to baseline / visit 3. (6) Parents or legal guardians must provide signed informed consent. Patient consent should be obtained in accordance with local regulatory (competent authority / ethics) guidelines, as appropriate, based on the patient's age and maturity.

[0165] Exclusion criteria: Exclusion criteria for Part A of the study were as follows: (1) weight <5 kg or ≥60 kg at screening; (2) participation in a clinical trial of dupilumab, or past or current treatment with dupilumab; (3) initiation or change of a food-elimination diet regimen or reintroduction of previously excluded food groups within 6 weeks prior to screening. Patients on a food-elimination diet had to maintain the same diet throughout the study. (4) esophageal eosinophilia Other causes of eosinophilia or the following conditions: eosinophilic gastroenteritis, hypereosinophilic syndrome, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome); (5) active Helicobacter pylori infection; (6) helminthic infection; (7) history of Crohn's disease, ulcerative colitis, celiac disease, or previous esophageal surgery; (8) any esophageal stricture that cannot be performed by standard diagnostic upper endoscopy or any severe esophageal stricture that requires dilation at screening; (9) any swallowing procedure within 8 weeks before the baseline standard endoscopy. (10) received subcutaneous immunotherapy (SCIT) unless on stable maintenance dose for at least 1 year; (11) received previous treatment with sublingual immunotherapy (SLIT), epicutaneous immunotherapy (EPIT), or oral immunotherapy (OIT); (12) started, discontinued, or changed the dosage regimen of the following medications within 8 weeks before baseline endoscopy: PPI, leukotriene inhibitor, and nasal and / or inhaled corticosteroids; (13) received systemic immunosuppressive / immunomodulatory medication within 3 months before screening. Including but not limited to systemic corticosteroids, mepolizumab, omalizumab, cyclosporine, mycophenolate-mofetil, interferon-γ [IFN-γ], Janus kinase inhibitors, azathioprine and methotrexate (Note: corticosteroids are allowed to be used once as part of the anesthetic preparation during each endoscopy); (14) Use of study drugs within 2 months or within 5 half-lives (if known) before the first visit (15) A history of bleeding disorders or esophageal varices that the investigator believes puts the patient at excessive risk of serious complications during endoscopy; (16) Planned or anticipated use of any prohibited medications and procedures during the study; (17) Planned or anticipated major surgical procedures during the study; (18) Treatment with live (attenuated) vaccines within 4 weeks prior to the baseline visit; (19) Active parasitic infection or suspected parasitic infection unless clinical and (if necessary) laboratory evaluations exclude active infection before randomization;(20) Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks prior to the baseline visit (note: patients may be rescreened after the infection resolves); (21) Known or suspected immunodeficiency, including a history of invasive opportunistic infections (e.g., tuberculosis [TB], nontuberculous mycobacterial infections, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis) despite resolution of the infection, or infections that recur at an unusual frequency, or long-term infections that indicate an immunocompromised state, as judged by the investigator; 22) Known history of human immunodeficiency virus (HIV) infection or positive hepatitis B or hepatitis C antigen; (23) Currently receiving treatment for liver disease including but not limited to acute or chronic hepatitis, cirrhosis or liver failure, or evidence of liver disease, as manifested by persistent elevation of transaminases (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) during the screening period (confirmed by repeated testing at intervals of ≥2 weeks) and the elevation exceeding 3 times the upper limit of normal [ULN]); (24) Any of the following abnormal laboratory values ​​at screening: platelets <100×10; 3 / μL, neutrophils <1.5×10 3 / μL, or estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m 2(25) Serious concomitant illnesses that the investigator judges will adversely affect the patient's participation in the study. Examples include, but are not limited to, short life expectancy, uncontrolled diabetes, cardiovascular disorders (e.g., NYHA Class III or IV heart failure), severe renal conditions (e.g., patients undergoing dialysis), hepatobiliary conditions (e.g., Child-Pugh Class B or C), neurologic conditions (e.g., demyelinating diseases), active major autoimmune conditions (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), and other serious endocrine, gastrointestinal, metabolic, pulmonary, or lymphatic diseases. (26) History of malignancy within 5 years prior to screening; (27) History of alcohol or drug abuse within 6 months prior to screening in the opinion of the investigator; (28) Any other medical or psychological condition, including laboratory abnormalities relevant at screening, that the investigator believes indicates the presence of a new and / or underappreciated disease that may expose the study patient to unreasonable risk due to his / her participation in this clinical trial, may make the patient's participation unreliable, or may interfere with study assessments; (29) The patient's immediate family member is a member of the investigational team; (30) The patient is female and is pregnant, breastfeeding, or plans to become pregnant or breastfeed during the study; (31) The patient is of childbearing potential but is unwilling to use highly effective contraceptive measures before the initial dose / start of the first treatment, during the study, and for at least 12 weeks after the last dose; (32) Female patients who have experienced menarche and are unwilling to comply with the precautions for women of childbearing potential (WOCBP); (33) Known systemic allergic reaction to dupilumab or the excipients of the drug product.

[0166] Exclusion criteria for Part B (extended active treatment) of the study were as follows: (1) patients who experienced a SAE and / or AE that was considered related to study drug during the double-blind treatment period and led to discontinuation of study drug (patients who discontinued study drug prematurely due to lack of efficacy were eligible for Part B); (2) patients who withdrew prematurely during the double-blind treatment period due to protocol violations, poor compliance, or inability to complete required study assessments; (3) patients who did not undergo endoscopy and biopsy at week 16 or before receiving rescue treatment; and (4) female patients who experienced menarche and were unwilling to follow WOCBP precautions.

[0167] For patients who continued to participate in the study, the exclusion criteria for Part C (OLE) of the study were as follows: (1) patients who experienced a SAE and / or AE that was considered related to the study drug and led to discontinuation of the study drug during the extended active treatment period (patients who discontinued the study drug prematurely due to lack of efficacy were eligible for Part C); (2) patients who withdrew prematurely during the extended active treatment period due to protocol violations, poor compliance, or inability to complete required study assessments; (3) patients who did not undergo endoscopy and biopsy at week 52 or before receiving rescue treatment; and (4) female patients who experienced menarche and were unwilling to follow WOCBP precautions. Study Treatment

[0168] Study drug treatments were as follows: Dupilumab 150 mg / mL: Each 2.25 mL disposable prefilled glass syringe with a snap-off cap delivers 300 mg of study drug (2.0 mL of a 150 mg / mL solution). Dupilumab 175 mg / mL: Each 1.14 mL disposable prefilled glass syringe with a snap-off cap delivers 200 mg of study drug (1.14 mL of a 175 mg / mL solution). Dupilumab 150 mg / mL: Each 0.67 mL disposable prefilled glass syringe with a snap-off cap delivers 100 mg of study drug (0.67 mL of a 150 mg / mL solution). Placebo-matched dupilumab is prepared in the same formulation without added protein (i.e., active substance, anti-IL-4Rα monoclonal antibody). Three matching placebo formulations will be used: 2 mL of placebo matching the 300 mg dupilumab formulation 1.14 mL of placebo matching the 200 mg dupilumab formulation 0.67 mL of placebo matching the 100 mg dupilumab formulation

[0169] Part A was the double-blind, placebo-controlled portion of the study. In Part A, patients were randomly assigned in a 1:1:1 ratio to receive either higher-exposure dupilumab or lower-exposure dupilumab (using a graded, weight-based dosing schedule according to baseline body weight) or placebo via subcutaneous (SC) administration over 16 weeks.

[0170] The dosing schedule for Part A is as follows: Higher-exposure dupilumab regimen (Part A): For patients weighing ≥5 kg to <15 kg, 100 mg every 2 weeks For patients weighing ≥15 kg to <30 kg, 200 mg every 2 weeks For patients weighing ≥30 kg to <60 kg, 300 mg every 2 weeks Lower exposure dupilumab regimen (Part A): For patients weighing ≥5 kg to <15 kg, 200 mg every 4 weeks For patients weighing ≥15 kg to <30 kg, 300 mg every 4 weeks For patients weighing ≥30 kg to <60 kg, 200 mg every 2 weeks NOTE: In Part A, patients will receive dupilumab injections every 2 weeks or every 4 weeks, with matching placebo alternating with the dupilumab dose, so for the purpose of protocol-blinded testing based on treatment assignment in Part A, the injection frequency will be Q2 weeks in both groups. Placebo in Part A: Dose-matched placebo was administered Q2W or alternating with dupilumab Q4W, so that for the purpose of protocol-blind testing in Part A, the frequency was Q2W in both groups.

[0171] Part B is the extended active treatment portion of the study. All patients (Part A active and placebo) will be randomly assigned to receive dupilumab in either the higher or lower exposure groups based on their weight at Visit 8 (Week 16, end of the double-blind treatment period or start of the extended treatment period). If weight tiers increase at Visit 12 / Week 32, patients will be reassigned to the extended active treatment regimen based on the following weight-tiered dosing schedule: Higher-exposure dupilumab regimen (Part B): For patients weighing ≥5 kg to <15 kg, 100 mg every 2 weeks For patients weighing ≥15 kg to <30 kg, 200 mg every 2 weeks For patients weighing ≥30 kg to <60 kg, 300 mg every 2 weeks For patients weighing ≥60 kg, 300 mg every 2 weeks Lower exposure dupilumab regimen (Part B): For patients weighing ≥5 kg to <15 kg, 200 mg every 4 weeks For patients weighing ≥15 kg to <30 kg, 300 mg every 4 weeks For patients weighing ≥30 kg to <60 kg, 200 mg every 2 weeks For patients weighing ≥60 kg, 300 mg every 2 weeks Note: In Part B, study drug or matching placebo will be administered Q2W to all patients in the <60 kg group and QW to all patients in the ≥60 kg group. For protocol-blinded testing, patients will receive alternating doses of dupilumab or placebo Q2W (specify a Q4W schedule for patients <60 kg) or QW (specify a Q2W schedule for patients ≥60 kg). Placebo in Part B: Dose-matched placebo was administered alternating with dupilumab every 2 weeks or every 4 weeks, so that for the purpose of protocol-blind testing in Part B, the frequency was every 2 weeks for the group weighing <60 kg and every week for the group weighing ≥60 kg.

[0172] Part C is the open-label extension period of the study. All patients (Part C) will receive the higher-exposure dupilumab regimen based on weight at Visit 17 (Week 52, end of the extended active treatment period) or the start of the open-label period (for re-enrolled patients). All patients who received a lower-exposure dupilumab regimen during Part B will be reassigned to the higher-exposure dupilumab regimen at the start of the open-label period (Part C). If weight gain places a patient in a higher weight tier at Visit 17 / Week 52 (or the start of the open-label period for re-enrolled patients) or at a designated clinical visit in Part C, the patient will be reassigned to the open-label treatment regimen based on the weight-tiered dosing schedule specified below. Higher exposure dupilumab regimen (Part C): For patients weighing ≥5 kg to <15 kg, 200 mg every 3 weeks For patients weighing ≥15 kg to <30 kg, 200 mg every 2 weeks For patients weighing ≥30 kg to <60 kg, 300 mg every 2 weeks For patients weighing ≥60 kg, 300 mg every 2 weeks NOTE: In Part C, only active study drug (duplimab) will be administered. Matching placebo will not be administered in Part C. For Part C, patients located in countries where dupilumab is commercially available for the treatment of patients ≥12 years of age with EoE will receive study drug until they are (1) at least 12 years of age and (2) weigh at least 40 kg or the minimum weight for the approved indication for EoE. These patients will have an end-of-treatment visit at the next scheduled study visit after meeting these two criteria and an end-of-study follow-up visit 12 weeks later.

[0173] Background treatmentPatients who were receiving a PPI on trial therapy prior to screening or during Part A screening could choose to remain on the PPI regimen throughout the study or discontinue the PPI regimen before baseline; they then had to remain PPI-free throughout the study.

[0174] Rescue treatment Study patients are permitted to use rescue medication (systemic and / or topical corticosteroids) or urgent esophageal dilation if medically necessary (e.g., for the treatment of intolerable EoE symptoms). An endoscopy and biopsy will be performed prior to the initiation of rescue therapy. Patients who undergo an endoscopy and biopsy due to the initiation of rescue therapy will not receive subsequent scheduled endoscopy / biopsy at Week 16 and / or Week 52. Patients who receive rescue therapy during the double-blind phase of the study will not be eligible for the extended active treatment period unless an endoscopy and biopsy are performed prior to the initiation of rescue therapy. Patients who receive rescue therapy may continue to receive study medication. They will remain blinded and will be required to return to the clinic for all remaining study visits during the double-blind treatment and follow-up periods. For the purposes of efficacy analyses, patients who receive rescue therapy during the study will be considered treatment failures. Evaluation results

[0175] The primary endpoint was the proportion of patients achieving a peak esophageal intraepithelial eosinophil count ≤6eos / hpf (400x) at week 16.

[0176] Key secondary endpoints were: proportion of patients achieving a peak esophageal intraepithelial eosinophil count <15eos / hpf at week 16; percent change in peak esophageal intraepithelial eosinophil count (eos / hpf) from baseline to week 16; absolute change in mean EoE grade score on the EoE-HSS from baseline to week 16; absolute change in mean EoE stage score on the EoE-HSS from baseline to week 16; and absolute change in mean EoE stage score on the EoE-HSS from baseline to week 16. absolute change in EREFS; change from baseline in the Type 2 Inflammation Transcriptional Signature Score at Weeks 16 and 52; change from baseline to Week 16 in the proportion of days with one or more signs of EoE, as measured by the Pediatric EoE Signs / Symptoms Questionnaire-Caregiver Version (PESQ-C) (for patients aged ≥1 to <12 years); change from baseline to Week 16 in the proportion of total segments of the day (nighttime, morning, afternoon, evening) with one or more signs of EoE, as measured by the PESQ-C (for patients aged ≥1 to <12 years); change from baseline to Week 16 in the proportion of days with one or more symptoms of EoE, as measured by the PESQ- The results were as follows: change from baseline to week 16 in the proportion of total segments of the day (nighttime, morning, afternoon, evening) with one or more EoE symptoms, as measured by the PESQ-P (for patients aged ≥8 to <12 years); change from baseline to week 16 in the total score, as measured by the PEESSv2.0-Caregiver version questionnaire (for patients aged ≥1 to <12 years); normalized enrichment scores (NES) for the relative change from baseline to week 16 in the transcriptomic signatures of the EoE Diagnostic Panel (EDP); and NES for the relative change from baseline to week 16 in the transcriptomic signatures of type 2 inflammation.

[0177] Other endpoints included safety endpoints, clinical pharmacology endpoints, and exploratory endpoints, such as the effect of dupilumab treatment on the global impression of change and severity of disease, and the effect of dupilumab treatment on changes in weight and growth. Methods for evaluating efficacy are described below and are also described in WO 2019 / 028367 and WO 2021 / 237110, which are incorporated herein by reference.

[0178] Pediatric EoE Signs / Symptoms Questionnaire (PESQ):PESQ is a new 8-item sign / symptom questionnaire that measures the heterogeneous symptom experience of children. PESQ has a patient version (PESQ-P) and a caregiver version (PESQ-C). PESQ-P is a patient-reported outcome measure that is intended to be completed independently by EoE patients aged >8 to <12 years. PESQ-P measures the occurrence and severity of EoE symptoms and is completed once a day via an electronic diary. Data from the 14-day period before the baseline visit and the 14-day period before the 16-week visit are used to calculate the number of days with one or more EoE symptoms or the proportion of the total time segment (nighttime, morning, afternoon, evening) in a day. PESQ-C is an observer-reported outcome measure that is intended to be completed independently by the caregivers of all pediatric EoE patients in the study. PESQ-C measures the occurrence of EoE signs and is completed once a day via an electronic diary. Data from the 14-day period before the baseline visit and the 14-day period before the week 16 visit were used to calculate the number of days or the proportion of total time periods of the day (nighttime, morning, afternoon, evening) with one or more signs of EoE.

[0179] Pediatric EoE Impact Scale (PEIS) The Pediatric EoE Impact Scale (PEIS) has a patient version (PEIS-P) and a caregiver version (PEIS-C). The PEIS-P is a patient-reported outcome measure that is intended to be completed independently by pediatric EoE patients aged >8 to <12 years. The PEIS-P assesses the impact of EoE on the patient's health-related aspects over the past week. The PEIS-C is intended to be completed independently by caregivers of pediatric EoE patients aged >1 to <12 years. The PEIS-C assesses the impact of the pediatric patient's EoE on the caregiver's anxiety, social and occupational activities, daily living activities, and relationships over the past week.

[0180] Global Impression of Change (GIC): The GIC has a patient version (GIC-P), a caregiver version (GIC-C), and a clinician version (GIC-Clin). The GIC-P is a single-item patient-reported outcome measure that is intended to be completed independently by pediatric EoE patients aged >8 to <12 years. The GIC-P assesses the patient's impression of the overall change (improvement or worsening) in his / her EoE condition since the start of study treatment. The GIC-C is a single-item observer-reported outcome measure that is intended to be completed independently by the caregiver of pediatric EoE patients aged >1 to <12 years. The GIC-C assesses the caregiver's impression of the overall change (improvement or worsening) in the pediatric patient's EoE condition since the start of study treatment. The GIC-Clin is a single-item observer-reported outcome measure that is intended to be completed independently by the investigator-physician of all pediatric EoE patients in the study. The GIC-Clin assesses the investigator / clinician's impression of the overall change (improvement or worsening) in the pediatric patient's EoE condition since the start of study treatment.

[0181] Overall impression of severity (GIS): The GIS has a patient version (GIS-P), a caregiver version (GIS-C), and a clinician version (GIS-Clin). The GIS-P is a single-item patient-reported outcome measure that is intended to be completed independently by pediatric EoE patients aged >8 to <12 years. The GIS-P assesses the patient's impression of the overall severity of his / her EoE condition during the past week. The GIS-C is a single-item observer-reported outcome measure that is intended to be completed independently by the caregiver of pediatric EoE patients aged >1 to <12 years. The GIS-C assesses the caregiver's impression of the overall severity of the pediatric patient's EoE condition during the past week. The GIS-Clin is a single-item observer-reported outcome measure that is intended to be completed independently by the investigator-physician of all pediatric EoE patients in the study. The GIS-Clin assesses the investigator / clinician's impression of the overall severity of the pediatric patient's EoE condition during the past week.

[0182] Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) v2.0 - Caregiver Version is a caregiver-reported outcome measure that assesses the frequency and severity of EoE symptoms in pediatric patients. The PEESSv2.0 Caregiver Version consists of 20 items and has a one-month recall period. The total PEESSv2.0 score ranges from 0 to 100; higher scores indicate a greater symptom burden in pediatric EoE patients.

[0183] EoE-EREFSEoE esophageal features will be analyzed based on the EoE-EREFS, a validated scoring system that uses an overall score and scores for each individual feature to score the inflammatory and remodeling features of the disease (Hirano, 2013). Proximal and distal esophageal regions are scored separately; scores for each region range from 0 to 9, and the overall score ranges from 0 to 18. Major esophageal features include: edema (absent, present); rings (absent, mild, moderate, severe); exudates (absent, mild, severe); grooves (absent, mild, severe); and strictures (absent, present). In addition to these major features, the physician performing the endoscopic procedure also captures data on the following minor features: crepe-paper esophagus (fragility or tearing of the mucosa during passage of the diagnostic endoscope): absent, present; narrow-caliber esophagus (a tubular esophagus with a reduced diameter of the lumen): absent, present; and stricture diameter. Mucosal changes associated with gastroesophageal reflux disease were also documented using the Los Angeles erosion classification system (no erosion or grades A, B, C, or D).

[0184] biopsy : During the double-blind treatment period, biopsies were obtained by endoscopy immediately at the second screening visit (Visit 2), the 16th and 52th week visits, and before the start of rescue medication or procedures. A total of 9 mucosal clip biopsies were collected from 3 esophageal regions at each time point: 3 proximal, 3 middle, and 3 distal. Two samples from each region were used for histology (required for study inclusion criteria and endpoint assessment), while the other samples were used for RNA extraction or exploratory studies. In order to participate in the study, patients must have a peak intraepithelial eosinophil count of ≥15eos / hpf (400×) in at least 2 of the 3 esophageal regions sampled. In addition, biopsy samples from the stomach and / or duodenum were obtained in all patients at Visit 2 to rule out other causes of esophageal eosinophilia. The peak eosinophil count per hpf of the biopsy samples for histopathological analysis was evaluated and the EoE grade score and stage score were assigned. The EoE grade and stage score evaluates eight features: eosinophil density, basal hyperplasia, eosinophilic abscesses, eosinophilic surface stratification, enlarged intercellular spaces, surface epithelial changes, dyskeratotic epithelial cells, and lamina propria fibrosis (absent / present). Pharmacokinetic and Exploratory Biomarker Programs

[0185] In this study, investigational assessments will be conducted to explore EoE, how dupilumab can modify the underlying disease processes in EoE and type 2 inflammation, and predictors of dupilumab's safety and efficacy. Samples may also be evaluated for markers associated with toxicity, if indicated. Total IgE, serum, and eotaxin-3 (heparinized plasma) samples will be collected at specific time points. The biomarkers studied are related to the pathophysiology of EoE, response to treatment (i.e., assessment of type 2 inflammation), and the mechanism of action of dupilumab. EoE diagnostic panel and type 2 inflammation transcriptomics

[0186] The differential gene expression profile of esophageal biopsies from patients with EoE compared to healthy controls is the EoE disease transcriptome (Sherrill et al., Genes Immun 2014, 15(6):361-369). This disease gene expression signature has been further refined into a smaller set of genes, used as the EoE diagnostic panel (EDP) (Dellon et al., Clin Transl Gastroenterol 2017, 8(2):e74). Gene signatures representing type 2 inflammation were compiled from the literature, preclinical experiments conducted by Regeneron, and dupilumab response signatures in a phase 2 study of atopic dermatitis and EoE.

[0187] The normalized enrichment score (NES) reflects the extent to which the activity level of a group of transcripts is too high at the extremes (top or bottom) of the entire ranked list of transcripts within a sample and is normalized by taking into account the number of transcripts in the group (Subramanian, 2005; Barbie, 2009). NES scores were calculated for each transcriptome signature for each sample. Example 2: Results of Part A of the Clinical Trial

[0188] Part A of the study was a double-blind, 16-week treatment period in which patients were randomized in a 1:1:1 ratio to receive placebo, higher-exposure dupilumab, or lower-exposure dupilumab according to a tiered, weight-based dosing schedule based on baseline weight as disclosed above. A total of 102 patients were randomized (34 to placebo, 31 to lower-exposure dupilumab, and 37 to higher-exposure dupilumab). Of these patients, nearly all completed Week 16 (32 / 34 (94.1%) for placebo; 29 / 31 (93.5%) for lower-exposure dupilumab; 37 / 37 (100%) for higher-exposure dupilumab; and 98 / 102 (96.1%) overall.

[0189] Baseline demographics are summarized in Table 1. Baseline demographics were generally comparable across treatment groups. Baseline disease characteristics are summarized in Table 2. Overall, patients were symptomatic, with a high proportion (approximately 80%) previously taking topical corticosteroids, and approximately 50% of patients receiving a PPI at randomization. Patients in the higher-exposure dupilumab group had, on average, higher peak eosinophil counts but fewer symptoms as measured by PESQ-C scores compared with the other groups. As shown in Table 3, the high prevalence of atopic comorbidities in the patient population emphasizes the common type 2 pathophysiology underlying these diseases. Table 1: Baseline demographics Table 2: Baseline disease characteristics Table 3: Concurrent atopic / allergic conditions Treatment effect

[0190] Table 4 below shows the efficacy results for the primary and secondary endpoints of Part A. Both dupilumab exposure regimens (higher dupilumab and lower dupilumab) showed significant improvements in achieving histologic remission. The primary endpoint assessed the proportion of patients achieving a peak eosinophil count ≤6 eos / hpf at Week 16. While only 2.9% of placebo patients (n=1 / 34) achieved ≤6 eos / hpf at Week 16, 67.6% of patients (n=25 / 37) in the higher dupilumab regimen and 55.1% of patients (n=18 / 31) in the lower dupilumab regimen achieved ≤6 eos / hpf at Week 16.

[0191] The higher-exposure dupilumab regimen met all prespecified secondary efficacy endpoints for histology, endoscopy, and transcriptomics (all p-values ​​< 0.0001) (Table 4). Children who received the higher-exposure dupilumab regimen experienced the following changes at week 16: Peak esophageal intraepithelial eosinophil count decreased by 86% from baseline, compared to a 21% increase in the placebo group (p<0.0001) At the microscopic level, disease severity and disease extent decreased by 0.88 and 0.84, respectively, from baseline (as measured by the EoEHSS mean grade score and mean stage score, respectively), compared with increases of 0.02 and 0.05 in the placebo group (both p<0.0001) Abnormal endoscopic findings decreased by 3.5 points from baseline (as measured by the EoE-EREFS score), compared with an increase of 0.3 points in the placebo group (p<0.0001)

[0192] The higher-exposure dupilumab regimen also showed superiority over placebo in the secondary symptom endpoint of the absolute change (LS mean) in the proportion of days with one or more signs of EoE from baseline to week 16, as measured by the PESQ-C, although this did not reach statistical significance (placebo: -0.17; higher-exposure dupilumab regimen: -0.28; Δ -0.10 (p = 0.15); this corresponds to approximately 1.5 fewer days with signs of EoE compared to placebo). The lower-exposure dupilumab regimen was comparable to or numerically lower than the higher-exposure dupilumab regimen in prespecified secondary efficacy endpoints (histology, endoscopy, transcriptome, and symptoms, as shown in Table 4). In addition, the higher-exposure dupilumab regimen showed greater improvements than the lower-exposure dupilumab regimen in other patient-reported outcomes, global impression, and quality of life. weight

[0193] An exploratory endpoint was the change from baseline in weight by age percentile at Week 16. Both dupilumab treatment groups demonstrated a greater change from baseline in weight by age percentile at Week 16 compared with the placebo group (placebo: mean change of 0.29; higher-exposure dupilumab: mean change of 3.09; lower-exposure dupilumab: mean change of 2.88). Security

[0194] Both the higher- and lower-exposure dupilumab regimens were well tolerated and demonstrated an acceptable safety profile, with no new safety concerns identified. Safety results were generally consistent with the known safety profile of Dupixent in its approved EoE indication in children 12 years of age and older and adults. Over the 16-week treatment period, the overall incidence of adverse events (AEs) was 79% for Dupixent and 91% for placebo. Adverse reactions that were more common (≥5%) with Dupixent compared to placebo included COVID-19 (21% Dupixel, 0% placebo; all cases were mild or moderate and did not lead to treatment discontinuation), rash (9% Dupixel, 6% placebo), headache (8% Dupixel, 3% placebo), viral gastroenteritis (6% Dupixel, 3% placebo), diarrhea (6% Dupixel, 3% placebo), and nausea (6% Dupixel, 0% placebo). The rate of treatment discontinuation due to AEs before Week 16 was 0% for Dupixent and 6% for placebo.

[0195] No rescue treatment was required in the placebo group, the lower-exposure primilumab group, or the higher-exposure primilumab group. in conclusion

[0196] Part A of this two-part study was designed to evaluate the efficacy and safety of dupilumab in patients aged ≥1 to <12 years with EoE, treated with either a higher-exposure dupilumab or a lower-exposure dupilumab according to a tiered, weight-based dosing schedule based on baseline weight. The primary histology endpoint was achieved at Week 16 with the higher-exposure dupilumab. All secondary efficacy endpoints of histology, endoscopy, and transcriptomics were met with the higher-exposure dupilumab. Pediatric patients treated with the higher-exposure dupilumab achieved numerically superior or comparable results to adults and adolescents with 300 mg QW dosing for histology, endoscopy, and transcriptomics efficacy endpoints. Dupilumab was well tolerated and demonstrated a safety profile similar to that of dupilumab in adults and adolescents with EoE. Example 3: Results of Part B of the Clinical Trial

[0197] Part B of the study was an open-label, 36-week extension of treatment for patients enrolled in Part A. A total of 98 patients (out of 102) from Part A were enrolled in Part B. All patients were aware that they were receiving active treatment in Part B but were blinded to the dosing regimen. The treatment groups for Part B are shown in Table 5 below: Table 5: Treatment Groups in Part B (Extended Active Treatment Period Beyond 36 Weeks) Efficacy

[0198] As shown in Table 6 below, the treatment effects of dupilumab on histology, endoscopy, symptoms, and transcriptome effects observed at Week 16 were found to be sustained through Week 52. When patients treated with placebo from Part A were switched to dupilumab in Part B, the efficacy was generally similar to that observed in patients treated with dupilumab in Part A. Table 6: Efficacy Results for Primary and Secondary Endpoints BL of Part A = Baseline of Part A Security

[0199] The overall incidence of TEAEs was comparable between treatment groups, with most being mild or moderate in intensity. The incidence of SAEs and AEs leading to treatment discontinuation was low. All SAEs were considered unrelated to study drug.

[0200] The present invention is not limited to the scope of the specific embodiments described herein. In fact, various modifications of the present disclosure, in addition to those described herein, will become apparent to those skilled in the art based on the foregoing description and drawings. These modifications are intended to fall within the scope of the appended claims. Table 7: Informal Sequence Listing

Claims

1. A method for treating, preventing or ameliorating at least one symptom of eosinophilic esophagitis (EoE) in a subject aged <12 years, the method comprising administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, wherein the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), 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.

2. The method according to claim 1, wherein the subject is ≥1 year old and <12 years old.

3. The method according to claim 1 or 2, wherein prior to the initiation of IL-4R antagonist treatment, the subject has a peak cell count of intraepithelial eosinophil infiltration ≥ 15eos / hpf as measured by endoscopic biopsy in at least two of the proximal esophageal region, the mid-esophageal region, and the distal esophageal region.

4. The method according to any one of claims 1 to 3, wherein the subject has previously been treated with swallowed topical corticosteroids and / or proton pump inhibitors (PPIs).

5. The method according to any one of claims 1 to 4, wherein the subject has no response, an inadequate response or intolerance to oral topical corticosteroid and / or PPI therapy, or wherein standard of care therapy is contraindicated.

6. The method according to any one of claims 1 to 5, wherein the subject suffers from a concomitant atopic disease.

7. The method according to claim 6, wherein the concomitant atopic disease is food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis or allergic conjunctivitis.

8. The method according to any one of claims 1 to 7, wherein the subject has a body weight of ≥ 5 kg.

9. The method according to any one of claims 1 to 8, wherein the subject has a body weight < 60 kg.

10. The method according to any one of claims 1 to 9, wherein before the start of treatment, the subject: peak baseline intraepithelial eosinophil count ≥70eos / hpf; mean baseline intraepithelial eosinophil count ≥50eos / hpf; A baseline EoE endoscopy reference score (EoE-EREFS) of at least 6; and / or Baseline serum total IgE level was at least 400 IU / L.

11. The method according to any one of claims 1 to 10, wherein the subject is selected based on not showing one or more exclusion criteria selected from: (a) Weight <5kg; (b) body weight ≥ 60 kg; (c) suffer from eosinophilic gastroenteritis, hypereosinophilic syndrome, or eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome); (d) a history of Crohn's disease, ulcerative colitis, celiac disease, or previous esophageal surgery; (e) esophageal strictures that could not be managed with standard diagnostic upper gastrointestinal endoscopy or esophageal strictures that required dilatation; (f) received oral topical corticosteroids within the previous 8 weeks; (g) previously received subcutaneous immunotherapy (SCIT) unless treated at a stable maintenance dose for at least 1 year; (h) previously treated with sublingual immunotherapy (SLIT), epicutaneous immunotherapy (EPIT), or oral immunotherapy (OIT); (i) receiving systemic immunosuppressive or immunomodulatory drug treatment within the previous 3 months; (j) starting or changing a food elimination diet within the previous 6 weeks; (k) starting, stopping, or changing the dosing regimen of a PPI, leukotriene inhibitor, nasal corticosteroid, or inhaled corticosteroid within the previous 8 weeks; (l) received live (attenuated) vaccine treatment within the previous 4 weeks; (m) have active Helicobacter pylori infection, helminth infection, active parasitic infection, or chronic or acute infection requiring treatment with systemic antibiotics, antiviral agents, or antifungal agents; (n) have a known or suspected immunodeficiency disorder; (o) have liver disease; and (p) Platelet level <100×10 3 / μL, neutrophil level ≤1.5×10 3 / μL, or estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m 2 .

12. The method according to any one of claims 1 to 11, wherein the anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

13. The method according to any one of claims 1 to 12, wherein the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

14. The method according to any one of claims 1 to 13, wherein the IL-4R antagonist is dupilumab.

15. The method according to any one of claims 1 to 14, wherein the IL-4R antagonist is administered at a dose of about 50 mg to 600 mg.

16. The method according to any one of claims 1 to 15, wherein the subject has a body weight of ≥ 5 kg, wherein: For subjects weighing ≥5 kg to <15 kg, the IL-4R antagonist is administered at a dose of about 100 mg Q2W, about 200 mg Q3W, or about 200 mg Q4W; For subjects weighing ≥15 kg to <30 kg, the IL-4R antagonist is administered at a dose of about 200 mg Q2W or about 300 mg Q4W; For subjects weighing ≥30 kg to <60 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W or about 200 mg Q2W; and / or For subjects weighing ≥ 60 kg, the IL-4R antagonist is administered at a dose of about 300 mg QW or about 300 mg Q2W.

17. The method according to any one of claims 1 to 15, wherein the subject has a body weight of ≥ 5 kg, wherein: For subjects weighing ≥5 kg to <15 kg, the IL-4R antagonist is administered at a dose of about 100 mg Q2W or about 200 mg Q3W; For subjects weighing ≥15 kg to <30 kg, the IL-4R antagonist is administered at a dose of approximately 200 mg Q2W; For subjects weighing ≥30 kg to <60 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W; and / or For subjects weighing ≥60 kg, the IL-4R antagonist is administered at a dose of approximately 300 mg QW.

18. The method according to any one of claims 1 to 15, wherein the subject has a body weight of ≥ 5 kg, wherein: For subjects weighing ≥5 kg to <15 kg, the IL-4R antagonist is administered at a dose of approximately 200 mg Q3W; For subjects weighing ≥15 kg to <30 kg, the IL-4R antagonist is administered at a dose of approximately 200 mg Q2W; For subjects weighing ≥30 kg to <40 kg, the IL-4R antagonist is administered at a dose of about 300 mg Q2W; and / or For subjects weighing ≥40 kg, the IL-4R antagonist is administered at a dose of approximately 300 mg QW.

19. The method according to any one of claims 1 to 16, wherein the subject has a body weight of ≥5 kg to <15 kg.

20. The method of claim 19, wherein the IL-4R antagonist is administered at a dose of about 100 mg Q2W.

21. The method of claim 19, wherein the IL-4R antagonist is administered at a dose of about 200 mg Q3W.

22. The method of claim 19, wherein the IL-4R antagonist is administered at a dose of about 200 mg Q4W.

23. The method according to any one of claims 1 to 16, wherein the subject has a body weight of ≥ 15 kg to < 30 kg.

24. The method of claim 23, wherein the IL-4R antagonist is administered at a dose of about 200 mg Q2W.

25. The method of claim 23, wherein the IL-4R antagonist is administered at a dose of about 300 mg Q4W.

26. The method according to any one of claims 1 to 16, wherein the subject has a body weight of ≥30 kg to <60 kg.

27. The method of claim 26, wherein the IL-4R antagonist is administered at a dose of about 300 mg Q2W.

28. The method of claim 26, wherein the IL-4R antagonist is administered at a dose of about 200 mg Q2W.

29. The method according to any one of claims 1 to 16, wherein the subject has a body weight of ≥ 60 kg.

30. The method of claim 29, wherein the IL-4R antagonist is administered at a dose of about 300 mg QW.

31. The method of claim 29, wherein the IL-4R antagonist is administered at a dose of about 300 mg Q2W.

32. The method according to any one of claims 1 to 15 or 18, wherein the subject weighs ≥30 kg to <40 kg and the IL-4R antagonist is administered at a dose of about 300 mg Q2W.

33. The method according to any one of claims 1 to 15 or 18, wherein the subject weighs ≥ 40 kg and the IL-4R antagonist is administered at a dose of about 300 mg QW.

34. The method according to any one of claims 1 to 15, wherein the IL-4R antagonist is administered once weekly or biweekly at a dose of about 100 mg to about 300 mg.

35. The method according to any one of claims 1 to 15, wherein the IL-4R antagonist is administered once every three weeks at a dose of about 100 mg to about 300 mg.

36. The method according to any one of claims 1 to 35, wherein the IL-4R antagonist is administered subcutaneously.

37. The method according to any one of claims 1 to 36, wherein the IL-4R antagonist is administered in combination with a second therapeutic agent or therapy.

38. The method according to claim 37, wherein the second therapeutic agent or therapy is dietary management.

39. The method according to claim 37, wherein the second therapeutic agent or therapy is a proton pump inhibitor (PPI).

40. The method of any one of claims 1 to 39, wherein treatment with the IL-4R antagonist for at least 16 weeks results in: a decrease in peak esophageal intraepithelial eosinophil count; a reduction in the severity and / or extent of disease as measured by the Eosinophilic Esophagitis-Histology Scoring System (EoE-HSS); Improvement in esophageal anatomical features, as measured by the Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-EREFS); Increase in weight for age percentile; and / or Reduction in the normalized enrichment score (NES) of genes in the type 2 inflammation group and / or EoE diagnostic group.

41. The method of claim 40, wherein treatment with the IL-4R antagonist for 16 weeks results in a peak esophageal intraepithelial eosinophil count of ≤ 6eos / hpf, and / or a reduction in peak esophageal intraepithelial eosinophil count of at least 75%.

42. The method of any one of claims 1 to 41, wherein the IL-4R antagonist is contained in a container selected from the group consisting of a vial, a syringe, a prefilled syringe, a pen delivery device, and an autoinjector.

43. The method of claim 42, wherein the IL-4R antagonist is contained in a prefilled syringe.

44. The method according to claim 43, wherein the prefilled syringe is a single-dose prefilled syringe.

45. The method of claim 42, wherein the IL-4R antagonist is contained in an autoinjector.

46. ​​The method of claim 42, wherein the IL-4R antagonist is contained in a pen delivery device.

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