Methods for treating eosinophilic gastroenteritis by administering an IL-4R antagonist.

Description

Methods for treating eosinophilic gastroenteritis by administering an IL-4R antagonist. CROSS-REFERENCE ON RELATED REQUEST

[001] This application is being filed on March 26, 2024, as a PCT International Patent Application and claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 492,425, filed on March 27, 2023, the disclosure of which is incorporated herein by reference in its entirety. REFERENCE TO AN XML SEQUENCE LISTING

[002] This request contains a Sequence Listing that was submitted electronically in XML format. The Sequence Listing XML is incorporated into this document by reference. The said XML file, created on March 14, 2024, is named 40848_0120WOU1_SL.xml and has a size of 269,767 bytes. FIELD OF THE INVENTION

[003] This disclosure relates to the use of interleukin-4 receptor (IL-4R) inhibitors to treat or prevent eosinophilic gastroenteritis, such as eosinophilic gastritis with or without eosinophilic duodenitis, in an individual in need. BACKGROUND

[004] Eosinophilic gastrointestinal disorders (EGIDs) are rare, chronic, allergic / immune-mediated conditions affecting the gastrointestinal (GI) tract. EGIDs can occur in pediatric and adult patients and may involve individual regions of the gastrointestinal tract (i.e., esophagus, stomach, small intestine, and colon) or a combination of regions (Rossi, et al., Clin Transl Allergy, 2022, 12:e12146).

[005] Eosinophilic gastritis (EoG) is a rare stomach disease, distinct from eosinophilic esophagitis (EoE). EoG is characterized by Petition 870250087280, dated 09 / 26 / 2025, page 10 / 153 2 / 120 irregular or diffuse infiltration of eosinophils in the stomach (Collins, et al., Front Med, 2017, 4:261). Patients with EoG may also have comorbid eosinophilic duodenitis (EoD), which is characterized by irregular or diffuse infiltration of eosinophils in the small intestine. Mucosal biopsies from patients with EoG and EoD show >30 eosinophils (eos) per 5 high-power fields (hpfs) in the stomach and >30 eosinophils per 3 hpf in the small intestine, respectively; these are also used as diagnostic criteria for EoG and EoD, respectively (Dellon, et al., N Engl J Med, 2020, 383: 1624-1634). Eosinophilic gastroenteritis (EGE) occurs in both the stomach and small intestine and encompasses both EoG and EoD.

[006] The diagnosis of EoG with or without EoD is made based on clinical symptoms combined with eosinophilic infiltration in gastric biopsy samples with or without eosinophilic inflammation in the duodenum and the absence of other causes for eosinophilia (e.g., malignancy, parasitic infections). The signs and symptoms of EoG with and without EoD depend on the location, extent, and layers of the intestine involved with eosinophilic infiltration (Méndez Sánchez, et al., Dig Dis Sci, 2007, 52:2904-2911). The most frequent symptoms of eosinophilic infiltration of the mucosa are nausea, early satiety, vomiting, bloating, abdominal pain, abdominal cramps, loss of appetite, diarrhea, and weight loss. Patients with eosinophilic infiltration of the muscular layer may have symptoms of intestinal obstruction with nausea, vomiting, and abdominal distension. Patients with subserosal involvement may present with isolated ascites or ascites in combination with symptoms characteristic of mucosal and / or muscular disease.Most patients have a chronic course. The disease may involve deeper layers of the affected gastrointestinal tract, resulting in complications (e.g., intestinal obstruction) (Pineton de Chambrun, et al., Clin Gastroenterol Hepatol, 2011,9:950-956). Petition 870250087280, dated 09 / 26 / 2025, page 11 / 153 3 / 120

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

[008] Patients with EoG (with or without EoD) have significantly impaired quality of life (QoL) and experience psychological, social, financial, and body image impacts. Patients have been found to experience depression following the development of their illness, emotional distress related to dietary restrictions, and financial impact due to their illness, either directly through the cost of special foods or indirectly through the inability to work or attend school (Bedell, et al., Dig Sic Sci, 2018, 63:1148-1157).

[009] There are no approved treatments for EoG (with or without EoD) in the US, Europe, or Japan. There are two main strategies for managing EoG disease (with or without EoD): dietary modification and off-label pharmacological interventions, predominantly systemic corticosteroids. Dietary modification and / or pharmacological therapies may be effective for treating some patients. However, maintaining effectiveness requires strict adherence to therapy and a restricted diet, and pharmacological therapies, such as systemic corticosteroids, are not a solution for long-term treatment due to their numerous systemic side effects. Consequently, an unmet need for te Petition 870250087280, dated 09 / 26 / 2025, p. 12 / 153 4 / 120 safe and effective long-term therapies that address the underlying inflammation of EoG (with or without EoD), prevent disease progression, and improve clinical symptoms. SUMMARY

[0010] In one aspect, the present disclosure provides methods for treating, preventing, or relieving at least one symptom of eosinophilic gastroenteritis. In some embodiments, the method comprises administering to an individual with eosinophilic gastroenteritis one or more doses of an interleukin-4 receptor antagonist (IL-4R).

[0011] In another aspect, the present disclosure provides methods for treating, preventing, or relieving at least one symptom of eosinophilic gastritis. In some embodiments, the method comprises administering to an individual with eosinophilic gastritis one or more doses of an IL-4R antagonist.

[0012] In another aspect, the present disclosure provides an interleukin-4 receptor (IL-4R) antagonist for use in the treatment, prevention, or relief of at least one symptom of eosinophilic gastroenteritis in an individual.

[0013] In another aspect, the present disclosure provides an IL-4R antagonist for use in the treatment, prevention or relief of at least one symptom of eosinophilic gastritis in an individual.

[0014] In another aspect, the present disclosure provides an interleukin-4 receptor (IL-4R) antagonist for use in the preparation of a medicament for the treatment, prevention or relief of at least one symptom of eosinophilic gastroenteritis in an individual.

[0015] In another aspect, the present disclosure provides an IL-4R antagonist for use in the preparation of a medicament for the treatment, prevention or relief of at least one symptom of eosinophilic gastritis in an individual.

[0016] In another aspect, the present disclosure provides methods Petition 870250087280, dated 09 / 26 / 2025, page 13 / 153 A 5 / 120 reduction in the use of a systemic corticosteroid or a swallowed topical corticosteroid in an individual with eosinophilic gastroenteritis is achieved by administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to the individual. In some embodiments, at the start of treatment with the IL-4R antagonist, the individual receives a steady-state dose of a maintenance systemic corticosteroid or a swallowed topical corticosteroid. In some embodiments, treatment with the IL-4R antagonist reduces the individual's dependence on the systemic corticosteroid or a swallowed topical corticosteroid. In some embodiments, treatment with the IL-4R antagonist eliminates the need for the systemic corticosteroid or a swallowed topical corticosteroid.

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

[0018] In some modalities, the individual has been previously treated with a systemic corticosteroid or an ingested topical corticosteroid. In some modalities, the individual does not respond, responds inadequately, or is intolerant to treatment with a systemic corticosteroid or an ingested topical corticosteroid, or in which the treatment pattern is contraindicated.

[0019] In some modalities, the individual is > 12 years of age. In some modalities, the individual is an adult. In some modalities, the individual is an adolescent.

[0020] In some modalities, the individual has a concomitant atopic disease. In some modalities, the atopic disease Petition 870250087280, dated 09 / 26 / 2025, page 14 / 153 6 / 120 concomitant is a food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis. In some forms, the individual has a concomitant atopic disease that is not eosinophilic esophagitis.

[0021] In some modalities, prior to initiation of treatment with the IL-4R antagonist, the individual has an eosinophil count >30 eos / hpf, as measured by endoscopic biopsy in at least five distinct regions of the stomach and / or an eosinophil count >30 eos / hpf, as measured by endoscopic biopsy in at least three distinct regions of the small intestine. In some modalities, prior to initiation of treatment with the IL-4R antagonist, the individual has a baseline total symptom score (TSS) >20, as measured by the EoG / EoD Symptom Questionnaire.In some modalities, prior to initiation of treatment with the IL-4R antagonist, the individual has an average baseline severity score of > 4 per week for at least two weeks for at least two components of the EoG / EoD-SQ, where the components are selected from the group consisting of stomach pain, stomach cramps, nausea, bloating, early satiety, and loss of appetite. In some modalities, prior to initiation of treatment with the IL-4R antagonist, the individual has a history of at least two episodes of EoG symptoms per week for at least 8 weeks, where the symptoms are selected from the group consisting of stomach pain, stomach cramps, nausea, bloating, early satiety, and loss of appetite.

[0022] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof with one or more CDR, HCVR, and / or LCVR sequences listed in Table 1. In Petition 870250087280, dated 09 / 26 / 2025, p. 15 / 153 7 / 120 In some modalities, the IL-4R antagonist is an anti-IL4R 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. In some embodiments, the anti-IL4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and comprises 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 SEQ ID NO: 9 and a light chain comprising the amino acid sequence SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab.

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

[0024] In some modalities, the IL-4R antagonist is administered in combination with a second therapeutic agent or therapist. Petition 870250087280, dated 09 / 26 / 2025, p. 16 / 153 8 / 120 sink.

[0025] In some embodiments, the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen dispensing device, and an autoinjector. In some embodiments, the IL-4R antagonist is contained in a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose pre-filled syringe. In some embodiments, the IL-4R antagonist is contained in an autoinjector. In some embodiments, the IL-4R antagonist is contained in a pen dispensing device.

[0026] In another aspect, this disclosure provides methods of treating an individual with eosinophilic gastroenteritis (e.g., EoG and / or EoD) by administering combination therapy. In some embodiments, the combination therapy comprises (i) an interleukin-4 receptor (IL-4R) antagonist and (ii) a systemic corticosteroid or an ingested topical corticosteroid. In some embodiments, the combination therapy comprises an IL-4R antagonist as disclosed in this document (e.g., an anti-IL-4R antibody or an antigen-binding fragment thereof, e.g., dupilumab) and a systemic corticosteroid (e.g., prednisone or prednisolone). In some modalities, combination therapy comprises an IL-4R antagonist as disclosed in this document (e.g., an anti-IL-4R antibody or an antigen-binding fragment thereof, e.g., dupilumab) and an ingested topical corticosteroid (e.g., budesonide or fluticasone).

[0027] In another aspect, the present disclosure provides a combination for the treatment of an individual with eosinophilic gastroenteritis (e.g., EoG and / or EoD). In some embodiments, the combination comprises (i) an IL-4R antagonist and (ii) a corticosteroid. Petition 870250087280, dated 09 / 26 / 2025, p. 17 / 153 9 / 120 systemic steroid or a swallowed topical corticosteroid. In some embodiments, the combination comprises an IL-4R antagonist as disclosed in this document (e.g., an anti-IL-4R antibody or an antigen-binding fragment thereof, e.g., dupilumab) and a systemic corticosteroid (e.g., prednisone or prednisolone). In some embodiments, the combination comprises an IL-4R antagonist as disclosed in this document (e.g., an anti-IL-4R antibody or an antigen-binding fragment thereof, e.g., dupilumab) and a swallowed topical corticosteroid (e.g., budesonide or fluticasone).

[0028] Other modalities will become apparent from a review of the detailed description that follows. BRIEF DESCRIPTION OF THE FIGURES

[0029] FIG. 1 shows that treatment with an IL-4R antagonist significantly reduced the frequency of eosinophils in the stomach tissue of the mouse model of eosinophilic gastritis. Female C57BL / 6J mice (n = 5-7 / group at baseline) were administered a single dose of 25 μg of mIL-25 plasmid DNA or vector control plasmid DNA using HDD by IV injection on day 0. On days -4, 1, and 3, mice were administered 25 mg / kg of REGN1103, isotype control antibody, or no Ab control by SC injection. Data are expressed as group mean ± SD, and symbols show individual animal data. Normality was tested using the Shapiro-Wilk test. Statistical significance was determined using Brown-Forsythe and Welch ANOVA tests, and multiple comparisons were made using Dunnett's T3 multiple comparison test.Throughout the study, 3 mice, no more than 2 per group, were excluded from the analysis because they died before the experiment was completed. *, p < 0.05; **, p < 0.01; ***, p < 0.001.

[0030] FIGS. 2A and 2B show that treatment with a tapir Petition 870250087280, dated 09 / 26 / 2025, p. 18 / 153 A 10 / 120 IL-4R agonist significantly reduced Ccl11 and Ccl24 mRNA levels in the stomach tissue of a mouse model of eosinophilic gastritis. Female C57BL / 6J mice (n = 57 / group at baseline) were administered a single 25 μg dose of mIL-25 plasmid DNA or vector control plasmid DNA via HDD by IV injection on day 0. On days -4, 1, and 3, mice were administered 25 mg / kg of REGN1103, isotype control antibody, or no Ab control by SC injection. Samples were collected on day 8. Ccl11 (FIG. 2A) and Ccl24 (FIG. 2B) mRNA levels relative to Actb mRNA levels in stomach tissue were measured. Data are expressed as group mean ± SD, and symbols show individual animal data. Normality was tested using the Shapiro-Wilk test. P-values ​​were determined using the Kruskal-Wallis test, and multiple comparisons were made using Dunn's multiple comparisons test.Throughout the study, 3 mice, no more than 2 per group, were excluded from the analysis because they died before the experiment was completed. *, p < 0.05; **, p < 0.01.

[0031] Figures 3A and 3B show that treatment with an IL-4R antagonist significantly prevented pathology in a mouse model of eosinophilic gastritis. Female C57BL / 6J mice (n = 5-7 / group at baseline) were administered a single dose of 25 μg of mIL-25 plasmid DNA or vector control plasmid DNA using HDD by IV injection on day 0. On days -4, 1, and 3, mice were administered 25 mg / kg of REGN1103, isotype control antibody, or no-antibody control by SC injection. Samples were collected on day 8, sectioned, and stained with hematoxylin and eosin. The group mean of the total non-glandular and glandular stomach tissue pathology score (Fig. 3A) and representative images (Fig. 3B) for each group are shown. The Petition 870250087280, dated 09 / 26 / 2025, p. 19 / 153 11 / 120 data in panel A are expressed as the group mean of total pathology scores ± SD, and the symbols show data for individual animals. Statistical significance was determined using one-way ANOVA followed by Tukey's HSD test. The vertical horizontal line in the images in panel B is a scale bar representing 2 mm in length. Throughout the study, 3 mice, no more than 2 per group, were excluded from the analysis as they died before the experiment was completed. **, p < 0.01; ***, p < 0.001; ****, p < 0.0001. DETAILED DESCRIPTION Definitions

[0032] Before the present invention is described, it should be understood that the invention is not limited to the particular methods and experimental conditions described, since such methods and conditions may vary. It should also be understood that the terminology used in this document is intended to describe only particular embodiments and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0033] Unless defined otherwise, all technical and scientific terms used in this document have the same meaning as commonly understood by one skilled in the art to which this invention pertains.

[0034] As used in this document, the term approximately, when used in reference to a particular quoted numerical value, means that the value may vary from the quoted value by no more than 1%. For example, as used in this document, the expression approximately 100 includes 99 and 101 and all values ​​between them (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0035] As used in this document, the terms treat, treating or similar terms mean to alleviate symptoms, eliminate the cause of Petition 870250087280, dated 09 / 26 / 2025, page 20 / 153 12 / 120 symptoms in a temporary or permanent manner, or to prevent or delay the onset of symptoms of the aforementioned disorder or condition.

[0036] Eosinophilic gastritis, or EoG, refers to an inflammatory disease characterized by abnormal eosinophilic inflammation in the stomach. The main symptoms of EoG include, but are not limited to, nausea, early satiety, vomiting, bloating, abdominal pain, abdominal cramps, loss of appetite, diarrhea, and weight loss. EoG is typically diagnosed based on clinical symptoms combined with eosinophilic infiltration in stomach biopsy samples. The current diagnostic criteria for EoG is > 30 eosinophils (eos) per high-power field (hpf) in the stomach.

[0037] Eosinophilic duodenitis, or EoD, refers to an inflammatory disease characterized by irregular or diffuse infiltration of eosinophils in the small intestine. The main symptoms of EoD include, among others, nausea, early satiety, vomiting, bloating, abdominal pain, abdominal cramps, loss of appetite, diarrhea, and weight loss. EoD is typically diagnosed based on clinical symptoms combined with eosinophilic infiltration in small bowel biopsy samples. The current diagnostic criteria for EoD is > 30 eosinophils (eos) per high-power field (hpf) in the small intestine.

[0038] As used in this document, the term individual in need refers to a human or non-human animal exhibiting one or more symptoms or indications of eosinophilic gastroenteritis and / or who has been diagnosed with eosinophilic gastroenteritis, for example, EoG and / or EoD. In certain embodiments, the term includes individuals showing elevated levels of one or more biomarkers associated with EoG (described elsewhere in this document). For example, in some embodiments, an individual to be treated according to the disclosure methods is an individual with high IgE levels, Petition 870250087280, dated 09 / 26 / 2025, p. 21 / 153 13 / 120 Serum TARC, eotaxin-3, CCL11, or CCL24. As used in this document, the terms individual and patient are used interchangeably.

[0039] The term individual in need may also include, for example, individuals who, prior to treatment, exhibit (or have exhibited) one or more indications of EGE, such as eosinophilic infiltration of the gastrointestinal tract, nausea, early satiety, vomiting, bloating, abdominal pain, abdominal cramps, loss of appetite, diarrhea, weight loss and / or an elevated level of a biomarker associated with EGE. The term also includes individuals with elevated peripheral eosinophil counts (e.g., >100, >150, >200 or >300 cells^L) or elevated serum IgE (e.g., >150 kU / L).

[0040] The term eosinophilic infiltration refers to the presence of eosinophils in an organ or tissue, including blood, esophagus, stomach, duodenum, jejunum, ileum, and colon of an individual. In the context of this disclosure, the term eosinophilic infiltration refers to the presence of eosinophils in the mucosal lining of a region of the gastrointestinal tract including, but not limited to, the stomach and small intestine (e.g., in the mucosal lining of such region or regions). Eosinophilic infiltration is analyzed, for example, using a tissue biopsy. According to some embodiments, eosinophilic infiltration refers to the presence of > 30 eosinophils per high-power field in the stomach, or in two, three, four, five, or more distinct regions of the region (e.g., stomach or small intestine).The term high-power field refers to a standard total magnification of 400X by a microscope used to visualize eosinophils in a tissue, for example, from the stomach or small intestine of an individual. Thus, in some modalities, an individual in need refers to an individual showing the presence of > 30 eosinophils (eos) per high-power field (hpf) in the gastrointestinal tract. Petition 870250087280, dated 09 / 26 / 2025, page 22 / 153 14 / 120 for example, in two, three, four, five or more of the proximal, middle and distal regions of the stomach or small intestine. In certain modalities, eosinophilic infiltration includes infiltration into a tissue by leukocytes, for example, lymphocytes, neutrophils and mast cells. Leukocyte infiltration in, for example, gastrointestinal tissue can be detected by cell surface markers, such as macrophage-specific markers (e.g., CD11b+, F4 / 80+, CD14+, EMR1+ and CD68+), neutrophil-specific markers (e.g., CD11b+, Ly6G+, Ly6C+, CD11b+ and CD66b+) and T cell-specific markers (e.g., CD3+, CD4+ and CD8+).

[0041] Although any methods and materials similar or equivalent to those described in this document may be used in the practice of disclosure, typical methods and materials are described. All publications mentioned in this document are incorporated herein by reference in their entirety. Therapeutic Methods

[0042] In one aspect, methods are provided for treating, preventing, or alleviating one or more symptoms of eosinophilic gastroenteritis (EGE) in an individual. In some modalities, the individual to be treated has eosinophilic gastritis (EoG). In some modalities, the individual to be treated has EoG with eosinophilic duodenitis (EoD). In some modalities, the individual to be treated has EoG without EoD. In some modalities, the individual to be treated has EoD without EoG. In some modalities, the individual to be treated has EGE (e.g., EoG and / or EoD) with esophageal involvement. In some modalities, the individual has concomitant eosinophilic esophagitis (EoE). In some modalities, the individual does not have EoE.

[0043] In some modalities, the individual is > 12 years of age. In some modalities, the individual is an adolescent. In some modalities, the individual is an adult. In some modalities Petition 870250087280, dated 09 / 26 / 2025, p. 23 / 153 15 / 120 modalities, the individual is a pediatric individual <18 years of age, for example, <12 years of age. In some modalities, the individual has a body weight >40 kg. In some modalities, the individual is >12 years of age and has a body weight >40 kg.

[0044] In some modalities, an individual to be treated according to the methods disclosed in this document has a documented diagnostic history of EoG by endoscopic biopsy, as demonstrated by intraepithelial eosinophilic infiltration of at least 2, 3, 4, or 5 distinct regions of the stomach. In some modalities, the individual has an initial assessment eosinophil count >30 eos / hpf in at least 5 distinct regions of the stomach. Eosinophil count, as used in this document, refers to the number of eosinophils contained in a high-power field (hpf), for example, at 400*. In some modalities, the individual has an average eosinophil count of >35 eos / hpf, >40 eos / hpf, >45 eos / hpf, >50 eos / hpf, >55 eos / hpf, >60 eos / hpf, >65 eos / hpf, >70 eos / hpf, >75 eos / hpf, >80 eos / hpf, >85 eos / hpf, or >90 eos / hpf.

[0045] In some modalities, an individual to be treated according to the methods disclosed in this document has a documented diagnostic history of EoD by endoscopic biopsy, as demonstrated by intraepithelial eosinophilic infiltration of at least 2, 3, 4, or 5 distinct regions of the small intestine. In some modalities, the individual has an initial assessment eosinophil count >30 eos / hpf in at least 3 distinct regions of the small intestine. In some modalities, the individual has an average eosinophil count of >35 eos / hpf, >40 eos / hpf, >45 eos / hpf, >50 eos / hpf, >55 eos / hpf, >60 eos / hpf, >65 eos / hpf, >70 eos / hpf, >75 eos / hpf, >80 eos / hpf, >85 eos / hpf, or >90 eos / hpf.

[0046] In some modalities, an individual to be treated according to the methods disclosed in this document has a history Petition 870250087280, dated 09 / 26 / 2025, page 24 / 153 16 / 120 of one or more symptoms of GER, EoG, or EoD, such as, but not limited to, nausea, early satiety, vomiting, bloating, abdominal pain, abdominal cramps, loss of appetite, diarrhea, and weight loss. In some modalities, the individual has a history of one or more symptoms of GER 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 more. In some modalities, the individual has a history of one or more symptoms of GER, EoG, or EoD for at least 6 months, at least 1 year, at least 2 years or more.

[0047] In some modalities, an individual to be treated according to the methods disclosed in this document has a history of prior treatment with one or more standard care therapies for EGE, such as, but not limited to, dietary modification (e.g., food elimination diets), systemic corticosteroids, swallowed topical corticosteroids (e.g., oral beclomethasone, budesonide, or fluticasone), antihistamines, or immunomodulators. In some modalities, an individual to be treated is an individual who does not respond, responds inadequately, is intolerant, or is resistant to one or more of the current standard care therapies for EGE, EoG, or EoD. In some modalities, an individual to be treated has a contraindication to one or more standard care therapies.

[0048] In some embodiments, an individual to be treated receives a stable dose of a systemic maintenance corticosteroid or an swallowed topical corticosteroid. In some embodiments, an individual to be treated receives a stable dose of a PPI. In some embodiments, an individual to be treated receives a stable dose of a leukotriene inhibitor. In some embodiments, an individual to Petition 870250087280, dated 09 / 26 / 2025, page 25 / 153 17 / 120 to be treated receives a stable food elimination diet.

[0049] In some modalities, an individual to be treated has, or has had, at least one comorbidity. In some modalities, an individual to be treated has, or has had, a concomitant type 2 inflammatory condition. As used in this document, a type 2 inflammatory condition is a disease, disorder, or condition associated with a T helper 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 rhinosinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), unified airway disease, eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), atopic conjunctivitis, atopic dermatitis, vasculitis, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic 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 modalities, the individual has a concomitant atopic disease or condition selected from the group consisting of food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis. In some modalities, the individual has a concomitant atopic disease or condition that is not eosinophilic esophagitis.

[0050] In some modalities, an individual to be treated is an individual who is susceptible to an allergen, for example, an individual with a food allergy or oral allergy syndrome. For example, in some modalities, the individual may exhibit one of the following characteristics: (a) is prone to allergic reactions or responses when Petition 870250087280, dated 09 / 26 / 2025, page 26 / 153 18 / 120 of exposure 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 a sign or symptom of an allergic response or anaphylaxis. As used in this document, the phrases allergic response, allergic reaction, allergic symptom, and the like include one or more signs or symptoms selected from the group consisting of hives (e.g., itching), angioedema, rhinitis, asthma, vomiting, sneezing, runny nose, sinus inflammation, watery eyes, wheezing, bronchospasm, reduced peak expiratory flow (PEF), gastrointestinal discomfort, flushing, swollen lips, swollen tongue, reduced blood pressure, anaphylaxis, and organ dysfunction / failure.An allergic response, allergic reaction, allergic symptom, etc., also includes immunological responses and reactions, such as increased IgE production, increased production of allergen-specific immunoglobulin, and / or eosinophilia. In some forms, the allergen is contained in or derived from a food item, such as dairy products (e.g., cow's milk), egg, wheat, soy, corn, rye, fish, shellfish, peanuts, tree nuts. In some forms, 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., bee, wasp, mosquito venom, etc.), mold, animal dander, latex, medication, pharmaceuticals, ragweed, grass, or birch.

[0051] In some modalities, an individual to be treated is selected based on exhibiting one or more inclusion criteria disclosed in Example 2. In some modalities, an individual to be treated is further selected based on not exhibiting one or more exclusion criteria disclosed in Example 2. Interleukin-4 Receptor Antagonists

[0052] In some forms, the methods of the present disclosure Petition 870250087280, dated 09 / 26 / 2025, page 27 / 153 19 / 120 ration involves administering to an individual in need (e.g., an individual with EGE, EoG, or EoD) an interleukin-4 receptor (IL-4R) antagonist or a pharmaceutical composition comprising an IL-4R antagonist. As used in this document, an IL-4R antagonist (also referred to in this document as an IL-4R inhibitor, an IL-4R blocker, or an IL-4Rα antagonist) is any agent that binds to or interacts with IL-4Rα or an IL-4R ligand and inhibits or attenuates the normal biological signaling function of a type 1 and / or type 2 IL-4 receptor. Human IL4Rα has the amino acid sequence SEQ ID NO:11. A type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and a yc chain. An IL-4 type 2 receptor is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain.Type 1 IL-4 receptors interact with and are stimulated by IL-4, while type 2 IL-4 receptors interact with and are stimulated by both IL-4 and IL-13. Thus, IL-4R antagonists that can be used in the methods of the present disclosure can function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4 and IL-13-mediated signaling. The IL-4R antagonists of the present disclosure can thus prevent the interaction of IL-4 and / or IL-13 with a type 1 or type 2 receptor.

[0053] Non-limiting examples of IL-4R antagonist categories include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., pepticopter molecules), receptor bodies (e.g., engineered molecules comprising the ligand-binding domain of an IL-4R component), and antibodies or antibody antigen-binding fragments that specifically bind to human IL-4Rα. As used in this document, IL-4R antagonists also include antigen-binding proteins that specifically bind to human IL-4Rα. Petition 870250087280, dated 09 / 26 / 2025, page 28 / 153 20 / 120 exclusively to IL-4 and / or IL-13. Anti-IL-4Ra Antibodies and Antigen-Binding Fragments thereof

[0054] In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof. The term antibody, as used in this document, includes immunoglobulin molecules comprising four polypeptide chains, two heavy chains (H) and two light chains (L) interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a variable heavy chain region (abbreviated in this document as HCVR or Vh) and a constant heavy chain region. The constant heavy chain region comprises three domains, Ch1, Ch2, and Ch3. Each light chain comprises a variable light chain region (abbreviated in this document as LCVR or Vl) and a constant light chain region. The constant light chain region comprises one domain (Cl1).The Vh and Vl regions can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called frame regions (FRs). Each Vh and Vl is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-IL-4R antibody (or an antigen-binding portion thereof) are identical to human germline sequences. In some embodiments, one or more FRs of the anti-IL-4R antibody (or an antigen-binding portion thereof) are modified naturally or artificially.

[0055] The term antibody, as used in this document, also includes antigen-binding fragments of antigen molecules. Petition 870250087280, dated 09 / 26 / 2025, p. 29 / 153 21 / 120 complete antibody complexes. The terms antigen-binding portion of an antibody, antigen-binding fragment of an antibody, and the like, as used in this document, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, for example, from complete antibody molecules using any suitable standard techniques, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding variable and optionally constant antibody domains. This DNA is known and / or readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or may be synthesized.DNA can be sequenced and manipulated chemically or using molecular biology techniques, for example, to arrange one or more variable and / or constant domains in a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add or delete amino acids, etc.

[0056] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv molecules (scFv); (vi) dAb fragments; and (vii) minimal recognition 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 restricted FR3-CDR3-FR4 peptide. Other manipulated molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, Petition 870250087280, dated 09 / 26 / 2025, page 30 / 153 22 / 120 nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceutical products (SMIPs), and variable shark IgNAR domains are also encompassed by the term antigen-binding fragment, as used in this document.

[0057] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR that is adjacent to or in structure with one or more frame sequences. In antigen-binding fragments with a Vh domain associated with a Vl domain, the Vh and Vl domains may be situated relative to each other in any suitable arrangement. For example, the variable region may be dimeric and contain Vh-Vh, Vh-Vl, or Vl-Vl dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric Vh or Vl domain.

[0058] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) VhCh1; (ii) Vh-Ch2; (iii) Vh-Ch3; (iv) Vh-Ch1-Ch2; (v) Vh-Ch1-Ch2-Ch3; (vi) Vh-Ch2-Ch3; (vii) Vh-Cl; (viii) Vl-Ch1; (ix) Vl-Ch2; (x) Vl-Ch3; (xi) VlCh1-Ch2; (xii) Vl-Ch1-Ch2-Ch3; (xiii) Vl-Ch2-Ch3; and (xiv) Vl-Cl. In any configuration of variable and constant domains, including any of the example configurations listed above, the variable and constant domains can be directly linked to each other or can be linked through a hinge or linker region, either complete or partial. A hinge region can consist of Petition 870250087280, dated 09 / 26 / 2025, page 31 / 153 23 / 120 in at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, an antigen-binding fragment of an antibody of the present disclosure may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with each other and / or with one or more monomeric Vh or Vl domains (e.g., by disulfide bonds).

[0059] The constant region of an antibody is important in the antibody's ability to fix complement and mediate cell-dependent cytotoxicity. Thus, in some embodiments, the isotype of an antibody can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0060] The term antibody, as used in this document, also includes multispecific (e.g., bispecific) antibodies. A multispecific antibody or antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in the context of an antibody or antigen-binding fragment of an antibody of the present disclosure using routine techniques available in the art. For example, in some embodiments, the methods of the present disclosure comprise the use of bispecific antibodies wherein one arm of an 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 may be used in the context of this disclosure. Petition 870250087280, dated 09 / 26 / 2025, p. 32 / 153 24 / 120 include, without limitation, for example, bispecific formats based on scFv or diabody, IgG-scFv fusions, dual variable domain (DVD)Ig, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, Duobody, IgG1 / IgG2, dual-action Fab (DAF)-IgG and bispecific Mab2 formats (see, for example, Klein et al. 2012, mAbs 4:6, 1-11 and references cited therein for a review of the previous formats). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, for example, where unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with defined composition, valence, and geometry. (See, for example, Kazane et al., J. Am. Chem. Soc., [Epub: Dec. 4, 2012]).

[0061] In some embodiments, the antibodies used in the methods of this disclosure are human antibodies. The term human antibody, as used in this document, is intended to include antibodies with variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the disclosure may, nevertheless, include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example, in CDRs and, particularly, in CDR3. However, the term human antibody, as used in this document, is not intended to include antibodies in which germline-derived CDR sequences from another mammalian species, such as a mouse, have been grafted onto human framework sequences. Petition 870250087280, dated 09 / 26 / 2025, page 33 / 153 25 / 120

[0062] The antibodies used in the methods of this disclosure may be recombinant human antibodies. The term recombinant human antibody, as used in this document, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see, for example, Taylor et al., (1992) Nucl. Acids Res., 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means involving the splicing of human immunoglobulin gene sequences to other DNA sequences.These recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when a transgenic animal for human Ig sequences is used, in vivo somatic mutagenesis) and, thus, the amino acid sequences of the Vh and Vl regions of the recombinant antibodies are sequences that, although derived from and related to the VH and VL sequences of the human germline, may not naturally exist in the germline repertoire of the human antibody in vivo.

[0063] 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 exists. Petition 870250087280, dated 09 / 26 / 2025, p. 34 / 153 26 / 120 naturally occurring or naturally produced antibodies are isolated antibodies. An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0064] According to certain embodiments, the antibodies used in the methods of the present disclosure bind specifically to IL4Rα. The term binds specifically, as used in this document, means that an antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody binds specifically 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 binds to IL-4Rα or a portion thereof with an equilibrium dissociation constant (Kd) 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 approximately 0.05 nM, as measured in a surface plasmon resonance assay (e.g., BIAcore™, Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) as well. Petition 870250087280, dated 09 / 26 / 2025, p. 35 / 153 27 / 120 can specifically bind to another antigen, for example, an ortholog of the target antigen. For example, in some embodiments, a single antibody that specifically binds to human IL-4Rα exhibits cross-reactivity with other antigens, such as IL-4Rα molecules from other (non-human) species.

[0065] 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), light chain variable region (LCVR) and / or complementarity-determining regions (CDRs) comprising any of the amino acid sequences of the anti-IL-4R antibodies, as set forth in U.S. Patent 7,608,693, incorporated by reference herein. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or antigen-binding fragment thereof comprising the heavy chain complementarity-determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and the light chain complementarity-determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2.In some embodiments, the IL-4Rα 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. Petition 870250087280, dated 09 / 26 / 2025, p. 36 / 153 28 / 120

[0066] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, LGS, and SEQ ID NO:8, respectively, and further comprises an HCVR with at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) with the amino acid sequence of SEQ ID NO:1 and an LCVR with at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) with the amino acid sequence of SEQ ID NO:2. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO:1 and an LCVR comprising SEQ ID NO:2.

[0067] In some embodiments, the anti-IL-4R antibody comprises a variable heavy chain region 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.

[0068] 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 the fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present disclosure comprise the use of dupilumab. As used in this document, dupilumab also includes dupilumab bioequivalents. The term bioequivalent, as used in this document with reference to dupilumab, refers to anti-IL-4R antibodies or IL-4R-binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternatives. Petition 870250087280, dated 09 / 26 / 2025, p. 37 / 153 29 / 120 ticas whose absorption rate and / or extent do not show a significant difference from that of dupilumab when administered at the same molar dose under similar experimental conditions, single or multiple doses. In some embodiments, the term refers to antigen-binding proteins that bind to IL-4R that do not have clinically significant differences from dupilumab in their safety, purity and / or potency.

[0069] Other anti-IL-4Rα antibodies that may be used in the context of the methods of the present disclosure include, for example, the antibody referred to and known in the art as AMG317 (Corren, et al., 2010, Am J Respir Crit Care Med., 181(8): 788-796), or MEDI 9314, or any of the anti-IL-4Rα antibodies as set forth in 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 No. WO2020 / 096381, WO 2020 / 182197, WO2020 / 239134, WO2021 / 213329, WO2022 / 052974, WO2022 / 136669 or WO2022 / 136675, the content of each of which is incorporated by reference into this document.

[0070] In some embodiments, an anti-IL-4Ra 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 set out in Table 1 below.

[0071] In some embodiments, an anti-IL-4Ra 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 Petition 870250087280, dated 09 / 26 / 2025, p. 38 / 153 30 / 120 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-VH72), SEQ ID NO:46 (SCB-VH-73), SEQ ID NO:47 (SCB-VH-74), SEQ ID NO:48 (SCB-VH-75), SEQ ID NO:49 (SCB-VH-76), SEQ ID NO:50 (SCB-VH-77), SEQ ID NO:51 (SCB-VH-78), SEQ ID NO:52 (SCB-VH79), 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-VH86), 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) ou SEQ ID NO:66 (SCBVH-93);and (ii) an LCVR comprising the amino acid sequence of 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-VL52), 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 an HCVR comprising the amino acid sequence of SEQ ID NO:64 (SCB-VH-91) and an 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 (SCBVL-55).

[0072] In some embodiments, an anti-IL-4Rα antibody comprises a pair of amino acid sequences selected from the group consisting of: SEQ ID NOs:67 / 68 (MEDI-1-VH / MEDI-1-VL); SEQ ID NOs:69 / 70 (MEDI-2-VH / MEDI-2-VL); SEQ ID NOs:71 / 72 (MEDI-3 Petition 870250087280, dated 09 / 26 / 2025, p. 39 / 153 31 / 120 VH / MEDI-3-VL); SEQ ID NOs:73 / 74 (MEDI-4-VH / MEDI-4-VL); SEQ ID NOs:75 / 76 (MEDI-5-VH / MEDI-5-VL); SEQ ID NOs:77 / 78 (MEDI-6VH / MEDI-6 / VL); SEQ ID NOs:79 / 80 (MEDI-7-VH / MEDI-7-VL); SEQ ID NOs:81 / 82 (MEDI-8-VH / MEDI-8-VL); SEQ ID NOs:83 / 84 (MEDI-9VH / MEDI-9-VL); SEQ ID NOs:85 / 86 (MEDI-10-VH / MEDI-10-VL); SEQ ID NOs:87 / 88 (MEDI-11-VH / MEDI-11 / VL); SEQ ID NOs:89 / 90 (MEDI12-VH / MEDI-12-VL); SEQ ID NOs:91 / 92 (MEDI-13-VH / MEDI-13-VL); SEQ ID NOs:93 / 94 (MEDI-14-VH / MEDI-14-VL); SEQ ID NOs:95 / 96 (MEDI-15-VH / MEDI-15-VL); SEQ ID NOs:97 / 98 (MEDI-16-VH / MEDI16 / VL); SEQ ID NOs:99 / 100 (MEDI-17-VH / MEDI-17-VL); SEQ ID NOs:101 / 102 (MEDI-18-VH / MEDI-18-VL); SEQ ID NOs:103 / 104 (MEDI-19-VH / MEDI-19-VL); SEQ ID NOs:105 / 106 (MEDI-20-VH / MEDI-20VL); SEQ ID NOs:107 / 108 (MEDI-21-VH / MEDI-21-VL); SEQ ID NOs:109 / 110 (MEDI-22-VH / MEDI-22-VL); SEQ ID NOs:111 / 112 (MEDI-23-VH / MEDI-23-VL); SEQ ID NOs:113 / 114 (MEDI-24-VH / MEDI-24VL); SEQ ID NOs:115 / 116 (MEDI-25-VH / MEDI-25-VL); SEQ ID NOs:117 / 118 (MEDI-26-VH / MEDI-26-VL);SEQ ID NOs:119 / 120 (MEDI-27-VH / MEDI-27-VL); SEQ ID NOs:121 / 122 (MEDI-28-VH / MEDI-28VL); SEQ ID NOs:123 / 124 (MEDI-29-VH / MEDI-29-VL); SEQ ID NOs:125 / 126 (MEDI-30-VH / MEDI-30-VL); SEQ ID NOs:127 / 128 (MEDI-31-VH / MEDI-31-VL); SEQ ID NOs:129 / 130 (MEDI-32-VH / MEDI-32VL); SEQ ID NOs:131 / 132 (MEDI-33-VH / MEDI-33-VL); SEQ ID NOs:133 / 134 (MEDI-34-VH / MEDI-34-VL); SEQ ID NOs:135 / 136 (MEDI-35-VH / MEDI-35-VL); SEQ ID NOs:137 / 138 (MEDI-36-VH / MEDI-36VL); SEQ ID NOs:139 / 140 (MEDI-37-VH / MEDI-37-VL); SEQ ID NOs:141 / 142 (MEDI-38-VH / MEDI-38-VL); SEQ ID NOs:143 / 144 (MEDI-39-VH / MEDI-39-VL); SEQ ID NOs:145 / 146 (MEDI-40-VH / MEDI-40VL); SEQ ID NOs:147 / 148 (MEDI-41-VH / MEDI-41-VL); SEQ ID NOs:149 / 150 (MEDI-42-VH / MEDI-42-VL); and SEQ ID NOs:151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).; Petition 870250087280, dated 09 / 26 / 2025, page 40 / 153 32 / 120

[0073] In some embodiments, an anti-IL-4Ra antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:153 (AJOU-1-VH), SEQ ID NO:154 (AJOU-2-VH), SEQ ID NO:154 (AJOU-2-VH) 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 (AJOU9-VH), SEQ ID NO:162 (AJOU-10-VH), SEQ ID NO:163 (AJOU-69VH), 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 the amino acid sequence of SEQ ID NO:168 (UPDATE-33-VL), SEQ ID NO:169 (UPDATE-34-VL), SEQ ID NO:170 (UPDATE-35-VL), SEQ ID NO:172 (UPDATE-37-VL), SEQ ID NO:174 (UPDATE-39-VL), SEQ ID NO:176 (UPDATE-41-VL), SEQ ID NO:178 (UPDATE-77-VL), SEQ ID NO:180 (UPDATE-79-VL), SEQ ID NO:182 (UPDATE-86-VL), SEQ ID NO:184 (UPDATE-88-VL), SEQ ID NO:171 (AJOU-36-VL), SEQ ID NO:173 (AJOU-38-VL), SEQ ID NO:175 (AJOU-40-VL), SEQ ID NO:177 (AJOU-42-VL), SEQ ID NO:179 (AJOU-78-VL), SEQ ID NO:181 (AJOU-80-VL), SEQ ID NO:183 (AJOU-87-VL), SEQ ID NO:185 (AJOU-89-VL), SEQ ID NO:186 (ADD-90-VL) or SEQ ID NO:187 (ADD-91-VL).

[0074] In some embodiments, an anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:188 (REGN-VH-3), SEQ ID NO:189 (REGN-VH-19), SEQ ID NO:19 (REGN-VH-19), SEQ ID NO:19 (REGN-VH-19), (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-17), or SEQ ID NO:197 (REGN-VH-163); and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO:198 (REGN-VL-11), SEQ ID NO:199 (REGN-VL-27), SEQ ID NO:200 (REGN-VL-43), SEQ ID NO:201 (REGN-VL-59), SEQ ID NO:201 (REGN-VL-59), SEQ ID NO:199 Petition 870250087280, of 26 / 09 / 2025, p. 41 / 153 33 / 120 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).

[0075] In some embodiments, an anti-IL-4Ra antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:208 (STSA-C27-VH), SEQ ID NO:209 (STSA-C27-633-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-C27-56-56VH), SEQ ID NO:215 (STSA-C27-78-78-VH), SEQ ID NO:216 (STSAC27-82-58-VH), SEQ ID NO:217 (STSA-C27-54-54-VH), SEQ ID NO:218 (STSA-C27-36-36-VH), SEQ ID NO:219 (STSA-C27-53-53VH), SEQ ID NO:220 (STSA-C27-67-67-VH), SEQ ID NO:221 (STSAC27-55-55-VH), SEQ ID NO:222 (STSA-C27-59-59-VH), SEQ ID NO:223 (STSA-C27-58-58-VH), SEQ ID NO:224 (STSA-C27-52-52VH) or SEQ ID NO:225 (STSA-C27-Y2-Y2-VH);and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO:226 (STSAC27-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-C27-33-33VL), SEQ ID NO:232 (STSA-C27-56-56-VL), SEQ ID NO:233 (STSAC27-78-78-VL), SEQ ID NO:234 ​​(STSA-C27-82-58-VL), SEQ ID NO:235 (STSA-C27-54-54-VL), SEQ ID NO:236 (STSA-C27-36-36VL), SEQ ID NO:237 (STSA-C27-53-53-VL), SEQ ID NO:238 (STSAC27-67-67-VL), SEQ ID NO:239 (STSA-C27-55-55-VL), SEQ ID NO:240 (STSA-C27-59-59-VL), SEQ ID NO:241 (STSA-C27-58-58VL), SEQ ID NO:242 (STSA-C27-52-52-VL) or SEQ ID NO:243 (STSA-C27-Y2-Y2-VL).;

[0076] In some embodiments, an anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence Petition 870250087280, dated 09 / 26 / 2025, page 42 / 153 34 / 120 de SEQ ID NO:244 (Y0188-1 VH), SEQ ID NO:245 (Y0188-2 VH), SEQ ID NO:246 (Y0188-3 VH), SEQ ID NO:247 (Y0188-4 VH), SEQ ID NO:248 (Y0188-6 VH), SEQ ID NO:249 (Y0188-8 VH), SEQ ID NO:250 (Y0188-9 VH), SEQ ID NO:251 (Y0188-10 VH), SEQ ID NO:252 (Y0188-14 VH), SEQ ID NO:253 (HV3-15-14 VH), SEQ ID NO:254 (HV3-48-14 VH), SEQ ID NO:255 (HV3-73*2-14 VH), SEQ ID NO:256 (HV3-72-14 VH), SEQ ID NO:257 (Y01-14 VH), SEQ ID NO:258 (16214 VH) ou SEQ ID NO:259 (VH73-14 VH); e (ii) uma LCVR compreendendo a sequência de aminoácidos de SEQ ID NO:260 (Y0188-1 VL), SEQ ID NO:261 (Y0188-2 VL), SEQ ID NO:262 (Y0188-3 VL), SEQ ID NO:263 (Y0188-4 VL), SEQ ID NO:264 (Y0188-6 VL), SEQ ID NO:265 (Y0188-8 VL), SEQ ID NO:266 (Y0188-9 VL), SEQ ID NO:267 (Y018810 VL), SEQ ID NO:268 (Y0188-14 VL), SEQ ID NO:269 (Y01-14 VL), SEQ ID NO:270 (164-14 VL), SEQ ID NO:271 (KV4-14 VL), SEQ ID NO:272 (KV1-27-14 VL), SEQ ID NO:273 (KV1-9-14 VL), SEQ ID NO:274 (KV1-NL1-14 VL) ou SEQ ID NO:275 (KV1D-43-14 VL).

[0077] In some embodiments, an anti-IL-4Rα antibody used in the methods of this disclosure may have pH-dependent binding characteristics. For example, an anti-IL-4Rα antibody for use as disclosed herein may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody for use as disclosed herein may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The term acidic pH includes pH values ​​less than about 6.2, for example, 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. As used in this document, the term neutral pH means a pH of about 7.0 to about 7.4. The term 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. Petition 870250087280, dated 09 / 26 / 2025, p. 43 / 153 35 / 120

[0078] In certain cases, reduced IL-4Ra binding at acidic pH compared to neutral pH is expressed in terms of a ratio of the Kd value of antibody binding to IL-4Rα at acidic pH to the Kd value of antibody binding to IL-4Rα at neutral pH (or vice versa). For example, an antibody or antigen-binding fragment thereof may be considered to exhibit reduced IL-4Rα binding at acidic pH compared to neutral pH for the purposes of this disclosure if the antibody or antigen-binding fragment thereof exhibits an acidic / neutral Kd ratio of about 3.0 or higher. In certain exemplary embodiments, the acid / neutral Kd ratio for an antibody or antigen-binding fragment of the present disclosure 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 higher.

[0079] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. Furthermore, 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 of an antigen-binding domain (e.g., within a CDR) with a histidine residue, an antibody with reduced antigen binding at acidic pH compared to neutral pH can be obtained. Preparation of Human Antibodies

[0080] Methods for generating human antibodies in transgenic mice are known in the art. Any of these known methods can be used in the context of the present disclosure to make human antibodies that bind specifically to Petition 870250087280, dated 09 / 26 / 2025, p. 44 / 153 36 / 120 Human IL-4R.

[0081] Using VELOCIMMUNE™ technology (see, for example, US 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, high-affinity chimeric antibodies to IL-4R are initially isolated having a human variable region and a mouse constant region. VELOCIMMUNE® technology involves generating a transgenic mouse with a genome comprising human heavy and light chain variable regions operationally ligated to mouse constant region sites, such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. The DNA encoding the antibody's heavy and light chain variable regions is isolated and operationally ligated to the DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing the fully human antibody.

[0082] Generally, a VELOCIMMUNE® mouse is challenged with the antigen of interest, and lymphatic cells (such as B cells) are retrieved from the antibody-expressing mice. The lymphatic cells can be fused with a myeloma cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. The DNA encoding the variable regions of the heavy chain and light chain can be isolated and ligated to desirable isotypic constant regions of the heavy chain and light chain. An antibody protein like this can be produced in a cell, such as a CHO cell. Alternatively, the DNA encoding the antigen-specific chimeric antibodies or Petition 870250087280, dated 09 / 26 / 2025, page 45 / 153 37 / 120 The variable domains of the light and heavy chains can be isolated directly from antigen-specific lymphocytes.

[0083] Initially, high-affinity chimeric antibodies are isolated with a human variable region and a mouse constant region. The antibodies are characterized and selected for desirable features, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant regions are replaced with a desired human constant region to generate the fully human antibody of the dissemination, for example, wild type or modified IgG1 or IgG4. Although the selected constant region may vary according to the specific use, the high-affinity antigen binding and target specificity characteristics reside in the variable region.

[0084] In general, the antibodies that can be used in the methods of the present disclosure have high affinities, as described above, when measured by binding to the antigen immobilized in solid phase or in solution phase. The mouse constant regions are replaced by desired human constant regions to generate the fully human antibodies of the disclosure. Although the selected constant region may vary according to the specific use, the high-affinity antigen binding and target specificity characteristics reside in the variable region.

[0085] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R and that can be used in the methods disclosed in this document comprises the three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained in a variable heavy chain region (HCVR) with an amino acid sequence of SEQ ID NO:1 and the three light chain CDRs (LCVR1, LCVR2 and LCVR3) contained in a variable region of Petition 870250087280, dated 09 / 26 / 2025, p. 46 / 153 38 / 120 light chain (LCVR) with an amino acid sequence of SEQ ID NO:2. Methods and techniques for identifying CDRs within the amino acid sequences of HCVR and LCVR are well known in the art and can be used to identify CDRs within the specified HCVR and / or LCVR amino acid sequences disclosed in this document. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, 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 middle ground between the Kabat and Chothia approaches. See, for example, Kabat, Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani, et al., J. Mol. Biol., 273:927-948 (1997); and Martin, et al., Proc. Natl. Academic. Sci., USA 86: 9268-9272 (1989).Public databases are also available for identifying CDR sequences in an antibody. Pharmaceutical Compositions and Kits

[0086] In one aspect, the present disclosure provides methods comprising administering an IL-4R antagonist to an individual, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained in a pharmaceutical composition comprising one or more pharmaceutically acceptable vehicles, carriers, and / or excipients. Several pharmaceutically acceptable carriers and excipients are well known in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.

[0087] Methods of administration include, among others, intra Petition 870250087280, dated 09 / 26 / 2025, p. 47 / 153 39 / 120 dermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural and oral. The composition can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with other biologically active agents. In some embodiments, a pharmaceutical composition as disclosed in this document is administered intravenously. In some embodiments, a pharmaceutical composition as disclosed in this document is administered subcutaneously.

[0088] In some embodiments, the pharmaceutical composition comprises an injectable preparation, such as a dosage form for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by known methods. For example, injectable preparations may be prepared, for instance, by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As an aqueous medium for injections, there is, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which can be used in combination with an appropriate solubilizing agent, such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a non-ionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) hydrogenated castor oil adduct)], etc.As an oily medium, sesame oil, soybean oil, etc., are used, which can be combined with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared can be placed in an appropriate ampoule. Petition 870250087280, dated 09 / 26 / 2025, page 48 / 153 40 / 120

[0089] The antibody dose administered to an individual according to the methods of this disclosure may vary depending on the individual's age and size, symptoms, conditions, route of administration, and the like. The dose is typically calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment may be adjusted. Effective dosages and schedules for the administration of pharmaceutical compositions comprising anti-IL-4R antibodies can be determined empirically; for example, the individual's progress can be monitored by periodic assessment and the dose adjusted accordingly. Furthermore, interspecies dose escalation can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res., 8:1351).Specific example doses of anti-IL-4R antibodies and administration regimens involving them, which may be used in the context of this disclosure, are disclosed elsewhere in this document.

[0090] In some embodiments, an IL-4R antagonist or a pharmaceutical composition of the present disclosure is contained within a container. Thus, in another aspect, containers comprising an IL-4R antagonist or a pharmaceutical composition as disclosed in this document are provided. For example, in some embodiments, a pharmaceutical composition is contained within a container selected from the group consisting of a glass vial, a syringe, a pen dispensing device, and an autoinjector.

[0091] In some embodiments, a pharmaceutical composition of the present disclosure is distributed, for example, subcutaneously or intravenously, using a standard needle and syringe. In some embodiments, the syringe is a pre-filled syringe. In some Petition 870250087280, dated 09 / 26 / 2025, p. 49 / 153 In 41 / 120 embodiments, a pen dispensing device or autoinjector is used to dispense a pharmaceutical composition of the present disclosure (e.g., for subcutaneous distribution). A pen dispensing device may be reusable or disposable. Typically, a reusable pen dispensing device uses a replaceable cartridge containing a pharmaceutical composition. Once the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen-type dispensing device can then be reused. In a disposable pen dispensing device, there is no replaceable cartridge. Instead, the disposable pen dispensing device comes pre-filled with the pharmaceutical composition contained in a reservoir within the device.Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0092] Examples of suitable pen dispensing devices and autoinjectors include, but are not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, United Kingdom), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™ and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen delivery devices with applications in the subcutaneous delivery of a pharmaceutical composition of this disclosure include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk) and KWIKPEN™ (Eli Lilly), and the SURE Autoinjector. Petition 870250087280, dated 09 / 26 / 2025, page 50 / 153 42 / 120 CLICK™ (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRA™ Pen (Abbott Labs, Abbott Park, IL).

[0093] In some embodiments, the pharmaceutical composition is delivered using a controlled-release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials may be used (see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida). In yet another embodiment, a controlled-release system may be placed in close proximity to the target of the composition, thus requiring only a fraction of the systemic dose (see, for example, Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled-release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.Other delivery systems are known and can be used to administer the pharmaceutical composition, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, for example, Wu, et al., 1987, J. Biol. Chem. 262:4429-4432).

[0094] 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 of section 5.2 of ISO 11608-1:2014(E). As described in ISO 11608-1:2014(E), needle-based injection systems can be broadly distinguished into multi-dose container systems and single-dose container systems (with partial or total evacuation). The container may be a replaceable container or a non-replaceable container. Petition 870250087280, dated 09 / 26 / 2025, page 51 / 153 43 / 120 integrated.

[0095] As further described in ISO 11608-1:2014(E), a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (predefined by the user). Another multi-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (predefined by the user).

[0096] As further described in ISO 11608-1:2014(E), a single-dose container system may involve a needle-based injection device with a replaceable container. In one example of such a system, each container holds a single dose, with which the entire dispensable volume is expelled (complete evacuation). In a further example, each container holds a single dose, with which a portion of the dispensable volume is expelled (partial evacuation). As also described in ISO 11608-1:2014(E), a single-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In one example of such a system, each container holds a single dose, with which the entire dispensable volume is expelled (complete evacuation). In a further example, each container holds a single dose, with which a portion of the dispensable volume is expelled (partial evacuation).

[0097] An exemplary glove-operated autoinjector with manual needle insertion is described in International Publication WO2015 / 004052. Exemplary audible end-of-dose feedback mechanisms are described in International Publications WO2016 / 193346 and WO2016 / 193348. A safety mechanism of Petition 870250087280, dated 09 / 26 / 2025, page 52 / 153 An exemplary 44 / 120 needle after use of an autoinjector is described in International Publication WO2016 / 193352. An exemplary needle sheath removal mechanism for a syringe autoinjector is described in International Publication WO2016 / 193353. An exemplary support mechanism for supporting an axial position of a syringe is described in International Publication WO2016 / 193355.

[0098] In some embodiments, pharmaceutical compositions for use as described in this document are prepared in dosage forms in a unit dose suitable to accommodate a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0099] Exemplary pharmaceutical compositions comprising an anti-IL-4R antibody that may be used in the context of the present disclosure are disclosed, for example, in U.S. Patent No. 8,945,559.

[00100] In another aspect, kits comprising an IL-4R antagonist or a pharmaceutical composition as disclosed in this document are provided. In some embodiments, the kit comprises an anti-IL-4R antibody or a pharmaceutical composition comprising an anti-IL-4R antibody and instructions for its use in the treatment of eosinophilic gastroenteritis in an individual. In some embodiments, the instructions for use comprise administering the anti-IL-4R antibody or pharmaceutical composition in an amount, dosing frequency and / or for a period of time as disclosed elsewhere in this document. Dosage and Administration

[00101] In some modalities, an IL-4R antagonist (e.g., anti-IL-4R antibody) is administered to an individual (e.g., an individual with EGE, EoG, or EoD) according to the methods Petition 870250087280, dated 09 / 26 / 2025, page 53 / 153 45 / 120 all of this disclosure in a therapeutically effective amount. As used in this document with reference to an IL-4R antagonist, the phrase therapeutically effective amount means an amount of IL-4R antagonist that results in one or more of the following: (a) a reduction in the severity or duration of one or more symptoms of eosinophilic gastroenteritis (e.g., EoG and / or EoD); (b) a reduction in the number of eosinophils in a region of the gastrointestinal tract (e.g., stomach or small intestine); (c) an improvement in one or more anatomical, endoscopic, or histological features of the gastrointestinal tract (e.g., stomach or small intestine); (d) normalization of one or more EGE-associated biomarkers or gene expression signatures; and / or (e) a reduction in the use of, or need for, concomitant or rescue treatment with another agent (e.g., reduced or eliminated use of systemic and / or swallowed topical corticosteroids).

[00102] In the case of an anti-IL-4R antibody, a therapeutically effective amount may 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 Petition 870250087280, dated 09 / 26 / 2025, page 54 / 153 46 / 120 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, or approximately 600 mg of the anti-IL-4R antibody. In some embodiments, a therapeutically effective amount is approximately 50 mg to approximately 600 mg, or approximately 100 mg to approximately 600 mg, or approximately 50 mg to approximately 400 mg. In certain modalities, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 300 mg of an anti-IL-4R antibody are administered to an individual.

[00103] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in individual doses can be expressed in terms of milligrams of antibody per kilogram of the individual's body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to an individual at a dose of about 0.0001 to about 10 mg / kg of the individual's body weight, for example, at a dose of about 1 mg / kg to about 10 mg / kg, at a dose of about 2 mg / kg to about 9 mg / kg, or at a dose of about 3 mg / kg to about 8 mg / kg. In some modalities, the IL-4R antagonist can be administered to an individual at a dose of approximately 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg.

[00104] In some embodiments, the methods disclosed in this document comprise administering an IL-4R antagonist to an individual at a dosing frequency of approximately four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks. Petition 870250087280, dated 09 / 26 / 2025, p. 55 / 153 47 / 120 weeks, once every eight weeks, once every twelve weeks, or less frequently, provided a therapeutic response is achieved. In some embodiments, the methods disclosed in this document comprise administering an IL-4R antagonist to an individual once weekly, 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 in this document) is administered once weekly (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W) in an amount of about 50 mg to about 600 mg, for example, about 75 mg, 100 mg, 150 mg, 200 mg, or 300 mg.

[00105] In some embodiments, multiple doses of an IL-4R antagonist are administered to an individual over a defined period of time. In some embodiments, the methods of this disclosure comprise the sequential administration to an individual of multiple doses of an IL-4R antagonist. As used in this document, sequential administration means that each dose of the IL-4R antagonist is administered to the individual at a different point in time, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the methods of the disclosure comprise the sequential administration to the patient of a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of the IL-4R antagonist and optionally followed by one or more tertiary doses of the IL-4R antagonist.

[00106] The terms initial dose, secondary doses, and tertiary doses refer to the temporal sequence of administration of the IL-4R antagonist. Thus, the initial dose is the dose that is administered in Petition 870250087280, dated 09 / 26 / 2025, p. 56 / 153 48 / 120 initial doses are the initial dose of the treatment regimen (also referred to as the loading dose); secondary doses are the doses administered after the initial dose; and tertiary doses are the doses administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but they may generally differ from one another in terms of frequency of administration. In certain modalities, however, the amount of IL-4R antagonist contained in the initial, secondary, and / or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In some modalities, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as loading doses followed by subsequent doses that are administered on a less frequent basis (e.g., maintenance doses).In some embodiments, the initial or loading dose and one or more secondary or maintenance doses each contain the same amount of the IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of the IL-4R antagonist, and one or more secondary doses each comprise a second amount of the IL-4R antagonist. For example, the first amount of the IL-4R antagonist may be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x or more than 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.

[00107] In some embodiments, a loading dose is a divided dose that is administered as two or more doses (e.g., 2, 3, 4, or 5 doses) that are administered on separate days. In some embodiments, a loading dose is administered as a divided dose in which the two or more doses are administered with Petition 870250087280, dated 09 / 26 / 2025, page 57 / 153 49 / 120 at least about a week apart. In some embodiments, a loading dose is administered as a split dose where the two or more doses are given about 1 week, 2 weeks, 3 weeks, or 4 weeks apart. In some embodiments, the loading dose is evenly divided between the two or more doses (e.g., half of the loading dose is given as the first dose and half of the loading dose is given as the second dose). In some embodiments, the loading dose is not evenly divided between the two or more doses (e.g., more than half of the loading dose is given as the first dose and less than half of the loading dose is given as the second dose).

[00108] In some embodiments, each secondary and / or tertiary dose is administered from 1 to 14 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½). The phrase "the immediately preceding dose," as used in this document, means, in a sequence of multiple administrations, the dose of IL-4R antagonist that is administered to a patient before the administration of the next dose in the sequence without intervening doses.

[00109] Disclosure methods may involve administering to a patient any number of secondary and / or tertiary doses of an IL-4R antagonist. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) tertiary doses are administered. Petition 870250087280, dated 09 / 26 / 2025, p. 58 / 153 50 / 120 doses to the patient.

[00110] In some modalities involving multiple secondary doses, each secondary dose is administered at the same frequency as other secondary doses. For example, each secondary dose may be administered to the patient 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose. Similarly, in some modalities 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 at which secondary and / or tertiary doses are administered to a patient may vary throughout the treatment regimen. The frequency of administration may also be adjusted during the treatment period by a physician depending on the individual patient's needs after clinical examination.

[00111] In some embodiments, for an individual with eosinophilic gastroenteritis (e.g., EoG and / or EoD), a therapeutically effective amount of an IL-4R antagonist (e.g., anti-IL-4R antibody) comprises 300 mg administered every week (QW). In some embodiments, no loading dose is administered. In some embodiments, a loading dose is administered, for example, a loading dose of 600 mg.

[00112] In some embodiments, for an individual with eosinophilic gastroenteritis (e.g., EoG and / or EoD), a therapeutically effective amount of an IL-4R antagonist (e.g., 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 is administered, for example, a loading dose of 600 mg. Petition 870250087280, dated 09 / 26 / 2025, page 59 / 153 51 / 120 Therapeutic Dosage Forms

[00113] In another aspect, this disclosure provides therapeutic dosage forms of an IL-4R antagonist (e.g., an anti-IL-4R antibody or antigen-binding fragment thereof) for use in the treatment of an individual with eosinophilic gastroenteritis (e.g., EoG and / or EoD), as disclosed in this document. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof with one or more CDR, HCVR, and / or LCVR sequences listed in Table 1. In some embodiments, the IL-4R antagonist is an anti-IL4Rα antibody or antigen-binding fragment thereof comprising the HCDRs of an HCVR comprising the amino acid sequence of SEQ ID NO:1 and the LCDRs of an LCVR comprising the amino acid sequence of SEQ ID NO:2 (e.g., dupilumab).

[00114] In some modalities, the therapeutic dose is 300 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody) and is for administration every week (QW).

[00115] In some modalities, the therapeutic dose is 300 mg of the IL-4R antagonist (e.g., anti-IL-4R antibody) and is to be administered every two weeks (Q2W). Parameters Related to EGE

[00116] In some modalities, the therapeutic methods disclosed in this document result in an improvement in one or more EGE-related outcomes or parameters that are used to assess the presence or severity of EGE (e.g., EoG with or without EoD) in an individual. Examples of EGE-related parameters include, but are not limited to: (a) change (e.g., reduction) in eosinophil count (e.g., gastric eosinophil count or duodenal eosinophil count); (b) change in severity Petition 870250087280, dated 09 / 26 / 2025, page 60 / 153 52 / 120 and / or extent of histological features in the gastrointestinal tract (e.g., stomach or small intestine), for example, as measured using EoGHSS or EoDHSS; (c) change in one or more gastrointestinal features, for example, as measured using EG-REFS or ED-REFS; (d) change (e.g., normalization) in the levels of one or more EGE-associated biomarkers or in an EGE gene expression signature; (e) change (e.g., reduction) in the frequency and / or intensity of symptoms, for example, as measured using the EoG / EoD Symptom Questionnaire (EoG / EoD-SQ), the Patient Global Impression of Change (PGI-C), the Patient Global Impression of Severity (PGI-S), the Clinical Global Impression of Change (CGI-C), the Clinical Global Impression of Severity (CGI-S), the EoG / EoD Quality of Life Questionnaire (EoG / EoD QoL) or the European 5-Dimensional 5-Level Quality of Life Scale (EQ-5D-5L).The methods for evaluating these and other EGE-related parameters are described in the Examples section below.

[00117] To determine if an EGE-related parameter has improved, the parameter is quantified at baseline (e.g., before the start of treatment with the IL-4R antagonist) and at one or more time points after administration of the IL-4R antagonist. For example, an EGE-related parameter might 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 later, after initial treatment with a pharmaceutical composition of the present di Petition 870250087280, dated 09 / 26 / 2025, page 61 / 153 53 / 120 disclosure. The difference between the parameter value at a particular time point following the start of treatment and the parameter value at the initial assessment is used to establish whether there has been an improvement in the EGE-related parameter.

[00118] In some modalities, treatment of an individual with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement (e.g., reduction) in peak gastric eosinophil count or peak duodenal eosinophil count. Peak eosinophil count refers to the number of eosinophils contained in a high-power field (hpf).

[00119] In some modalities, treatment with an IL-4R antagonist results in a decrease in peak gastric eosinophil count relative to baseline assessment (e.g., an individual's peak count before treatment initiation). In some modalities, treatment with an IL-4R antagonist results in a peak gastric eosinophil count of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline assessment. In some modalities, treatment with an IL-4R antagonist results in a decrease in peak gastric eosinophil count to less than 30 eos / hpf, for example, < 20 eos / hpf, < 15 eos / hpf, < 10 eos / hpf, or < 6 eos / hpf. In some modalities, treatment with an IL-4R antagonist results in a decrease in peak gastric eosinophil count to <6 eos / hpf, <5 eos / hpf, <4 eos / hpf, <3 eos / hpf, <2 eos / hpf, or <1 eos / hpf.In some modalities, treatment with an IL-4R antagonist results in histological remission of the disease. In some modalities, the change in peak gastric eosinophil count is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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 antagonist. Petition 870250087280, dated 09 / 26 / 2025, p. 62 / 153 54 / 120 of IL-4R.

[00120] In some modalities, treatment with an IL-4R antagonist results in a decrease in peak duodenal eosinophil count relative to baseline assessment (e.g., an individual's peak count before treatment initiation). In some modalities, treatment with an IL-4R antagonist results in peak duodenal eosinophil counts of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more relative to baseline assessment. In some modalities, treatment with an IL-4R antagonist results in a decrease in peak duodenal eosinophil count to less than 30 eos / hpf, for example, < 20 eos / hpf, < 15 eos / hpf, < 10 eos / hpf, or < 6 eos / hpf. In some modalities, treatment with an IL-4R antagonist results in a decrease in peak duodenal eosinophil count to <6 eos / hpf, <5 eos / hpf, <4 eos / hpf, <3 eos / hpf, <2 eos / hpf, or <1 eos / hpf.In some modalities, treatment with an IL-4R antagonist results in histological remission of the disease. In some modalities, the change in peak duodenal eosinophil count is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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.

[00121] In some modalities, treatment of an individual with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in one or more EGE histological features (e.g., EoG and / or EoD). In some modalities, treatment of an individual with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in EoG scores of the Histology Scoring System (EoGHSS). In some modalities, treatment of an individual with an antagonist Petition 870250087280, dated 09 / 26 / 2025, p. 63 / 153 55 / 120 of IL-4R (e.g., an anti-IL-4R antibody) results in an improvement in EoD scores from the Histology Scoring System (EoDHSS).

[00122] EoGHSS scores assess 11 gastric tissue features: eosinophilic sheets of the lamina propria, periglandular circumferential collars, eosinophils in the surface epithelium, eosinophilic glandulitis, eosinophilic gland abscess, eosinophils in the mucosa and muscularis submucosa, lamina propria fibroplasia, lamina propria smooth muscle hyperplasia, reactive epithelial changes, acute inflammation, and superficial erosion / ulcer. In some modalities, each feature is scored from 0 to 3 (0=normal; 3=maximum change) and the total score is the sum of the feature scores divided by the maximum possible score. In some modalities, treatment with an IL-4R antagonist results in a decrease in the EoGHSS score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to the baseline assessment (e.g., an individual's EoGHSS score before treatment initiation).In some modalities, the change in EoGHSS score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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.

[00123] EoDHSS scores assess 11 characteristics of duodenal tissue: eosinophilic sheets in the lamina propria, pericryptal circumferential collars, eosinophils in the surface epithelium, eosinophilic cryptitis, subcryptal eosinophil aggregates, subcryptal lymphoplasmacytic inflammation, eosinophilic crypt abscess, eosinophils in the muscularis mucosa / submucosa, villous atrophy, elongated crypts, reactive epithelial changes, acute inflammatory cells, superficial erosion / ulceration, and intraepithelial lymphocytosis. In some modalities, each ca Petition 870250087280, dated 09 / 26 / 2025, page 64 / 153 56 / 120 each characteristic receives a score from 0 to 3 (0=normal; 3=maximum change) and the total score is the sum of the characteristic scores divided by the maximum possible score. In some modalities, treatment with an IL-4R antagonist results in a decrease in the EoDHSS score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to the baseline assessment (e.g., an individual's EoDHSS score before treatment initiation). In some modalities, the change in EoDHSS score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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.

[00124] In some modalities, treatment of an individual with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in one or more endoscopic features of EoG, for example, inflammatory and remodeling features in the stomach or duodenum. In some modalities, treatment of an individual with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in the EG-REFS score (for patients with EoG), ED-REFS score (for patients with EoD), or EoE-EREFS score (for patients with EoE comorbidity).

[00125] The Endoscopic EoG Reference Score (EGREFS) is an endoscopic classification system that was developed specifically to assess eosinophilic gastritis and is completed by the endoscopist. It has been used in therapeutic trials and captures granularity (scale 0-2), erosion / ulceration (0-6), raised lesions (0-2), erythema (0-2), friability / bleeding (0-2), and folds (0-1) of the gastric fundus, body, and antrum. Pyloric stenosis (0-1) is also captured. The maximum total EG-REFS score is 46. In some modalities, treatment with an IL-4R antagonist results in a Petition 870250087280, dated 09 / 26 / 2025, page 65 / 153 57 / 120 decrease in EG-REFS score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more from baseline (e.g., an individual's EG-REFS score before treatment initiation). In some modalities, the change in EG-REFS score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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 modalities, treatment with an IL-4R antagonist results in an improvement in one or more EG-REFS subscores.

[00126] The Endoscopic Reference Score for EoD (EDREFS) is an endoscopic classification system that was developed specifically to assess eosinophilic duodenitis and is completed by the endoscopist. It has been used in therapeutic trials and captures granularity (scale 0-2), erythema (0-2), friability / bleeding (0-2), ulceration (0-4), denuded patches (0-2), and stenosis (0-2). The maximum total ED-REFs score is 14. In some modalities, treatment with an IL-4R antagonist results in a decrease in the EG-REFs score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to baseline (e.g., an individual's ED-REFs score before treatment initiation).In some modalities, the change in ED-REFS score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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 modalities, treatment with an IL-4R antagonist results in an improvement in one or more ED-REFS subscores.

[00127] EoE-EREFS (edema, rings, exudates, sulci, stenoses) is a validated scoring system for inflammatory features. Petition 870250087280, dated 09 / 26 / 2025, p. 66 / 153 58 / 120 story and remodeling features of the disease that is used to measure inflammatory and remodeling characteristics of the endoscopically identified esophageal mucosa (EoE) (Hirano, et al., Gut, 2013, 62:489-495). In some modalities, treatment with an IL-4R antagonist results in a decrease in the EoE-EREFS score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to baseline assessment (e.g., an individual's EoE-EREFS score before treatment initiation). In some modalities, the change in EoE-EREFS score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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 modalities, treatment with an IL-4R antagonist results in an improvement in one or more EoEEFS subscores.

[00128] In some modalities, treatment of an individual with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in normalization of one or more EGE-associated biomarkers, a gene signature from the Eosinophilic Gastritis Diagnostic Panel (EGDP), a gene signature for Type 2 inflammation, and / or a Normalized Enrichment Score (NES) calculated for a set of EGE-associated genes (e.g., EoG-associated genes or EoD-associated genes). In some modalities, treatment of an individual with an IL-4R antagonist suppresses an EGDP gene signature, a gene signature for Type 2 inflammation, and / or an NES calculated for a set of EGE- or Type 2-associated inflammation genes. As used in this document, the term EGE-associated biomarker refers to a biological response, cell type, parameter, protein, polypeptide, enzyme, enzymatic activity, metabolite, nucleic acid, carbohydrate. Petition 870250087280, dated 09 / 26 / 2025, p. 67 / 153 59 / 120 or another biomolecule that is present or detectable in a patient with EGE at a level or quantity that is different (e.g., higher or lower than) the level or quantity of the marker present or detectable in a patient without EGE. Exemplary EGE-associated biomarkers include, among others, for example, gastric or duodenal eosinophils, cytokines / chemokines (CCL11, CCL18, CCL24, CCL26, IL13RA2, and IL5), eosinophilia (CLC), cell adhesion (CDH26), antimicrobial defense (KLK7, DEFB1), epithelium-related (MUC4), fibrosis (BMP3 and COL2A1), ion transport (SLC26A7), neurosensory activity (GABRA1, GLDN, NPY, and TAC1), and stomach-related processes (ATP4A and SST). The term EGE gene signature refers to a differential gene expression profile of gastric biopsies from patients with EGE (e.g., EoG with or without EoD) compared to healthy controls and is also referred to as an EGE disease transcriptome (Caldwell, et al.).(J Allergy Clin Med, 2014, 134: 1114-1124). In some embodiments, the EGE gene signature is a differential gene expression profile associated with EoG, also referred to in this document as an EoG disease transcriptome or an EoG gene signature. In some embodiments, an EGE gene signature is a smaller set of genes, such as the EGDP panel (Shoda, et al., J Allergy Clin Med, 2020, 145: 255-269). A Type 2 inflammation gene signature refers to a transcriptome for a set of genes associated with type 2 inflammation. Exemplary genes associated with Type 2 inflammation include, but are not limited to, CCL26, ALOX15, CCR3, and IL1RL1. A list of exemplary genes for a Type 2 inflammation gene signature is shown in WO2021 / 237110, incorporated by reference in this document. A Normalized Enrichment Score (NES) reflects the degree to which the activity level of a set of transcripts is over-represented at the extremes (upper or lower). Petition 870250087280, dated 09 / 26 / 2025, p. 68 / 153 60 / 120 or) of the entire sorted list of transcripts within a sample and is normalized by counting the number of transcripts in the set (Subramanian, et al., Proc Natl Acad Sci USA, 2005, 102: 15545-50) (Barbie, et al., Nature, 2009, 462: 108-112).

[00129] In some modalities, biomarkers associated with EGE, EGE gene signature, Type 2 inflammation gene signature, and / or NES are determined using a tissue sample from the individual (e.g., gastric or duodenal biopsy samples). In some modalities, treatment of an individual with an IL-4R antagonist results in a normalization of one or more EGE-associated biomarkers, an EGE gene signature, a Type 2 inflammation gene signature, and / or a NES, relative to baseline assessment (e.g., an individual's expression level of EGE-associated biomarkers, EGE gene signature, or NES before treatment initiation), for example, as measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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 modalities, treatment of an individual with an IL-4R antagonist suppresses a NES for one or more EGE-associated biomarkers, an EGE gene signature, or a Type 2 inflammation gene signature, relative to baseline assessment (e.g., an individual's NES before treatment initiation), for example, as measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following administration of the IL-4R inhibitor, or after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 24 weeks of treatment with the IL-4R antagonist.

[00130] In some modalities, treatment of an individual with an IL-4R antagonist (e.g., an anti-IL-4R antibody) results in an improvement in one or more other signs or symptoms of Petition 870250087280, dated 09 / 26 / 2025, p. 69 / 153 61 / 120 EGE (e.g., EoG and / or EoD) or in health-related quality of life.

[00131] In some modalities, treatment results in an improvement in the EoG / EoD Symptom Questionnaire score. The EoG / EoD-SQ is a novel PRO measure, designed to be collected daily, that was developed to assess EoG (with or without EoD) reported symptoms among adults and adolescents. The EoG / EoD-SQ assesses 9 EoG (with or without EoD) symptoms: stomach pain, stomach cramps, nausea, heartburn, bloating, early satiety, loss of appetite, vomiting, and diarrhea. The severity of stomach pain, stomach cramps, nausea, heartburn, bloating, early satiety, and loss of appetite is assessed using an 11-point numerical rating scale (NRS; zero to 10); for vomiting and diarrhea, the frequency of episodes is assessed. Higher scores indicate a greater symptom burden.The severity scores reported by the participant for each symptom in the Total Symptom Score (TSS) (stomach pain, stomach cramps, nausea, bloating, early satiety, loss of appetite; each reported on a scale of 0 to 10) are summed each day with eDiary data (maximum daily score of 60). The TSS is then calculated by averaging the daily sum scores across all days with eDiary data over a 7-day period, with a maximum TSS of 60. Heartburn is excluded from the TSS, as this symptom may be misinterpreted as esophageal dysfunction, while other symptoms are located in the stomach / small intestine (site of eosinophilic inflammation in EoG [with or without EoD]). In some modalities, prior to the start of treatment, the individual has an initial assessment TSS of EoG / EoD-SQ > 20, for example, an initial assessment TSS of at least 25, 30, 35, or 40.In some modalities, before the start of treatment, the individual has an initial average severity score. Petition 870250087280, dated 09 / 26 / 2025, page 70 / 153 62 / 120 al of > 4 for at least 2 components of the EoG / EoD-SQ TSS (i.e., two or more of the components stomach pain, stomach cramps, nausea, bloating, early satiety, and loss of appetite). In some modalities, the individual has an average baseline severity score of > 4 for at least 2, at least 4, at least 5, or all 6 components of the EoG / EoD-SQ TSS. In some modalities, the individual has an average baseline severity score of > 5 or > 6 for at least 2, at least 4, at least 5, or all 6 components of the EoG / EoD-SQ TSS. In some modalities, treatment with an IL-4R antagonist results in a decrease in the EoG / EoD-SQ score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to the baseline assessment.In some modalities, the change in EoG / EoD-SQ score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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 modalities, treatment with an IL-4R antagonist results in a decrease in the number of days or the number of total segments in a day (e.g., night, morning, afternoon, early evening) with 1 or more EGE signals, as measured by EoG / EoD-SQ. In some modalities, treatment with an IL-4R antagonist results in an improvement in one or more signs / symptoms measured by EoG / EoD-SQ.

[00132] In some modalities, treatment results in an improvement in the PGI-C score. The Patient Global Impression of Change (PGI-C) is a 10-item PRO measure that assesses the participant's impression of the overall change (improvement or worsening) in their EoG symptoms (with or without EoD) and change in individual EoG / EoD symptoms since the start of study treatment, using a scale Petition 870250087280, dated 09 / 26 / 2025, page 71 / 153 63 / 120 scale of response on a 7-level scale (from much better to much worse). In some modalities, treatment with an IL-4R antagonist results in a decrease in the PGI-C score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more from baseline. In some modalities, the change in the PGI-C score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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.

[00133] In some modalities, treatment results in an improvement in the PGI-S score. The Patient Global Impression of Severity (PGI-S) is a 10-item PRO measure that assesses the participant's impression of the overall severity of their EoG symptoms (with or without EoD) and the severity of individual EoG / EoD symptoms over the past 7 days, using a 5-level response scale (from none to very severe). In some modalities, treatment with an IL-4R antagonist results in a decrease in the PGI-S score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to baseline assessment. In some modalities, the change in PGI-S score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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.

[00134] In some modalities, treatment results in an improvement in the CGI-C score. The Physician's Global Impression of Change (CGI-C) is a single-item observer-reported outcome measure that assesses the study investigator / physician's impression of the overall change (improvement or worsening) in the participant's EoG (with or without EoD) since the start of study treatment, using a 7-level response scale (from much improved to much worse). Petition 870250087280, dated 09 / 26 / 2025, p. 72 / 153 64 / 120 In some modalities, treatment with an IL-4R antagonist results in a decrease in the CGI-C score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to baseline. In some modalities, the change in the CGI-C score is measured on day 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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.

[00135] In some modalities, treatment results in an improvement in the CGI-S score. The Physician Global Impression of Severity (CGI-S) is a single-item observer-reported outcome measure that assesses the investigator / physician's impression of the participant's overall EoG severity (with or without EoD) based on their assessment of the participant on the day of questionnaire completion, using a 4-level response scale (mild to very severe). In some modalities, treatment with an IL-4R antagonist results in a decrease in the CGI-S score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more from baseline. In some modalities, the change in CGI-S score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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.

[00136] In some modalities, treatment results in an improvement in the EoG / EoD Quality of Life Questionnaire (EoG / EoD QoL) score. EoG / EoD QoL is a disease-specific measure of health-related QoL in patients with EoG (with or without EoD) developed by the sponsor. EoG / EoD QoL measures the impact of EoG (with or without EoD) on emotional, social, functional, work and school, and sleep aspects. Petition 870250087280, dated 09 / 26 / 2025, p. 73 / 153 65 / 120 participants rate the degree of impact over the past 7 days using a 5-level scale (ranging from Not at all to Extremely or from Not at all to All the time, as appropriate). In some modalities, treatment with an IL-4R antagonist results in a decrease in QoL score with EoG / EoD of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to baseline assessment. In some modalities, the change in QoL score with EoG / EoD is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later following 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.

[00137] In some modalities, treatment results in an improvement in the score of the European 5-Level 5-Dimension Quality of Life Scale (EQ-5D-5L). The EQ-5D-5L is a standardized questionnaire used to assess health status (Brooks, 1996) (Rabin, et al., Value Health, 2014, 17:70-76). It consists of a descriptive system and the Visual Analogue Scale (VAS EQ). The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. For each dimension, participants select one of 5 levels: no problems, mild problems, moderate problems, severe problems, and extreme problems. The VAS EQ records the participant's self-rating of health on a vertical visual analog scale, where outcomes are marked as Best imaginable health status and Worst imaginable health status.In some modalities, treatment with an IL-4R antagonist results in an improvement in the EQ-5D-5L score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to the baseline assessment. In some modalities, the change in the EQ-5D-5L score is measured on days 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 113 or later in Petition 870250087280, dated 09 / 26 / 2025, p. 74 / 153. 66 / 120 guide to 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. Combined Therapies

[00138] In some embodiments, the methods of this disclosure comprise administering to the individual (e.g., an individual with EGE) an IL-4R antagonist as described in the disclosure (e.g., an anti-IL-4R antibody) in combination with one or more additional therapeutic agents. As used in this document, the expression "in combination with" means that the additional therapeutic agents are administered before, after, or concurrently with the pharmaceutical composition comprising the IL-4R antagonist. The term "in combination with" also includes the sequential or concurrent administration of an IL-4R antagonist and a second therapeutic agent or therapy.

[00139] For example, when administered before the pharmaceutical composition comprising the IL-4R antagonist, the additional therapeutic agent may be administered approximately 72 hours, approximately 60 hours, approximately 48 hours, approximately 36 hours, approximately 24 hours, approximately 12 hours, approximately 10 hours, approximately 8 hours, approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1 hour, approximately 30 minutes, approximately 15 minutes, or approximately 10 minutes before administration of the pharmaceutical composition comprising the IL-4R antagonist. When administered after the pharmaceutical composition comprising the IL-4R antagonist, the additional therapeutic agent may be administered approximately 10 minutes, approximately 15 minutes, approximately 30 minutes, approximately 1 hour, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 8 hours, approximately 10 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 60 hours, or approximately 72 hours after administration of the composition. Petition 870250087280, dated 09 / 26 / 2025, page 75 / 153 67 / 120 pharmaceutical composition comprising the IL-4R antagonist. Concomitant administration or administration with pharmaceutical compositions comprising the IL-4R antagonist means that the additional therapeutic agent is administered to the individual in a separate dosage form approximately 10 minutes (before, after or at the same time) as the administration of the pharmaceutical composition comprising the IL-4R antagonist or administered to the individual as a single combined dosage formulation comprising both the additional therapeutic agent and the IL-4R antagonist.

[00140] In some embodiments, the second therapeutic agent or therapy is an β-1β inhibitor, an IL-5 or IL-5R inhibitor (e.g., an anti-IL-5 or anti-IL-5R antibody, such as benralizumab, mepolizumab, or reslizumab), an IL-9 inhibitor, an IL-13 inhibitor (e.g., an anti-IL-13 antibody, such as tralokinumab, RPC4046, or QAX576), an IL-17 inhibitor, an IL-25 inhibitor, a TNFα inhibitor (e.g., an anti-TNFα antibody, such as infliximab or adalimumab), an eotaxin-3 inhibitor, an IgE inhibitor (e.g., an anti-IgE antibody, such as omalizumab), a TSLP inhibitor (e.g., an anti-TSLP antibody, such as tezepelumab), a CRTH2 inhibitor, a Siglec-8 inhibitor, a prostaglandin D2 inhibitor, an integrin inhibitor (e.g., an α4β7 integrin inhibitor such as vedolizumab), an eotaxin inhibitor, an immunosuppressant, a topical corticosteroid, an oral corticosteroid, a systemic corticosteroid, an inhaled corticosteroid,a glucocorticoid, a PPI, a decongestant, an antihistamine, a leukotriene inhibitor, a nonsteroidal anti-inflammatory drug (NSAID), allergen removal, or diet management. In some modalities, the IL-4R antagonist is used in combination with diet management. In some modalities, the IL-4R antagonist is used in combination with a PPI, for example, omeprazole, esomeprazole, lansoprazole, Petition 870250087280, dated 09 / 26 / 2025, page 76 / 153 68 / 120 zol, dexlansoprazole, rabeprazole, or pantoprazole. In some embodiments, the IL-4R antagonist is used in combination with an ingested topical corticosteroid, for example, budesonide or fluticasone. In some embodiments, the IL-4R antagonist is used in combination with a systemic corticosteroid, for example, prednisone or prednisolone.

[00141] In some modalities, administration of the IL-4R antagonist reduces dependence on, or the need for, concomitant therapy (e.g., a systemic corticosteroid or swallowed topical corticosteroid). In some modalities, administration of the IL-4R antagonist in combination with the second therapy reduces the amount of the second therapy used by the patient by at least 20%, at least 30%, at least 40%, or at least 50% compared to the amount used by the individual before treatment with the IL-4R antagonist. In some modalities, administration of the IL-4R antagonist eliminates the need for the second therapy.

[00142] In some embodiments, the methods of this disclosure comprise administering to the individual (e.g., an individual with EGE, EoG, or EoD) a combination therapy comprising (i) an IL-4R antagonist according to the disclosure (e.g., an anti-IL-4R antibody) and (ii) a systemic corticosteroid or an ingested topical corticosteroid. In some embodiments, the combination therapy comprises an IL-4R antagonist according to the disclosure (e.g., an anti-IL-4R antibody) and a systemic corticosteroid (e.g., prednisone or prednisolone). In some embodiments, the combination therapy comprises an IL-4R antagonist according to the disclosure (e.g., an anti-IL-4R antibody) and an ingested topical corticosteroid (e.g., budesonide or fluticasone). Petition 870250087280, dated 09 / 26 / 2025, p. 77 / 153 69 / 120 Table 1: Informal Sequence Listing SEQ ID NO Sequence Description 1 EVQLVESGGGLEQPGGSLRLSCAGSG FTFRDYAMTWVRQAPGKGLEWVSSIS GSGGNTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKDRLSITIRP RYYGLDVWGQGTTVTVS Amino acid sequence of HCVR of Dupilumab 2 DIVMTQSPLSLPVTPGEPASISCRSSQS LLYSIGYNYLDWYLQKSGQSPQLLIYLG SNRASGVPDRFSGSGSGTDFTLKISRV EAEDVGFYYCMQALQTPYTFGQGTKLE IK Amino acid sequence of LCVR of Dupilumab 3 GFTFRDYA Amino acid sequence of HCDR1 of Dupilumab 4 ISGSGGNT Amino acid sequence of HCDR2 of Dupilumab 5 AKDRLSITIRPRYYGLDV Sequence Amino acid sequence of HCDR3 of Dupilumab 6 QSLLYSIGYNY Amino acid sequence of LCDR1 of Dupilumab LGS Amino acid sequence of LCDR2 of Dupilumab 8 MQALQTPYT Amino acid sequence of LCDR3 of Dupilumab Petition 870250087280, dated 09 / 26 / 2025, p. 78 / 153 70 / 120 SEQ ID NO Sequence Description 9 EVQLVESGGGLEQPGGSLRLSCAGSG FTFRDYAMTWVRQAPGKGLEWVSSIS GSGGNTYYADSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCAKDRLSITIRP RYYGLDVWGQGTTVTVSSASTKGPSV FPLAPCSRSTSESTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPS NTKVDKRVESKYGPPCPPCPAPEFLGG PSVFLFPPKPKDTLMISRTPEVTCVVVD VSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSRLTVDKSRWQEGNVFSCS VMHEALHNHYTQKSLSLSLGK Heavy chain amino acid sequence of Dupilumab 10 DIVMTQSPLSLPVTPGEPASISCRSSQS LLYSIGYNYLDWYLQKSGQSPQLLIYLG SNRASGVPDRFSGSGSGTDFTLKISRV EAEDVGFYYCMQALQTPYTFGQGTKLE IKRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGE C Light chain amino acid sequence of Dupilumab 11 MKVLQEPTCVSDYMSISTCEWKMNGP TNCSTELRLLYQLVFLLSEAHTCIPENN GGAGCVCHLLMDDVVSADNYTLDLWA GQQLLWKGSFKPSEHVKPRAPGNLTV HTNVSDTLLLTWSNPYPPDNYLYNHLTYAVNIWSENDPADFRIYNVTYLEPSLRI AASTLKSGISYRARVRAWAQCYNTTWS EWSPSTKWHNSYREPFEQH IL-4Rα Human Petition 870250087280, dated 09 / 26 / 2025, page 79 / 153 71 / 120 SEQ ID NO Sequência Descrição 12 EIVLTQSPGTLSLSPGERATLSCRASQS VSNSYLAWYQQKPGQAPRLLIFGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYGSSPPWTFGQGTKVEIK SCB-VL-39 13 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIYGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYGSSPPWTFGQGTKVEIK SCB-VL-40 14 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIFGASSR APGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYGSSPPWTFGQGTKVEIK SCB-VL-41 15 EIVLTQSPGTLSLSPGERATLSCRASQS VSNSYLAWYQQKPGQAPRLLIYGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYGSSPPWTFGQGTKVEIK SCB-VL-42 16 EIVLTQSPGTLSLSPGERATLSCRASQS VSNSYLAWYQQKPGQAPRLLIFGASSR APGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYGSSPPWTFGQGTKVEIK SCB-VL-43 17 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIYGASSR APGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYGSSPPWTFGQGTKVEIK SCB-VL-44 18 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIFGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSPPWTFGQGTKVEIK SCB-VL-45 19 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIFGASSR ATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSAGWTFGQGTKVEIK SCB-VL-46 Petition 870250087280, dated 09 / 26 / 2025, page 80 / 153 72 / 120 SEQ ID NO Sequência Descrição 20 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIFGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSAGWTFGQGTKVEIK SCB-VL-47 21 EIVLTQSPGTLSLSPGERATLSCRASQS VSNSYLAWYQQKPGQAPRLLIFGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSPPWTFGQGTKVEIK SCB-VL-48 22 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIYGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSPPWTFGQGTKVEIK SCB-VL-49 23 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIFGASSR APGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSPPWTFGQGTKVEIK SCB-VL-50 24 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIYGASSR APGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSAGWTFGQGTKVEIK SCB-VL-51 25 EIVLTQSPGTLSLSPGERATLSCRASQS VSNSYLAWYQQKPGQAPRLLIFGASSR APGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSAGWTFGQGTKVEIK SCB-VL-52 26 EIVLTQSPGTLSLSPGERATLSCRASQS VSNSYLAWYQQKPGQAPRLLIYGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSAGWTFGQGTKVEIK SCB-VL-53 27 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIFGASSR APGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYDHSAGWTFGQGTKVEIK SCB-VL-54 Petition 870250087280, dated 09 / 26 / 2025, page 81 / 153 73 / 120 SEQ ID NO Sequência Descrição 28 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIYGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSAGWTFGQGTKVEIK SCB-VL-55 29 EIVLTQSPGTLSLSPGERATLSCRASQS VSNSYLAWYQQKPGQAPRLLIFGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSAGWTFGQGTKVEIK SCB-VL-56 30 EIVLTQSPGTLSLSPGERATLSCRASQS VSSSYLAWYQQKPGQAPRLLIFGASSR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYGSSPPWTFGQGTKVEIK SCB-VL-57 31 EIVLTQSPGTLSLSPGERATLSCRASQS VSNSYLAWYQQKPGQAPRLLIYGASSR APGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQQYDHSAGWTFGQGTKVEIK SCB-VL-58 32 EVQLVESGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-59 33 EVQLVQSGGGLVQPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-60 34 EVQLVQSGGGLVHPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-61 Petição 870250087280, de 26 / 09 / 2025, pág. 82 / 153 74 / 120 SEQ ID NO Sequência Descrição 35 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-62 36 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-63 37 EVQLVESGGGLVQPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-64 38 EVQLVESGGGLVHPGGSLRLSCAASGF TFSRNAMFWVRQAPGKGLEWVSGIGT GGATNYADSVKGRFTISRDNAKNSLYL QMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-65 39 EVQLVQSGGGLVQPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-66 40 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-67 41 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFPW WGQGTLVTVSS SCB-VH-68 Petition 870250087280, dated 09 / 26 / 2025, p. 83 / 153 75 / 120 SEQ ID NO Sequência Descrição 42 EVQLVESGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFPW WGQGTLVTVSS SCB-VH-69 43 EVQLVQSGGGLVQPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFPW WGQGTLVTVSS SCB-VH-70 44 EVQLVQSGGGLVHPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFPW WGQGTLVTVSS SCB-VH-71 45 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFPW WGQGTLVTVSS SCB-VH-72 46 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-73 47 EVQLVQSGGGLVHPGRSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-74 48 EVQLVQSGGGLVHPGGSLRLTCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-75 Petition 870250087280, dated 09 / 26 / 2025, p. 84 / 153 76 / 120 SEQ ID NO Sequência Descrição 49 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMHWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-76 50 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGEGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-77 51 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDEAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-78 52 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAGDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-79 53 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFDDYAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-80 54 EVQLVQSGGGLVQPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-81 55 EVQLVESGGGLVHPGGSLRLSCAASGF TFSRNAMFWVRQAPGKGLEWVSGIGT GGATSYADSVKGRFTISRDNAKNSLYL QMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-82 Petition 870250087280, dated 09 / 26 / 2025, p. 85 / 153 77 / 120 SEQ ID NO Sequência Descrição 56 EVQLVESGGGLVQPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-83 57 EVQLVESGGGLVQPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-84 58 EVQLVESGGGLVQPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFPW WGQGTLVTVSS SCB-VH-85 59 EVQLVQSGGGLVHPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-86 60 EVQLVQSGGGLVQPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-87 61 EVQLVESGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-88 62 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-89 Petition 870250087280, dated 09 / 26 / 2025, p. 86 / 153 78 / 120 SEQ ID NO Sequência Descrição 63 EVQLVESGGGLVQPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFPW WGQGTLVTVSS SCB-VH-90 64 EVQLVESGGGLVQPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-91 65 EVQLVQSGGGLVHPGGSLRLSCAGSG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATNYADSVKGRFTISRDNAKNSLY LQMNSLRAEDMAVYYCARGRYYFDYW GQGTLVTVSS SCB-VH-92 66 EVQLVESGGGLVQPGGSLRLSCAASG FTFSRNAMFWVRQAPGKGLEWVSGIG TGGATSYADSVKGRFTISRDNAKNSLY LQMNSLRAEDTAVYYCARGRYYFPWW GQGTLVTVSS SCB-VH-93 67 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLD YWGKGTLVTVSS MEDI-1-VH 68 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSLSANYVFGTGTKLT VL MEDI-1-VL 69 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLY NWGKGTLVTVSS MEDI-2-VH Petition 870250087280, dated 09 / 26 / 2025, p. 87 / 153 79 / 120 SEQ ID NO Sequência Descrição 70 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSQPPNPLFGTGTKLT VL MEDI-2-VL 71 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKLLKNP WGKGTLVTVSS MEDI-3-VH 72 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWFGTPASNYVFGTGTKLT VL MEDI-3-VL 73 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLY NWGKGTLVTVSS MEDI-4-VH 74 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSSPPQPIFGTGTKLT VL MEDI-4-VL 75 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLY DWGKGTLVTVSS MEDI-5-VH 76 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSSPPQPIFGTGTKLT VL MEDI-5-VL Petition 870250087280, dated 09 / 26 / 2025, p. 88 / 153 80 / 120 SEQ ID NO Sequência Descrição 77 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-6-VH 78 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTTYHPIFGTGTKLT VL MEDI-6-VL 79 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWW QYWGKGTLVTVSS MEDI-7-VH 80 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSSPPQPIFGTGTKLT VL MEDI-7-VL 81 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWW QYWGKGTLVTVSS MEDI-8-VH 82 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTTYHPIFGTGTKLT VL MEDI-8-VL 83 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLY NWGKGTLVTVSS MEDI-9-VH Petition 870250087280, dated 09 / 26 / 2025, p. 89 / 153 81 / 120 SEQ ID NO Sequência Descrição 84 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTTMYPLFGTGTKLT VL MEDI-9-VL 85 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLY DWGKGTLVTVSS MEDI-10-VH 86 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTVLTPIFGTGTKLTV L MEDI-10-VL 87 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWFY DWGKGTLVTVSS MEDI-11-VH 88 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSPSMIPLFGTGTKLT VL MEDI-11-VL 89 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWFY DWGKGTLVTVSS MEDI-12-VH 90 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTTMYPLFGTGTKLT VL MEDI-12-VL Petition 870250087280, dated 09 / 26 / 2025, p. 90 / 153 82 / 120 SEQ ID NO Sequência Descrição 91 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLY DWGKGTLVTVSS MEDI-13-VH 92 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTTLQPLFGTGTKLT VL MEDI-13-VL 93 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLY NWGKGTLVTVSS MEDI-14-VH 94 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSPPTKPLFGTGTKLT VL MEDI-14-VL 95 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLY NWGKGTLVTVSS MEDI-15-VH 96 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTHRHPLFGTGTKLT VL MEDI-15-VL 97 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWLY NWGKGTLVTVSS MEDI-16-VH Petition 870250087280, dated 09 / 26 / 2025, p. 91 / 153 83 / 120 SEQ ID NO Sequência Descrição 98 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTTYHPIFGTGTKLT VL MEDI-16-VL 99 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWW QHWGKGTLVTVSS MEDI-17-VH 100 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSPVDRPIFGTGTKLT VL MEDI-17-VL 101 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWW QHWGKGTLVTVSS MEDI-18-VH 102 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTTPMPVFGTGTKLT VL MEDI-18-VL 103 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKWWW QHWGKGTLVTVSS MEDI-19-VH 104 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTTYHPIFGTGTKLT VL MEDI-19-VL Petition 870250087280, dated 09 / 26 / 2025, p. 92 / 153 84 / 120 SEQ ID NO Sequência Descrição 105 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-20-VH 106 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTVWEWPFGTGTKL TVL MEDI-20-VL 107 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSASYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-21-VH 108 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEAVYFCGTWDTSTVWEWPFGTGTKL TVL MEDI-21-VL 109 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-22-VH 110 QPVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYFCGTWDTSTVWEWPFGTGTKL TVL MEDI-22-VL 111 QVQLVQSGAEVRKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-23-VH Petition 870250087280, dated 09 / 26 / 2025, p. 93 / 153 85 / 120 SEQ ID NO Sequência Descrição 112 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNNYVSWYQQLPGTAPKLLIYDNNK RPPGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTVWEWPFGTGTKL TVL MEDI-23-VL 113 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PRGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-24-VH 114 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYFCGTWDTSTVWEWPFGTGTKL TVL MEDI-24-VL 115 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PRGGSASYAQKFQGRVSMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-25-VH 116 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTTATLAITGLQTG DEADYYCGTWVTSTVWEWPFGTGTKL TVL MEDI-25-VL 117 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-26-VH 118 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYFCGTWDTSTVWEWPFGTGTKL TVL MEDI-26-VL Petition 870250087280, dated 09 / 26 / 2025, p. 94 / 153 86 / 120 SEQ ID NO Sequência Descrição 119 QVQLVQSGAEVRKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRPEDTAVYYCARGKYWMY DWGKGTQVTVSS MEDI-27-VH 120 QSVLTQPPLVSAAPGQKVTISCSGGSS NIGNSYVSWYQRLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTVWEWPFGTGTKL TVL MEDI-27-VL 121 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGNGTLVTVSS MEDI-28-VH 122 LPVLTQPPSVSAAPGQKVTISCSGGSS SIGNSYVSWYQQLPGAAPKLLIYDNNK RPSGIPDRFSGFRSGTSATLAITGLQTG DEADYYCGTWDTSPVWEWPFGTGTKL TVL MEDI-28-VL 123 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTRVTVSS MEDI-29-VH 124 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSPVWEWPFGTGTKL TVL MEDI-29-VL 125 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-30-VH Petition 870250087280, dated 09 / 26 / 2025, p. 95 / 153 87 / 120 SEQ ID NO Sequência Descrição 126 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQRLPGAAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTVWEWPFGTGTKL TVL MEDI-30-VL 127 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-31-VH 128 QSVLTQPPSVSAAPGQKVTISCSGGSS SIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWATSPVWEWPFGTGTKL TVL MEDI-31-VL 129 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-32-VH 130 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYFCGTWDTSTAWEWPFGTGTKL TVL MEDI-32-VL 131 QVQLVQSGAEEKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-33-VH 132 QSALTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYFCGTWDTSTVWEWPFGTGTKL TVL MEDI-33-VL Petition 870250087280, dated 09 / 26 / 2025, p. 96 / 153 88 / 120 SEQ ID NO Sequência Descrição 133 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVSMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-34-VH 134 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYFCGTWDTSTVWEWPFGTGTKL TVL MEDI-34-VL 135 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-35-VH 136 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSPVWEWPFGTGTKL TVL MEDI-35-VL 137 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSASYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-36-VH 138 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDSSTVWEWPFGTGTKL TVL MEDI-36-VL 139 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PRGGSTSYAQKFQGRVAMTRDTSTST VYMELSSLRPEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-37-VH Petition 870250087280, dated 09 / 26 / 2025, p. 97 / 153 89 / 120 SEQ ID NO Sequência Descrição 140 QSVLTQPPSVSAAPGQKVTISCSGGGS SIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGVPDRFSGSKSGTSATLAITGLQT GDEADYYCGTWDTSPVWEWPFGTGT KLTVL MEDI-37-VL 141 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSASYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-38-VH 142 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYFCGTWDTSTVWEWPFGTGTKL TVL MEDI-38-VL 143 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PRGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-39-VH 144 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTAWEWPFGTGTKL TVL MEDI-39-VL 145 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-40-VH 146 QSVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDSSTVWEWPFGTGTKL TVL MEDI-40-VL Petition 870250087280, dated 09 / 26 / 2025, p. 98 / 153 90 / 120 SEQ ID NO Sequência Descrição 147 QVQLVQSGAEVRKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWMGIIN PSGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRPEDTAVYYCARGKYWMY DWGKGTLVTVSG MEDI-41-VH 148 QSVLTQPPSVSAAPGQKVTISCSGGST NIGNSYVSWYQRLPGTAPKLLIYDNNK RPPGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTVWEWPFGTGTKL TVL MEDI-41-VL 149 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWARQAPGQGLEWVGIINP SGGSTSYAQKFQGRVTMTRDTSTSTV YMELSSLRSGDTAVYYCARGKYWMYD WGKGTLVTVSS MEDI-42-VH 150 QAVLTQPPSVSAAPGQKVTISCSGGSS NIGNSYVSWYQRLPGAAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLAITGLQTG DEADYYCGTWDTSTGWEWPFGTGTKL TVL MEDI-42-VL 151 QVQLVQSGAEVKKPGASVKVSCKASG YAFTSYYMHWVRQAPGQGLEWMGIIN PRGGSTSYAQKFQGRVTMTRDTSTST VYMELSSLRSEDTAVYYCARGKYWMY DWGKGTLVTVSS MEDI-37GL-VH 152 QSVLTQPPSVSAAPGQKVTISCSGGGS SIGNSYVSWYQQLPGTAPKLLIYDNNK RPSGIPDRFSGSKSGTSATLGITGLQTG DEADYYCGTWDTSPVWEWPFGTGTKL TVL MEDI-37GL-VL 153 EVQLLESGGGLVQPGGSLRLSCAVSGF TFSNYAMSWVRQAPGKGLEWVSAISS GGGNIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCAKLRRYFDYWG QGTLVTVSS AJOU-1-VH Petition 870250087280, dated 09 / 26 / 2025, p. 99 / 153 91 / 120 SEQ ID NO Sequência Descrição 154 EVQLLESGGGLVQPGGSLRLSCAASGF TFSDYAMSWVRQAPGKGLEWVSAISS GGSSIYYADSVKGRFTISRDNSKNTLHL QMNSLRAEDTAVYYCARGPQRSATAV FDYWGQGTLVTVSS AJOU-2-VH 155 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSWISP NSGNIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARRPLSAAWSH SSYYNAMDVWGQGTLVTVSS AJOU-3-VH 156 EVQLLESGGGLVQPGGSLRLSCAASGF TFSGYAMSWVRQAPGKGLEWVSLISH SGSNTYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARPHRAFDYWG QGTLVTVSS AJOU-4-VH 157 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSGISH GSGSIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARPHRAFDYWG QGTLVTVSS AJOU-5-VH 158 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSGISH GNGSIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCAKTGRHFDYWG QGTLVTVSS AJOU-6-VH 159 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSSISP SGSSIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARSYRAFDYWG QGTLVTVSS AJOU-7-VH 160 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSAISP SGGSIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARAKRAFDYWG QGTLVTVSS AJOU-8-VH Petition 870250087280, dated 09 / 26 / 2025, pp. 100 / 153 92 / 120 SEQ ID NO Sequência Descrição 161 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSAISP GSGSTYYADSVKGRFTISRDNSKNTLY LQMNSLRAEDTAVYYCAKFRRHFDYW GQGTLVTVSS AJOU-9-VH 162 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSAISS GGGNIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARVHRAFDYWG QGTLVTVSS AJOU-10-VH 163 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSAITS SGRSIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARVHRAFDYWG QGTLVTVSS AJOU-69-VH 164 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSAITS SGANIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARVHRAFDYWG QGTLVTVSS AJOU-70-VH 165 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSAITS SGGNIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARVHRAFDYWG QGTLVTVSS AJOU-71-VH 166 EVQLLESGGGLVQPGGSLRLSCAASGF TFSNYAMSWVRQAPGKGLEWVSAITA GGGSIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARVHRAFDYWG QGTLVTVSS AJOU-72-VH 167 EVQLLESGGGLVQPGGSLRLSCAASGF TFSRHAMAWVRQAPGKGLEWVSAITS SGRSIYYADSVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARVHRAFDYWG QGTLVTVSS AJOU-83-VH Petition 870250087280, dated 09 / 26 / 2025, pp. 101 / 153 93 / 120 SEQ ID NO Sequência Descrição 168 QSVLTQPPSASGTPGQRVTISCSGSSS NIGNNYVNWYQQLPGTAPKLLIYDNSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGTWDASLSAYVFGGGTKL TVL AJOU-33-VL 169 QSVLTQPPSASGTPGQRVTISCSGSSS NIGNNNVSWYQQLPGTAPKLLIYANSK RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGSWDDSLSAYVFGGGTKL TVL AJOU-34-VL 170 QSVLTQPPSAPGTPGQRVTISCTGSSS NIGSNSVNWYQQLPGTAPKLLIYDDSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCDAWDSSLSAYVFGGGTKL TVL AJOU-35-VL 171 QSVLTQPPSASGTPGQRVTLSCTGSSS NIGSNYVSWYQQLPGTAPKLLIYADSQ RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGTWDDSLSGYVFGGGTKL TVL AJOU-36-VL 172 QSVLTQPPSASGTPGQRVTISCSSSSS NIGSNYVSWYQQLPGTAPKLLIYSDSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGSWDYSLSAYVFGGGTKL TVL AJOU-37-VL 173 QSVLTQPPSASGTPGQRVTISCTGSSS NIGNNTVSWYQQLPGTAPKLLIYDNSH RPSGVPDRFSGSKSGTSASLAISGLQS EDEADYYCGSWDYSLSAYVFGGGTKL TVL AJOU-38-VL 174 QSVLTQPPSASGTPGQRVTISCTGSSS NIGNNDVNWYQQLPGTAPKLLIYYDSQ RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCATWDASLSAYVFGGGTKLT VL AJOU-39-VL Petição 870250087280, de 26 / 09 / 2025, pág. 102 / 153 94 / 120 SEQ ID NO Sequência Descrição 175 QSVLTQPPSASGTPGQRVTISCSGSSS NIGSNAVNWYQQLPGTAPKLLIYYDNQ RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGTWDDSLNGYVFGGGTKL TVL AJOU-40-VL 176 QSVLTQPPSASGTPGQRVTISCSGSSS NIGNNAVTWYQQLPGTAPKLLIYDDSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGSWDYSLSAYVFGGGTKL TVL AJOU-41-VL 177 QSVLTQPPSASGTPGQRVTISCSGSSS NIGSNTFNWYQQLPGTAPKLLIYADSHR PSGVPDRFSGSKSGTSASLAISGLRSE DEADYYCGTWDYSLSGYVLGGGTKLT VL AJOU-42-VL 178 QSVLTQPPSASGTPGQRVTISCSGSSS NIGSNTFNWYQQLPGTAPKLLIYADSHR PSGVPDRFSGSKSGTSASLAISGLRSE DEADYYCGTWDYSLSGYVLGGGTKLT VL AJOU-77-VL 179 QSVLTQPPSASGTPGQRVTISCSGSSS NIGSNTFNWYQQLPGTAPKLLIYADSHR PSGVPDRFSGSKSGTSASLAISGLRSE DEADYYCGTWDYSLRGYVLGGGTKLT VL AJOU-78-VL 180 QSVLTQPPSASGTPGQRVTISCSGSSS NIGSNTFNWYQQLPGTAPKLLIYADSHR PSGVPDRFSGSKSGTSASLAISGLRSE DEADYYCGYWDYSLSGYVLGGGTKLT VL AJOU-79-VL 181 QSVLTQPPSASGTPGQRVTISCSGSSS NIGSNTFNWYQQLPGTAPKLLIYADSHR PSGVPDRFSGSKSGTSASLAISGLRSE DEADYYCGTWDYSLSGYVLGGGTKLT VL AJOU-80-VL Petition 870250087280, dated 09 / 26 / 2025, pp. 103 / 153 95 / 120 SEQ ID NO Sequência Descrição 182 QSVLTQPPSASGTPGQRVTISCSGSSA NSRTDGFNWYQQLPGTAPKLLIYADSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGTWDYSLSGYVLGGGTKL TVLG AJOU-86-VL 183 QSVLTQPPSASGTPGQRVTISCSGSAQ FGSRDNFNWYQQLPGTAPKLLIYADSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGTWDYSLSGYVLGGGTKL TVLG AJOU-87-VL 184 QSVLTQPPSASGTPGQRVTISCSGSTK QMHNYQFNWYQQLPGTAPKLLIYADSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGTWDYSLSGYVLGGGTKL TVLG AJOU-88-VL 185 QSVLTQPPSASGTPGQRVTISCSGSLL RGENLQFNWYQQLPGTAPKLLIYADSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGTWDYSLSGYVLGGGTKL TVLG AJOU-89-VL 186 QSVLTQPPSASGTPGQRVTISCSGSPL FPDSGSFNWYQQLPGTAPKLLIYADSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGTWDYSLSGYVLGGGTKL TVLG AJOU-90-VL 187 QSVLTQPPSASGTPGQRVTISCSGSAA LDLSPSFNWYQQLPGTAPKLLIYADSH RPSGVPDRFSGSKSGTSASLAISGLRS EDEADYYCGTWDYSLSGYVLGGGTKL TVLG AJOU-91-VL 188 QVQLVQSGAEVKKPGASVKVSCKASG YTFTNYGISWVRQAPGQGLEWMGWIS VYNGKTNYAQKLQGRVTMTTDTS IIIA YMEMRSLRSDDTAVYYCARGSGYDLD YWGQGTLVSVSS REGN-VH-3 Petition 870250087280, dated 09 / 26 / 2025, pp. 104 / 153 96 / 120 SEQ ID NO Sequência Descripción 189 EVQLVESGGGLVQPGGSLRLSCAASG FTFSSFWMTWVRQAPGKGLEWVANIK QDGSEKYYYVDSVKGRFTISRDNAKNSL YLQMNSLRAEDTAVYYCARDPGRTMV RGGIRYYYGMDVWGQGTTVTVSS REGN-VH-19 190 EVKLAESGGGLVQPGGSLRLSCAASGF TFSSHWMNWVRQAPGKGLEWVANIKQ DGSDKYYVDSVKGRFTISRDNAKNSLY LQLNSLIAEDTAVYYCARDRGVRPPRG AFDIWGQGTMVTVSS REGN-VH-35 191 QVQLVQSGAEVKKPGASVKVSCKASG YTFNSYGISWVRQAPGQGLEWMGWIR TYNGNTNYAQKLQGRVTMTTDTSTSTA YMELRSLRSDDTAVYCARDEARIVVA GTTPYYYGMDVWGQGTTVTVSS REGN-VH-51 192 QVQLVESGGGLVQPGGSLRLSCAVSG FTISDHYMSWIRQAPGKGLEWISYISSS GSKIYYADSVKGRFTISRDNAKNSLFLQ MNSLRAEDTAVYYCARTRQLVGDYWG QGTLVTVSS REGN-VH-67 193 EVQLVESGGGLVQPGRSLRLSCAASGF TFDNYAMHWVRQAPGKGLEWVSGIRW NSGSIGYADSVKGRFTISRDNAKNSLYL QMNSLRAEDTALYYCAKEGGYSGYRP GPFFDYWGQGTLVTVSS REGN-VH-83 194 QVQLVQSGAEVKKPGASVKVSCKASG YTFTNYGISWVRQAPGQGLEWMGWIS VYNGHTNYAQKLQGRVTMTTDTSTSTA YMELRSLRSDDTAVYYCARGSGYDFD SWGQGTLVTVSS REGN-VH-99 195 QVQLVQSGAEVKKPGASVKVSCKASR YTFTSYDINWVRQATGQGLEWMGWM NPNSGNTGYAQKFQGRVTMTRNTSTS TAYMELSSLRSEDTAVYYCARVRRFFDYWGQGTLVTVSS REGN-VH-115 Petition 870250087280, dated 09 / 26 / 2025, pp. 105 / 153 97 / 120 SEQ ID NO Sequência Descrição 196 QVQLVQSGPEVKKPGASVKVSCKASG YTFTNYGISWVRQAPGQGLEWMGWIS VYNGNINYAQKLQGRVTMTTDTSTSTA YMDLRSLRSDDTAVYYCARGSGYDFD YWGQGTLVTVSS REGN-VH-147 197 QVQLVQSGAEVKKPGASVKVSCKDSA YTFNRYGISWVRQAPGQGLEWMGWIS AYTGNTVYAQKLQGRVTMTTDNSTSTA YMELRSLRSDDTAVYYCARDKSIFGVV RGFDYWGQGTLVTVSS REGN-VH-163 198 AIQMTQSPSSLSASVGDRVTITCRASQ GIRNALGWYQQKPGKAPKLLIYAASSL QSGVPSRFSGSGSGTDFTLTFSSLQPE DFATYYCLQDFNYPYTFGQGTKLEIK REGN-VL-11 199 DIQMTQSPSSVSASVGDRVTISCRASQ GVSSWLAWYQQKPGNAPKLLISAASSI QSGVPSRFSGSGSGSGTDFTLTISSLQPE DFATYYCQQANSFPLTFGGGTKVEIK REGN-VL-27 200 DIQMTQSPSSVSASVGDRVTITCRASQ GISSWLAWYQQKPGKAPKLLIYAASSF QSGVPSRFSGSGSGTDFTLTISSLQPE DFATYFCQQANSFPLTFGGGTTVEIK REGN-VL-43 201 DIQMTQSPSSVSASVGDRVTITCRASQ DISIWLAWYQQSPGKAPKLLINVASRLQ SGVPSRFSGSGSGTDFTLTINSLQPED FVTYYCQQANSFPITFGQGTRLATK REGN-VL-59 202 DIQLTQSPSFLSASVGDRVTITCWASQ GISSYLAWYQQKPGKAPKLLIFAASTLQ SGVPSRFSGSGSGTEFTLTISSLQPEDF ATYYCQQLNSYPLTFGGGTKVEIR REGN-VL-75 203 EIVMTQSPATLSVSPGERATLSCRASQ SVNYNLAWYQHKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSED FAVYYCQQYNNWPLTFGGGTKVEIK REGN-VL-91 Petition 870250087280, dated 09 / 26 / 2025, pp. 106 / 153 98 / 120 SEQ ID NO Sequência Descripción 204 AIQMTQSSSSLSASVGDRVTITCRASQA IRNALGWYQQKPGKAPKVLIYAASSLQ SGIPSRFSGSGSGTDFLTISSLQPEDF ATYYCLQDYDYPYTFGQGTKLEIK REGN-VL-107 205 DIQLTQSPSFLSASVGDRVTITCWASQ GIISYLAWYQQKPGKAPKLLIYAASTLHS GVPSRFSGSGSGTEFTLTISSLQPEDFA TYYCHQLKSYPITFGQGTRLEIK REGN-VL-123 206 AIQMTQSPSSLSASVGDRVTITCRASQ DIRNALGWYQQKPGKAPKLLIYAASSLQ SGVPSRFSGSASGTDFTLTISSLQPEDF AAYYCLQDYNYPYTFGQGTKLEIK REGN-VL-155 207 EIVMTQSPVTLSLSPGERATLPCRASQS VSSSLAWYQQKAGQSPRLLIYGASTRA TGIPARFSGSGSGTTEFTLTISNLQSEDF AVYYCQQYNNWPLTFGGGTKVEIK REGN-VL-171 208 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISSN GGSTYYANSVKGRFTISRDNPKNTLFL QMSSLRAEDTAVYYCVRVKVGYRGGM DVWGQGTTVTVSS STSA-C27-VH 209 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISPS GSSTYYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYYCVRSKVRYRGGMD VWGQGTTVTVSS STSA-C27-6-33-VH 210 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISPS GVSTYYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYYCVRVKYRGGMD VWGQGTTVTVSS STSA-C27-7-33-VH Petition 870250087280, dated 09 / 26 / 2025, pp. 107 / 153 99 / 120 SEQ ID NO Sequência Descripción 211 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPKGGLEYVSGISPT SGSTYYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYYCVRVKVRYRGGMD VWGQGTTVTVSS STSA-C27-24-56-VH 212 EVQLLESSGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPKGGLEYVSGISPT GTSTYYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYYCVRVKGAYRGGMD VWGQGTTVTVSS STSA-C27-47-56-VH 213 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISSS GSSTYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYYCVRVKVAYRGGMD VWGQGTTVTVSS STSA-C27-33-33-VH 214 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPKGGLEYVSGISPS STSTYYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYYCVRVKVLYRGGMD VWGQGTTVTVSS STSA-C27-56-56-VH 215 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPKGGLEYVSGISPS SASTYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYYCVRVKSKYRGGMD VWGQGTTVTVSS STSA-C27-78-78-VH 216 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISG NSASTYYANSVKGRFTISRDNPKNTLFL QMSSLRAEDTAVYYCVRVKLKYRGGM DVWGQGTTVTVSS STSA-C27-82-58-VH 217 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISG GTSTYYANSVKGRFTISRDNPKNTLFLQMSSLRAEDTAVYYCVRVRVLYRGGMD VWGQGTTVTVSS STSA-C27-54-54-VH Petition 870250087280, dated 09 / 26 / 2025, pp. 108 / 153 100 / 120 SEQ ID NO Sequência Descripción 218 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPKGGLEYVSGISPS GVSTYYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYCVRVKVKYRGGMD VWGQGTTVTVSS STSA-C27-36-36-VH 219 EVQLLESSGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPKGLEYVSGISSN GGSTYYANSVKGRFTISRDNPKNTLFL QMSSLRAEDTAVAYYCVRVFVRYRGGM DVWGQGTTVTVSS STSA-C27-53-53-VH 220 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISPT SASTYYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYCVRVKGRYRGGMD VWGQGTTVTVSS STSA-C27-67-67-VH 221 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISPT GGSTYYANSVKGRFTISRDNPKNTLFL QMSSLRAEDTAVYYCVRVKGRYRGGM DVWGQGTTVTVSS STSA-C27-55-55-VH 222 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKLEYVSGISHS GNSTYYANSVKGRFTISRDNPKNTLFL QMSSLRAEDTAVYYCVRVKGRYRGGM DVWGQGTTVTVSS STSA-C27-55-55-VH 222 STSA-C27-59-59-VH 223 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISPS SNSTYYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYCVRVKVRYRGGMD VWGQGTTVTVSS STSA-C27-58-58-VH 224 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISS GSSTYYANSVKGRFTISRDNPKNTLFLQMSSLRAEDTAVYYCVRVKPAYRGGMD VWGQGTTVTVSS STSA-C27-52-52-VH Petition 870250087280, dated 09 / 26 / 2025, pp. 109 / 153 101 / 120 SEQ ID NO Sequence Descrição 225 EVQLLESGGGLVQPGGSLRLSCAASGF TLSSYAMHWVRQAPGKGLEYVSGISYS SASTYYANSVKGRFTISRDNPKNTLFLQ MSSLRAEDTAVYYCVRVKVRYRGGMD VWGQGTTVTVSS STSA-C27-Y2-Y2-VH 226 ISSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGTDFTLTISRLEPED FAVYYCQLYGATSVTFGQGTKLEIK STSA-C27-6-33-VL 228 EIVLTQSPGTLSLSPGERATLLSCRASQG ISSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED STSA-C27-24-56-VL FAVYYCQLYGATSVTFGQGTKLEIK 230 EIVLTQSPGTLSLSPGERATLLSCRASQS VSSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQLYGASSVTFGQGTKLEIK STSA-C27-47-56-VL 231 EIVLTQSPGTLSLSPGERATLSCRASQG ISSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQLYGATSVTFGQGTKLEIK STSA-C27-33-33-VL 232EIVLTQSPGTLSLSPGERATLSCRASQS VSSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQLYGASSVTFGQGTKLEIK STSA-C27-56-56-VL Petition 870250087280, dated 09 / 26 / 2025, pp. 110 / 153 102 / 120 SEQ ID NO Sequência Descrição 233 EIVLTQSPGTLSLSPGERATLSCRASQS ISTAYLAWYQQKPGQAPRLLIYGTSRRA TGIPDRFSGSGSGTDFTLTISRLEPEDF AVYYCQLYGASSVTFGQGTKLEIK STSA-C27-78-78-VL 234 EIVLTQSPGTLSLSPGERATLSCRASQD ISSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQLYGATSVTFGQGTKLEIK STSA-C27-82-58-VL 235 EIVLTQSPGTLSLSPGERATLSCRASQD VSSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGTDFTLTISRLEPED FAVYYCQLYGATSVTFGQGTKLEIK STSA-C27-54-54-VL 236 EIVLTQSPGTLSLSPGERATLLSCRASQN ISTAYLAWYQQKPGQAPRLLIYGTSRRA TGIPDRFSGSGSGTDFTLTISRLEPEDF AVYYCQLYGATSVTFGQGTKLEIK STSA-C27-36-36-VL 237 EIVLTQSPGTLSLSPGERATLSCRASQD ASNAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQLYGSSSVTFGQGTKLEIK STSA-C27-53-53-VL 238 EIVLTQSPGTLSLSPGERATLLSCRASQG VSSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQLYGRSSVTFGQGTKLEIK STSA-C27-67-67-VL 239 EIVLTQSPGTLSLSPGERATLSCRASQN ISTAYLAWYQQKPGQAPRLLIYGTSRRA TGIPDRFSGSGSGTDFTLTISRLEPEDF AVYYCQLYGTSSVTFGQGTKLEIK STSA-C27-55-55-VL 240 EIVLTQSPGTLSLSPGERATLSCRASQSVSTAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFLTISRLEPED FAVYYCQLYGATSVTFGQGTKLEIK STSA-C27-59-59-VL Petition: 870250087280, on September 26, 2025, page. 111 / 153 103 / 120 SEQ ID NO Sequência Descrição 241 EIVLTQSPGTLSLSPGERATLSCRASQD ISSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQLYGATSVTFGQGTKLEIK STSA-C27-58-58-VL 242 EIVLTQSPGTLSLSPGERATLSCRASQG VSTAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQLYGATSVTFGQGTKLEIK STSA-C27-52-52-VL 243 EIVLPQSPGTLSLSPGERATLSCRASQG VSSAYLAWYQQKPGQAPRLLIYGTSRR ATGIPDRFSGSGSGTDFTLTISRLEPED FAVYYCQL YGSTSVTFGQGTKLEIK STSA-C27-Y2-Y2-VL 244 EVQLVESGGGLVQPKGSLKLSCAASGF TFNTYGMHWVRQAPGKGLEWVAHIRS KSSNYATYYADSVKDRFTISRDDSQSM LYLQMN NLKTEDTAMYYCVRWF RAMD YWGQGTSVTVSS Y0188-1 VH 245 EVQLIESGGGLVQPKGSLKLSCAASGF TFNMYAMDWVRQAPGKGLEWVARIRS KGSNFETNYADSVKDRFTISRDDSQSM VYLQMINLKTEDTAMYYCVRHRGGAW FAYWGQGTLVSVSA Y0188-2 VH 246 QVQLVETGGGLVRPGNSLKLSCVTSGF TFSNYRMHWLRQPPGKRLEWIAVITVK SNNYGANYAESVKGRFAISRDDSKSSV YLEMNRLREEDTATYFCSRERAYGNPF DYWGQGTTLTVSS Y0188-3 VH 247 EVQLVESGGGLVQPKGSLKLSCAASGF TFNMYAMNWVRQAPGQGLEWVARIRS KSNNYATYYADSVKDRFIISRDDSESMV YLQMSNLRAADTAMYYCVRHLRAMDY WGQGTSVTVSS Y0188-4 VH Petition 870250087280, dated 09 / 26 / 2025, pp. 112 / 153 104 / 120 SEQ ID NO Sequência Descrição 248 EVQLVESGGGLVQPKGSLKLSCAASGF SFNMYAMNWVRQAPGKGLEWVARIRT KSNHYSTYYADSVKDRFTISRDDSASM FYLQMNNLKTEDTAMYFCVRHLRAMD YWGQGTSVTVSS Y0188-6 VH 249 EVQLIESGGGLVQPKGSLKLSCAASGF TFNMYAMDWVRQAPGKGLEWVARIRS KGSNFETNYADSVKDRFTISRDDSQSM VYLQMNNLKTEDTAMYYCVRHRGGAW FAYWGQGTLVTVSA Y0188-8 VH 250 EVQLVESGGGLVRPKGSLKLSCAASGF SFNTYAMNWVRQAPGKGLEWIVWIRS KSHNYATYYADSVKDRFTISRDDSESM LYLQMNNLKTEDTAMYYCVRHLRAMD YWGQGTSVTVSS Y0188-9 VH 251 EVRLVESGGGLVQPKGSLKLSCEASGF SFNMYAMNWVRQAPGKGLEWITHIRS KSNNYATYYADSVKDRFIISRDDSESMV LYLQMN NLKTEDTAMYYCVRWF RAMD YWGQGTSVTVSS Y0188-14 VH 253 EVQLVESGGGLVKPGGSLRLSCAASGF TFSMYGMHWVRQAPGKGLEWVGHIRS KSSNYATYYADSVKDRFTISRDDSKNTL YLQMNSLKTEDTAVYYCTTWFRAMDY WGQGTLVTVSS HV3-15-14 VH 254 EVQLVESGGGLVQPGGSLRLSCAASG FTFSMYGMHWVRQAPGKGLEWVSHIR SKSSNYATYYADSVKDRFTISRDNAKN SLYLQMNSLRAEDTAVYYCARWFRAM DYWGQGTLVTVSSHV3-48-14 VH Petition 870250087280, dated 09 / 26 / 2025, pp. 113 / 153 105 / 120 SEQ ID NO Sequência Descrição 255 EVQLVESGGGLVQPGGSLKLSCAASGF TFSMYGMHWVRQASGKGLEWVGHIRS KSSNYATYYADSVKDRFTISRDDSKNT AYLQMNSLKTEDTAVYYCTRWFRAMD YWGQGTLVTVSS HV3-73*2-14 VH 256 EVQLVESGGGLVQPGGSLRLSCAASG FTFSMYGMHWVRQAPGKGLEWVGHIR SKSSNYATYYADSVKDRFTISRDDSKN SLYLQMNSLKTEDTAVYYCARWFRAM DYWGQGTLVTVSS HV3-72-14 VH 257 EVQLVESGGGLVQPGGSLRLSCAASG FTFSMYGMHWVRQAPGKGLEWVSHIR SKSSNYATYYADSVKDRFTISRDNAKN SLYLQMNSLRAEDTAVYYCARWFRAM DYWGQGTLVTVSS Y01-14 VH 258 EVQLVESGGGLEQPGGSLRLSCAGSG FTFRMYGMHWVRQAPGKGLEWVSHIR SKSSNYATYYADSVKDRFTISRDNSKN AYLQMNSLKTEDTAVYYCTRWFRAMD YWGQGTTVTVSS VH73-14 VH 260 DIVMTQSHKFMSTSVGDRVSITCKASQ DVSTAVAWYQEKPGQSPKLLIYWASTR HTGVPDRFTGSGSGTDYTLTISSVQAE DLALYYCQQHYSTPLTFGAGTKLELK Y0188-1 VL 261 DIVVTQSPASLAVSLGQRATISCRASKS VSTSGYSYMHWYQQKPGQPPKLLIYLA SNLESGVPARFSGSGSGTDFTLNIHPV EEEDVAIYYCQHSRELPLTFGAGTKLEL K Y0188-2 VL Petition 870250087280, dated 09 / 26 / 2025, pp. 114 / 153 106 / 120 SEQ ID NO Sequence Descrição 262 DIQMTQSPSSLSASLGERVSLTCRASQ EISGYLSWLQQKPDGTIKRLIYAASTLD SGVPKRFSGSRSGSDYSLTISSLESEDF ADYYCLQYGSYPYTFGGGTKLEIK Y0188-3 VL 263 DIVLTQSPASLTVSLGQRATISCRASKS VSTSGYSYMHWYQQKPGQPPKLLIYLA SNLESGVPARFSGSGSGTDFTLNIHPV EEEDAATYYCQHSRELPITFGSGTKLEI K Y0188-4 VL 264 DIVLTQSPASLVVSLGQRATISCRASQS VSTSGYSYMHWYQQKPGQPPKLLIYLA SNVQSGVPARFSGSGSGTDFTLNIHPV EEEDVATYYCHHNRDLPFTFGSGTKLEI K Y0188-6 VL 265 DIVVTQSPASLAVSLGQRATISCRASKS VSTSGYSYMHWYQQKPGQPPKLLIYLA SNLESGVPARFSGSGSGTDFTLNIHPV EEEDVAIYYCQHSRELPLTFGAGTKLEL K Y0188-8 VL 266 DIVLTQSPASLAVSLGQRATISCRASKS VSASGYSYMHWYQQKPGQPPKLLIYLA SNLQSGVPARFSGSGSGTDFTLNIHPV EEEDAATYYCQHSRELPPTFGGGTKLE IK HTGVPDRFTGSGSGTDYTLTISSVQAE DLALYYCQQHYSTPLTFGAGTKLELK Y0188-14 VL Petition: 870250087280, on September 26, 2025, page. 115 / 153 107 / 120 SEQ ID NO Sequência Descrição 269 EIVLTQSPGTLSLSPGERATLSCKASQD VSTAVAWYQQKPGQAPRLLIYWASTRH TGIPDRFSGSGSGTDFTLTISRLEPEDF AVYYCQQHYSTPLTFGQGTKVEIK Y01-14 VL 270 DIVMTQSPLSLPVTPGEPASISCKASQD VSTAVAWYLQKSGQSPQLLIYWASTRH TGVPDRFSGSGSGTDFTLKISRVEAED VGFYYCQQHYSTPLTFGQGTKLEIK 164-14 VL 271 DIVMTQSPDSLAVSLGERATINCKASQD VSTAVAWYQQKPGQPPKLLIYWASTRH TGVPDRFSGSGSGTDFTLTISSLQAED VAVYYCQQHYSTPLTFGGGTKVEIK KV4-14 VL 272 DIQMTQSPSSLSASVGDRVTITCKASQ DVSTAVAWYQQKPGKVPKLLIYWASTR HTGVPSRFSGSGSGTDFTLTISSLQPE DVATYYCQQHYSTPLTFGGGTKVEIK KV1-27-14 VL 273 DIQLTQSPSFLSASVGDRVTITCKASQD VSTAVAWYQQKPGKAPKLLIYWASTRH TGVPSRFSGSGSGTEFTLTISSLQPEDF ATYYCQQHYSTPLTFGGGTKVEIK KV1-9-14 VL 274 DIQMTQSPSSLSASVGDRVTITCKASQ DVSTAVAWYQQKPGKAPKLLLYWAST RHTGVPSRFSGSGSGTDYTLTISSLQP EDFATYYCQQHYSTPLTFGGGTKVEIK KV1-NL1-14 VL 275 AIRMTQSPFSLSASVGDRVTITCKASQD VSTAVAWYQQKPAKAPKLFIYWASTRH TGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQQHYSTPLTFGGGTKVEIK KV1D-43-14 VL 276 EVQLQQSGPELVKPGASVRMSCKASG YTFTDYNIHWVKQSHGKSLEWIGYIYPNNGDNGYNQKFRGKATLTVDKSSSTAY MELRSLTSDDSAVYYCARGRLRYFDV WGTGTTVTVSS HCVR of REGN1103 (anti-mIL-4Rα) Petition 870250087280, of 26 / 09 / 2025, p. 116 / 153 108 / 120 SEQ ID NO Sequence Description 277 NIVLTQSPASLAVSLGQRATISCRASES VDNYGHSFMHWYQQKPGQPPKLLIYLA SNLESGVPARFSGSGSRTDFTLTLDPV EADDAATYYCQQYNEDPPTFGSGTKLE IK LCVR d REGN10-10-4 (Rα-4) EXAMPLES

[00143] The following examples are presented so as to provide those skilled in the art with a complete disclosure and description of how to prepare and use the methods and compositions of the disclosure and are not intended to limit the scope of what may be considered as this invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantities, temperature, etc.), but some experimental errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, molecular weight is the average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric or near atmospheric. Example 1: Effects of IL-4R Inhibition in a Mouse Model of Eosinophilic Gastritis

[00144] An in vivo experiment was performed to evaluate the effects of prophylactic IL-4Rα blockade in a mouse model of eosinophilic gastritis generated by overexpression of mouse interleukin-25 (mIL-25). Overexpression of mIL-25 induces eosinophilia and type 2 triggered pathologies in stomach tissue. Therefore, overexpression of mIL-25 was used to generate a mouse model of eosinophilia, including eosinophilic gastritis.

[00145] Overexpression of mIL-25 was induced using hydrodynamic distribution (HDD) of 25 μg of plasmid DNA. Mice were administered mIL-25 or vector control via HDD on day 0. IL-4Rα blockade in this mouse model was mediated using a mouse IL-4Rα antibody, REGN1103, which was Petition 870250087280, dated 09 / 26 / 2025, pp. 117 / 153 109 / 120 administered by subcutaneous (SC) injection on days -4, 1, and 3; REGN1103 is a mouse IL-4Rα-specific monoclonal antibody that has binding characteristics and functional properties similar to dupilumab in humans. REGN1103 has the HCVR sequence of SEQ ID NO:276 and the LCVR sequence of SEQ ID NO:277. Mice were sacrificed on day 8 (i.e., 8 days after induction of mIL-25 overexpression and 5 days after the last antibody dose), and pathologies associated with mIL-25 overexpression in stomach tissue were tested by flow cytometry, determination of eotaxin mRNA levels, and histology.

[00146] Flow cytometry: To allow flow cytometric analysis of circulating immune cells versus tissue infiltrating cells in the lung, 5 minutes before sacrifice, mice were injected IV with BV650 anti-CD45 to selectively label immune cells still in the vasculature, while leaving cells that had infiltrated the stomach tissue unlabeled. The dissociated stomach tissue was then subsequently stained with an antibody mixture that included an anti-CD45 antibody from the same clone that was injected before sacrifice, but conjugated to a different fluorophore (BV786 anti-CD45). This ex vivo CD45 staining preferentially labels cells that were in the stomach tissue and were protected from the injected CD45 antibody in vivo.

[00147] A longitudinal section of stomach tissue was isolated and placed in chilled enzymatic digestion solution (0.6% FBS, 0.5 mg / ml Collagenase D, 0.1 mg / ml DNase I, 1 mg / ml Dispase II in calcium- and magnesium-free HBSS). The stomach tissue was chopped into thin pieces with scissors, transferred to a conical tube with additional enzymatic digestion solution, and incubated with shaking at 37 °C for 45 minutes. After incubation, the samples were dissected. Petition 870250087280, dated 09 / 26 / 2025, pp. 118 / 153 110 / 120 cells were filtered through a 70 μm mesh, collected, and sedimented by centrifugation at 4 °C. The supernatant was removed, and the sample cells were resuspended in Dulbecco's phosphate-buffered saline (DPBS) for staining.

[00148] Cells were stained with Live / Dead Fixable Dead Cell Stain on DPBS to allow for the exclusion of dead cells. Cells were incubated with anti-mouse CD16 / CD32 (Fc shield) followed by incubation with a cocktail of monoclonal antibodies: APC anti-CD11c, BV421 anti-Siglec-F, BV786 anti-CD45, PE anti-CD200R3, and APC-eFluor CD117. Samples were acquired on a Fortessa X 20 LSR or a FACSymphony cell analyzer using the HTS attachment. Eosinophils were defined as intact, singlet, live (low viability dye signal LIVE / DEAD), CD45+ (BV786), CDC11lo-int, SiglecFhi cells. Data analysis was performed using FlowJo v10 software.

[00149] Real-time PCR analysis: Tissues were homogenized and chloroform was used for phase separation. The aqueous phase, containing total RNA, was purified using MagMAX™-96 for Total RNA Isolation Kit from Microarrays according to the manufacturer's specifications. Genomic DNA was removed using the RNase-free DNase set. Beta-actin was used as a maintenance gene. Gene expression was normalized to Actb (Beta-actin).

[00150] Histology and Pathology Scoring: Sections of stomach tissue were collected at necropsy and processed for hematoxylin and eosin staining. After staining, images of whole slides of the tissue sections were blindly evaluated by a board-certified veterinary pathologist. A semi-quantitative grading system (0 - no lesions, 1 - minimal lesions, 2 - mild lesions, 3 - moderate lesions, 4 - severe lesions) was employed. Petition 870250087280, dated 09 / 26 / 2025, pp. 119 / 153 111 / 120 to score the following histological features in the stomach: orthokeratotic hyperkeratosis, squamous epithelial hyperplasia, vacuolization of the squamous epithelium and cytoplasmic inclusions in the squamous epithelium in the non-glandular stomach, hypertrophy / hyperplasia of mucous cells in the glandular stomach, mixed cellular inflammation (mononuclear cells, neutrophils and eosinophils), edema and hyperplasia / hypertrophy of the muscular tunic. The total pathology score was determined by summing the scores of the individual histological features, with a maximum score of 36.

[00151] Statistical analyses: All data are presented as group mean ± standard deviation (SD). For the experiment showing eosinophils as a frequency of CD45+ cells, normality was tested using the Shapiro-Wilk test and p-values ​​were determined using Brown-Forsythe-Welch analysis of variance (ANOVA) tests and multiple comparisons performed using Dunnett's T3 multiple comparisons test. For the experiment showing Ccl11 and Ccl24 mRNA levels in stomach tissue, normality was tested using the Shapiro-Wilk test and p-values ​​were determined using the Kruskal-Wallis test and multiple comparisons made using Dunn's multiple comparisons test. For the pathology score, statistical analysis of variance of the data was performed by one-way ANOVA after Tukey's Honest Significance Difference (HSD) test.P-values ​​less than 0.5 were considered statistically significant, and statistical analyses were performed using GraphPad Prism software. Results

[00152] The effect of REGN1103 on eosinophil frequency as a percentage of CD45+ cells, found in stomach tissue from a mouse model of eosinophilic gastritis was measured Petition 870250087280, dated 09 / 26 / 2025, pp. 120 / 153 112 / 120 do. Mouse IL-25 overexpression significantly increased the frequency of eosinophils, and among IL-25 overexpressing mice, administration of 25 mg / kg of REGN1103 significantly reduced the frequency of eosinophils found in stomach tissue compared to administration of isotype control antibody (FIG. 1). Furthermore, among IL-25 overexpressing mice, REGN1103 administration significantly reduced Ccl11 and Ccl24 mRNA expression in stomach tissue compared to mice administered with isotype control antibody or no Ab control, and REGN1103 reduced Ccl11 and Ccl24 mRNA in stomach tissues of mIL-25 overexpressing mice to levels indistinguishable from mice administered with HDD vector control (FIGs. 2A and 2B). Stained sections of stomach tissue were evaluated to determine the degree of pathology.Mice that overexpressed IL-25 and were administered either isotype control antibody or no Ab control exhibited significantly higher mean pathology scores compared to IL-25 overexpressed mice that were administered REGN1103 (FIGs. 3A and 3B). Mice without exogenous IL-25 expression and administered no Ab control showed no pathology.

[00153] In summary, in the stomach tissue of a mouse model of eosinophilic gastritis, administration of 25 mg / kg of REGN1103 by SC injection on days -4, 1 and 3 induced a statistically significant reduction in eosinophil frequency, Ccl11 and Ccl24 mRNA levels, and lesion development. Example 2: Clinical Study to Investigate the Efficacy and Safety of Dupilumab in Adult and Adolescent Patients with Eosinophilic Gastritis with or without Eosinophilic Duodenitis

[00154] This example describes a Phase 2 / 3 randomized study. Petition 870250087280, dated 09 / 26 / 2025, pp. 121 / 153 113 / 120 of the 3-part study to investigate the efficacy and safety of dupilumab in adult and adolescent participants with eosinophilic gastritis (EoG) with or without eosinophilic duodenitis (EoD). Part A (phase 2) and Part B (phase 3) are 24-week, randomized, double-blind, placebo-controlled study periods, and Part C is a 28-week extended active treatment period that will enroll participants from both Part A and Part B (i.e., total exposure of approximately 52 weeks).

[00155] For Part A, the primary objective is to determine the effect of dupilumab treatment compared with placebo in adult and adolescent participants with EoG with or without EoD after 24 weeks of treatment, as assessed by histological measures, and to inform / confirm the determination of the final sample size for Part B.

[00156] For Part B, the primary objective is to demonstrate the efficacy of dupilumab treatment compared with placebo in adult and adolescent participants with EoG (with or without EoD) after 24 weeks of treatment, as assessed by histological and clinical measures.

[00157] For Part C, the primary objective is to evaluate the safety and efficacy of dupilumab treatment in adult and adolescent participants with EoG (with or without EoD) after up to 52 weeks of treatment, as assessed by histological and clinical measures.

[00158] The secondary objectives of the study are: • To determine the effect of dupilumab treatment compared with placebo in adult and adolescent participants with EoG (with or without EoD) after 24 weeks of treatment, as assessed by clinical measures (Part A only). • To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up to 52 weeks in participants. Petition 870250087280, dated 09 / 26 / 2025, pp. 122 / 153 114 / 120 adults and adolescents with EoG (with or without EoD) • Characterize the minimum concentrations of functional dupilumab over time after administration of dupilumab in adult and adolescent participants with EoG (with or without EoD) • Evaluate the effects of dupilumab on transcriptomic signatures associated with EoG (with or without EoD) and type 2 inflammation.

[00159] Overall, approximately 279 participants will be included in the study.

[00160] In Part A, approximately 54 adult and adolescent participants will be randomized in a 1:1 ratio to dupilumab 300 mg once weekly (QW) or matching placebo administered subcutaneously (SC). At the end of the double-blind treatment visit (week 24) in Part A, eligible participants may enter a prolonged 28-week active treatment period (Part C). All Part A participants will receive active treatment with dupilumab 300 mg QW during Part C. During Part C, Part A participants will remain blinded to their treatment assignment in Part A.

[00161] In Part B, approximately 225 adult and adolescent participants will be randomized in a 1:1:1 ratio to dupilumab 300 mg QW, dupilumab 300 mg every 2 weeks (Q2W), or matching placebo administered SC. A reassessment of the sample size for Part B will be evaluated, which may result in an adjustment to the Part B sample size. At the end of the double-blind treatment visit (week 24) in Part B, eligible participants may enter a prolonged 28-week active treatment period (Part C). During Part C, Part B participants will remain blinded to their treatment assignment in Part B and treatment regimen in Part C.

[00162] Part B participants who are randomized to place Petition 870250087280, dated 09 / 26 / 2025, pages 123 / 153 Participants randomized to 115 / 120 mg QW during the double-blind treatment period will be re-randomized at a 1:1 ratio to dupilumab 300 mg QW or dupilumab 300 mg Q2W during Part C. All other participants will remain on the same dupilumab dose regimen to which they are randomized during the double-blind treatment period. Participants randomized to dupilumab 300 mg Q2W (in Part B or Part C) will also receive a matching placebo administered Q2W in Part C, alternating with dupilumab doses so that the injection frequency matches the other group for regimen blinding purposes.

[00163] Inclusion Criteria: The main inclusion criteria for Parts A and B include: • Male or female >12 years of age. (Note: Adolescent participants will only be enrolled in study sites in countries / regions as permitted by local regulatory authorities and ECs.) • Documented endoscopic biopsy supporting a pathological diagnosis of EoG at least 3 months prior to screening. (Note: Sufficient documentation must be available to support a pathological diagnosis of EoG.) • Screening endoscopic biopsies (which will serve as initial assessment) with a demonstration of eosinophilic infiltration for a diagnosis of EoG (>30 eos / hpf in at least 5 distinct hpfs in the stomach), as determined by central histological evaluation of biopsies collected during screening endoscopy without any other significant cause for gastric eosinophilia (e.g., parasitic infections, malignancy). • Have completed at least 11 out of 14 days of EoG / EoD-SQ eDiary data entry in the 2 weeks prior to the initial assessment visit • History (per participant report) of at least 2 Petition 870250087280, dated 09 / 26 / 2025, pages 124 / 153 116 / 120 episodes of EoG symptoms (e.g., stomach pain, stomach cramps, nausea, bloating, early satiety, loss of appetite) per week in the 8 weeks prior to screening • A mean TSS of >20 calculated using data collected via the EoG / EoD-SQ eDiary per week in the 2 weeks prior to the initial assessment. A mean severity score of >4 (on a scale of 0 to 10) per week in the 2 weeks prior to the initial consultation for at least 2 of the following 6 symptoms: stomach cramps, stomach pain, nausea, bloating, early satiety, loss of appetite.

[00164] Exclusion criteria: The main exclusion criteria for Parts A and B include: • Body weight <40 kg • Prior participation in a dupilumab clinical trial or prior or current treatment with dupilumab • Helicobacter pylori infection • Any esophageal stricture that cannot be passed with a standard, diagnostic, superior endoscope, or any critical esophageal stricture requiring dilation at screening • History of achalasia, Crohn's disease, eosinophilic colitis, ulcerative colitis, celiac disease, and prior gastric or duodenal surgery • Other causes of gastric and, if applicable, duodenal eosinophilia or the following conditions: eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) or hypereosinophilic syndrome • History of bleeding disorders, esophageal or gastric varices that, in the investigator's opinion, would place the participant at undue risk of significant complications from an endoscopy procedure • Initiation or alteration of an elimination diet regimen Petition 870250087280, dated 09 / 26 / 2025, pages 125 / 153 117 / 120 of foods or reintroduction of a food group previously eliminated in the 4 weeks prior to screening. Participants on a food elimination diet must remain on the same diet throughout the study. • Receiving enteral (tube feeding) or parenteral nutrition at screening • Treatment with swallowed topical corticosteroids not for the treatment of EoG (with or without EoD) and / or EoE within 8 weeks prior to initial assessment

[00165] Study Treatment: The study dosage regimens are as follows:

[00166] Part A: 24-week double-blind treatment period • Dupilumab 300 mg administered QW SC • Placebo administered QW SC containing the same formulation as dupilumab without the active substance

[00167] Part B: 24-week double-blind treatment period • Dupilumab 300 mg administered QW SC • Dupilumab 300 mg administered Q2W SC o For participants randomized to dupilumab 300 mg Q2W, there will be a matching SC placebo injection alternating with dupilumab doses so that the injection frequency is identical (QW) for both groups for regimen blinding purposes. • Placebo administered subcutaneously (QW) containing the same formulation as dupilumab without the active substance.

[00168] Part C: 28-week prolonged active treatment period • All Part A participants will receive dupilumab 300 mg QW SC during Part C. • All participants in Part B will receive dupilumab. Petition 870250087280, dated 09 / 26 / 2025, pages 126 / 153 118 / 120 300 mg QW or Q2W SC during Part C. For participants randomized to dupilumab 300 mg Q2W, there will be a matching SC injection of placebo alternating with dupilumab doses so that the injection frequency is identical (QW) for both groups for regimen blinding purposes.

[00169] Randomization for Part A will also be stratified by systemic corticosteroid or STC use (with or without EoD) at randomization (yes vs. no) and organ involvement at baseline assessment (stomach only vs. stomach and duodenum). Randomization for Part B will be stratified by region (Japan vs. rest of the world), age (>18 vs. >12 to <18 years of age), systemic corticosteroid or STC use for EoG (with or without EoD) at randomization (yes vs. no), and organ involvement at baseline assessment (stomach only vs. stomach and duodenum). Participants from study sites in Japan will not be additionally stratified by the other 3 stratification factors (age, STC or systemic use, organ involvement at baseline assessment). Primary and Secondary Outcomes:

[00170] The primary outcome for Part A of the study is the proportion of participants who achieve a peak gastric eosinophil count of <6 eos / hpf at week 24 (i.e., histological responder).

[00171] The two primary outcomes for Part B of the study are: proportion of participants who achieve a peak gastric eosinophil count of <6 eos / hpf at week 24 (i.e., histological responder) and absolute change in EoG / EoD-SQ TSS from baseline to week 24.

[00172] The secondary efficacy outcomes for Part A, Part B, and Part C of the study are: Petition 870250087280, dated 09 / 26 / 2025, pp. 127 / 153 119 / 120 • Proportion of participants achieving a peak gastric eosinophil count of <6 eos / hpf and a peak duodenal eosinophil count of <15 eos / hpf at week 24 (assessed for those with gastric and duodenal involvement) • Proportion of participants achieving a peak duodenal eosinophil count of <15 eos / hpf at week 24 (assessed for those with duodenal involvement) • Absolute change in EoG / EoD-SQ TSS from baseline to week 24 (Part A only [second primary outcome for Part B]) • Percentage change in EoG / EoD-SQ TSS from baseline to week 24 • Percentage change in peak gastric tissue eosinophil count (eos / hpf) from baseline to week 24 • Proportion of participants achieving a peak count of Gastric tissue eosinophils <30 eos / hpf at week 24 • Percentage change in peak duodenal tissue eosinophil count (eos / hpf) from baseline to theWeek 24 (assessed only for those with duodenal involvement) • Proportion of participants achieving a peak eosinophil count in duodenal tissue of <30 eos / hpf at week 24 (assessed only for those with duodenal involvement) • Absolute change in EoG scores from the EoG Histology Scoring System (EoGHSS) from baseline to week 24 • Change from baseline in the frequency of diarrhea episodes at week 24 (assessed only for those with diarrhea at baseline) • Change from baseline in the frequency of vomiting episodes at week 24 (assessed only for those with Petition 870250087280, dated 09 / 26 / 2025, pages 128 / 153 120 / 120 vomiting at baseline) • change from baseline to week 24 in Normalized Enrichment Scores (NES) for the type 2 inflammation transcriptome signature (assessed in gastric tissue) • change from baseline to week 24 in NES for the type 2 inflammation transcriptome signature (assessed in duodenal tissue of participants with EoD) • change from baseline to week 24 in NES for the EoG disease signature transcriptome signature (EGDP) (assessed in gastric tissue); and • proportion of participants receiving salvage medication or procedures during the 24-week placebo-controlled treatment period.

[00173] The present invention should not be limited in scope by the specific embodiments described in this document. In fact, various modifications of the invention beyond those shown and described in this document will become apparent to those skilled in the art from the preceding description and the accompanying figures. Such modifications are intended to be within the scope of the appended claims.

Claims

1. A method of treating, preventing, or relieving at least one symptom of eosinophilic gastroenteritis, characterized by the fact that it comprises administering to an individual with eosinophilic gastroenteritis one or more doses of an interleukin-4 receptor antagonist (IL-4R).

2. Method, according to claim 1, characterized in that the individual has eosinophilic gastritis (EoG) with eosinophilic duodenitis (EoD).

3. Method, according to claim 1, characterized in that the individual has eosinophilic gastritis (EoG) without eosinophilic duodenitis (EoD).

4. Method, according to claim 1, characterized in that the individual has eosinophilic duodenitis (EoD) without eosinophilic gastritis (EoG).

5. A method, according to any one of claims 1 to 4, characterized in that the individual has been previously treated with a systemic corticosteroid or an ingested topical corticosteroid.

6. A method, according to any one of claims 1 to 5, characterized in that the individual does not respond, responds inadequately, or is intolerant to treatment with a systemic corticosteroid or an ingested topical corticosteroid, or in which the standard treatment is contraindicated.

7. A method for reducing the use of a systemic corticosteroid or an ingested topical corticosteroid in an individual with eosinophilic gastroenteritis, characterized by comprising administering to the individual one or more doses of an interleukin-4 receptor antagonist (IL-4R).

8. Method, according to claim 7, characterized by the fact that the individual has eosinophilic gastritis (EoG) with eosinophilic duodenitis (EoD).

9. Method, according to claim 7, characterized in that the individual has eosinophilic gastritis (EoG) without eosinophilic duodenitis (EoD).

10. Method, according to claim 7, characterized in that the individual has eosinophilic duodenitis (EoD) without eosinophilic gastritis (EoG).

11. A method, according to any one of claims 7 to 10, characterized in that at the beginning of treatment with the IL-4R antagonist, the individual receives a stable dose of a systemic maintenance corticosteroid or an ingested topical corticosteroid.

12. Method, according to any one of claims 1 to 11, characterized in that the individual is > 12 years of age.

13. Method, according to any one of claims 1 to 12, characterized in that the individual is an adult.

14. A method, according to any one of claims 1 to 13, characterized in that the individual has a concomitant atopic disease.

15. Method, according to claim 14, characterized in that the concomitant atopic disease is a food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis.

16. Method, according to any one of claims 1 to 15, characterized in that, prior to the start of treatment with the IL-4R antagonist, the individual: (i) has an eosinophil count >30 eos / hpf, as measured by endoscopic biopsy in at least five distinct regions. Petition 870250087280, dated 09 / 26 / 2025, p.131 / 153 3 / 9 of the stomach; (ii) has an eosinophil count >30 eos / hpf, as measured by endoscopic biopsy in at least three distinct regions of the small intestine; (iii) has a baseline total symptom score (TSS) >20, as measured by the EoG / EoD Symptom Questionnaire (EoG / EoD-SQ); (iv) has a baseline mean severity score of >4 per week for at least two weeks for at least two components of the EoG / EoD-SQ, wherein the components are selected from the group consisting of stomach pain, stomach cramps, nausea, bloating, early satiety, and loss of appetite; and / or (v) has a history of at least two episodes of EoG symptoms per week for at least 8 weeks, wherein the symptoms are selected from the group consisting of stomach pain, stomach cramps, nausea, bloating, early satiety, and loss of appetite.

17. A method according to any one of claims 1 to 16, characterized in that the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof.

18. Method, according to any one of claims 1 to 17, characterized in that the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3) and three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of Petition 870250087280, dated 09 / 26 / 2025, p. 132 / 153 4 / 9 acids of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence of LGS and LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

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

2.

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

10.

21. A method, according to any one of claims 1 to 20, characterized in that the IL-4R antagonist is dupilumab.

22. Method, according to any one of claims 1 to 21, characterized in that the IL-4R antagonist is administered at a dose of about 50 mg to about 600 mg.

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

24. Method according to claim 22 or 23, characterized in that the IL-4R antagonist is administered at a dose of approximately 300 mg QW. Petition 870250087280, dated 09 / 26 / 2025, pp. 133 / 153 5 / 9 25. Method according to claim 22 or 23, characterized in that the IL-4R antagonist is administered at a dose of approximately 300 mg Q2W.

26. Method, according to any one of claims 1 to 25, characterized in that the IL-4R antagonist is administered subcutaneously.

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

28. A method for treating eosinophilic gastroenteritis in an individual, characterized in that it comprises administering to the individual a combination therapy comprising (i) an interleukin-4 receptor (IL-4R) antagonist and (ii) a systemic corticosteroid or an ingested topical corticosteroid.

29. Method according to claim 28, characterized in that the combination therapy comprises an IL-4R antagonist and a systemic corticosteroid.

30. Method according to claim 29, characterized in that the systemic corticosteroid is prednisone or prednisolone.

31. Method according to claim 28, characterized in that the combination therapy comprises an IL-4R antagonist and an ingested topical corticosteroid.

32. Method according to claim 31, characterized in that the swallowed topical corticosteroid is budesonide or fluticasone.

33. Method, according to any one of claims 28 to 32, characterized in that the individual has eosinophilic gastritis (EoG) with eosinophilic duodenitis (EoD). Petition 870250087280, dated 09 / 26 / 2025, pp. 134 / 153 6 / 9 34. A method, according to any one of claims 28 to 32, characterized in that the individual has eosinophilic gastritis (EoG) without eosinophilic duodenitis (EoD).

35. A method, according to any one of claims 28 to 32, characterized in that the individual has eosinophilic duodenitis (EoD) without eosinophilic gastritis (EoG).

36. Method, according to any one of claims 28 to 35, characterized in that the individual is > 12 years of age.

37. Method, according to any one of claims 28 to 36, characterized in that the individual is an adult.

38. A method, according to any one of claims 28 to 37, characterized in that the individual has a concomitant atopic disease.

39. Method according to claim 38, characterized in that the concomitant atopic disease is a food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis.

40. Method according to any one of claims 28 to 39, characterized in that the individual to be treated with the combination therapy: (i) has an eosinophil count >30 eos / hpf, as measured by endoscopic biopsy in at least five distinct regions of the stomach; (ii) has an eosinophil count >30 eos / hpf, as measured by endoscopic biopsy in at least three distinct regions of the small intestine; (iii) has an initial assessment total symptom score (TSS) >20, as measured by the EoG / EoD Symptom Questionnaire (EoG / EoD-SQ); Petition 870250087280, dated 09 / 26 / 2025, p.135 / 153 7 / 9 (iv) has an average baseline severity score of > 4 per week for at least two weeks for at least two components of the EoG / EoD-SQ, wherein the components are selected from the group consisting of stomach pain, stomach cramps, nausea, bloating, early satiety, and loss of appetite; and / or (v) has a history of at least two episodes of EoG symptoms per week for at least 8 weeks, wherein the symptoms are selected from the group consisting of stomach pain, stomach cramps, nausea, bloating, early satiety, and loss of appetite.

41. A method according to any one of claims 28 to 40, characterized in that the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof.

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

8.

43. Method, according to any one of claims 28 to 42, characterized in that the IL-4R antagonist is Petition 870250087280, dated 09 / 26 / 2025, page 136 / 153 8 / 9 an anti-IL-4R antibody or an antigen-binding fragment thereof comprising a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and comprising a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

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

10.

45. Method, according to any one of claims 28 to 44, characterized in that the IL-4R antagonist is dupilumab.

46. ​​A method according to any one of claims 28 to 45, characterized in that the IL-4R antagonist is administered at a dose of about 50 mg to about 600 mg.

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

48. Method according to claim 46 or 47, characterized in that the IL-4R antagonist is administered at a dose of approximately 300 mg QW.

49. Method according to claim 46 or 47, characterized in that the IL-4R antagonist is administered at a dose of approximately 300 mg Q2W.

50. Method, according to any one of claims 28 to 49, characterized in that the IL-4R antagonist is administered subcutaneously.

51. Method, according to any of claims 1 to 50, characterized in that the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen dispensing device and an autoinjector.

52. Method according to claim 51, characterized in that the IL-4R antagonist is contained in a pre-filled syringe.

53. Method according to claim 52, characterized in that the pre-filled syringe is a single-dose pre-filled syringe.

54. Method according to claim 51, characterized in that the IL-4R antagonist is contained in an autoinjector.

55. Method according to claim 51, characterized in that the IL-4R antagonist is contained in a pen-type delivery device.

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