Method for treating chronically induced cold urticaria by administering an IL-4R antagonist

Abstract

Methods for treating or preventing chronically induced urticaria, such as chronically induced cold urticaria (ColdU), in a subject are provided, including administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist (e.g., an anti-IL-4R antibody or an antigen-binding fragment thereof).

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 401,756, filed August 29, 2022, and European Patent Application No. 23315021.8, filed February 2, 2023, the contents of which are incorporated herein by reference.

[0002] The present disclosure relates to the treatment and / or prevention of chronically triggered urticaria in a subject in need thereof.The present disclosure relates to the administration of an interleukin-4 receptor (IL-4R) antagonist to treat or prevent chronically triggered urticaria in a subject in need thereof. [Background technology]

[0003] Chronic provoked urticaria is a condition characterized by the appearance of wheals, angioedema, or both in response to specific, reproducible triggers. A common form of chronic provoked urticaria is physical urticaria, which is associated with exposure to physical triggers such as cold, heat, vibration, and pressure. Physical urticaria (e.g., heat urticaria, cold urticaria, symptomatic dermatographism, delayed pressure urticaria, solar urticaria, and vibratory angioedema) is distinct from other provoked urticaria, such as cholinergic urticaria, contact urticaria, and aquagenic urticaria. Chronic provoked urticaria symptoms are typically limited to areas of skin exposed to specific triggers. Chronic provoked urticaria is diagnosed based on the patient's medical history and the results of provocation testing. The purpose of provocation testing is to determine the relevant triggers in each individual subject and assess the threshold for triggers.

[0004] Among physical urticaria, chronic inducible cold urticaria (ColdU) is defined as a type of physical urticaria characterized by the formation of wheals and the development of angioedema triggered by cold. ColdU is defined as the appearance of wheals after contact cooling and rewarming of the skin. In ColdU, symptoms usually appear within minutes of being triggered by contacting the skin with cold air, cold liquids, or cold solids.

[0005] As used herein, "primary acquired cold urinary tract disease" refers to non-familial cold urinary tract disease that is considered idiopathic. Historically, it has been shown that the majority of acquired cold urinary tract disease (96% of subjects) is primary cold urinary tract disease, with only rare secondary cold urinary tract disease (see Neittaanmaki (1985) J. Am. Acad. Dermatol. 13(4):636-44 for details).

[0006] The prevalence of chronically provoked urticaria in the general population is estimated to be approximately 0.5% and significantly impacts the quality of life (QoL) of many patients, primarily due to the need to avoid triggers. Within the group of chronically provoked urticaria, most subtypes are rare and therefore very difficult to study. The most common are symptomatic dermatographia, cholinergic urticaria, and Cold U. Chronic provoked Cold U is the second most common type of physical urticaria, with an estimated annual incidence of 0.05%.

[0007] Cold U is a debilitating condition that severely impacts quality of life. Avoiding the offending triggers is usually impossible without significant changes to daily life. Most patients with Cold U experience systemic reactions, including anaphylaxis in severe cases. Currently, there are no approved treatments for Cold U, and treatment recommendations in the EAACI / GA2LEN / EDF / WAO guidelines are primarily based on approved treatments for chronic spontaneous urticaria (CSU). Many patients with Cold U are refractory to these CSU treatments.

[0008] Therefore, there remains a high unmet need for novel therapies to treat chronic induced urticaria, such as ColdU. Summary of the Invention [Means for solving the problem]

[0009] In one aspect, a method of treating a subject with chronically induced cold urticaria (ColdU) comprises administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the cold urticaria activity score (ColdUAS) is improved.

[0010] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0011] In certain exemplary embodiments, an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof, hi certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0012] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses. In certain exemplary embodiments, the initial dose is about 600 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0013] In certain exemplary embodiments, the subject is between 12 and under 18 years of age.

[0014] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as an initial dose, followed by one or more secondary doses.

[0015] In certain exemplary embodiments, the subject weighs 30 kg or greater but less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0016] In certain exemplary embodiments, the subject weighs at least 60 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0017] In certain exemplary embodiments, the subject is between 6 and under 12 years of age.

[0018] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as an initial dose, followed by one or more secondary doses.

[0019] In certain exemplary embodiments, the subject weighs at least 30 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0020] In certain exemplary embodiments, the subject is between the ages of 2 and under 12 years old.

[0021] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as an initial dose, followed by one or more secondary doses.

[0022] In certain exemplary embodiments, the subject weighs at least 30 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0023] In certain exemplary embodiments, the subject weighs less than 30 kg, but at least 15 kg, and the initial dose is about 600 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every four weeks.

[0024] In certain exemplary embodiments, the subject weighs less than 30 kg but at least 15 kg, the initial dose is about 300 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every four weeks.

[0025] In certain exemplary embodiments, the subject is at least 2 years old and less than 6 years old.

[0026] In certain exemplary embodiments, the subject weighs less than 15 kg, but at least 5 kg, the initial dose is about 200 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every four weeks.

[0027] In certain exemplary embodiments, the treatment improves the clinical outcomes of patients with urticaria using a 4-item version of the Ice Cube Provocation Test score, a Likert Scale score for wheal intensity, a numerical rating scale (NRS) score for itch peak, a NRS score for pain peak, a NRS score for burning peak, a 4-item version of the Urticaria Control Test (UCT), a children's dermatology quality of life index (CDLQI) score, an infants' dermatitis quality of life index (IDQOL) score, a patient global impression of change (PGIC) score, a patient global impression of severity (PGIS) score, an acquired cold urticaria severity index (AColdUSI) score, a 5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional The objective of this study was to improve one or more ColdU-related outcomes selected from the group consisting of: questionnaire:EQ-5D-5L score, and healthcare resource utilization / productivity score.

[0028] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 12 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0029] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0030] In certain exemplary embodiments, the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

[0031] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by the subject.

[0032] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

[0033] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids.

[0034] In certain exemplary embodiments, the required oral corticosteroid dosage is reduced.

[0035] In certain exemplary embodiments, the number of days oral corticosteroid therapy is required is reduced.

[0036] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue drug.

[0037] In certain exemplary embodiments, a reduced dose of antihistamine rescue medication is required.

[0038] In certain exemplary embodiments, the number of days requiring antihistamine rescue medication is reduced.

[0039] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof consists of the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0040] In certain exemplary embodiments, the antibody is dupilumab.

[0041] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0042] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0043] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0044] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0045] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0046] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0047] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0048] In another aspect, a method of treating a subject with chronically inducible cold urticaria (ColdU) comprises administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, wherein the subject has previously failed treatment with an H1 antihistamine, and the subject experiences an improvement in cold urticaria activity score (ColdUAS) score.

[0049] In certain exemplary embodiments, an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof, hi certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0050] In certain exemplary embodiments, the subject is an adult. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses. In certain exemplary embodiments, the initial dose is about 600 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0051] In certain exemplary embodiments, the subject is between 12 and under 18 years of age.

[0052] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as an initial dose, followed by one or more secondary doses.

[0053] In certain exemplary embodiments, the subject weighs 30 kg or greater but less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0054] In certain exemplary embodiments, the subject weighs at least 60 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0055] In certain exemplary embodiments, the subject is between 6 and under 12 years of age.

[0056] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as an initial dose, followed by one or more secondary doses.

[0057] In certain exemplary embodiments, the subject weighs at least 30 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0058] In certain exemplary embodiments, the subject is between the ages of 2 and under 12 years old.

[0059] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered to a subject as an initial dose, followed by one or more secondary doses.

[0060] In certain exemplary embodiments, the subject weighs at least 30 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0061] In certain exemplary embodiments, the subject weighs less than 30 kg, but at least 15 kg, and the initial dose is about 600 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every four weeks.

[0062] In certain exemplary embodiments, the subject weighs less than 30 kg but at least 15 kg, the initial dose is about 300 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every four weeks.

[0063] In certain exemplary embodiments, the subject is at least 2 years old and less than 6 years old.

[0064] In certain exemplary embodiments, the subject weighs less than 15 kg, but at least 5 kg, the initial dose is about 200 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every four weeks.

[0065] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0066] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0067] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0068] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0069] In another aspect, a method of treatment is provided, comprising administering to a subject with chronically inducible cold urticaria (ColdU) an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, the subject is 12 to under 18 years of age, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses, the antibody or antigen-binding fragment thereof is administered to the subject in weight-dependent doses, and the cold urticaria activity score (ColdUAS) score is improved in the subject.

[0070] In certain exemplary embodiments, the subject weighs 30 kg or greater and less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg.

[0071] In certain exemplary embodiments, the subject weighs at least 60 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

[0072] In certain exemplary embodiments, the secondary doses occur every two weeks.

[0073] In certain exemplary embodiments, an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

[0074] In certain exemplary embodiments, the treatment improves the clinical outcomes of patients with urticaria using a 4-item version of the Ice Cube Provocation Test score, a Likert Scale score for wheal intensity, a numerical rating scale (NRS) score for itch peak, a NRS score for pain peak, a NRS score for burning peak, a 4-item version of the Urticaria Control Test (UCT), a children's dermatology quality of life index (CDLQI) score, an infants' dermatitis quality of life index (IDQOL) score, a patient global impression of change (PGIC) score, a patient global impression of severity (PGIS) score, an acquired cold urticaria severity index (AColdUSI) score, a 5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional The objective of this study was to improve one or more ColdU-related outcomes selected from the group consisting of: questionnaire:EQ-5D-5L score, and healthcare resource utilization / productivity score.

[0075] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 12 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0076] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0077] In certain exemplary embodiments, the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

[0078] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by the subject.

[0079] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

[0080] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids.

[0081] In certain exemplary embodiments, the required oral corticosteroid dosage is reduced.

[0082] In certain exemplary embodiments, the number of days oral corticosteroid therapy is required is reduced.

[0083] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue drug.

[0084] In certain exemplary embodiments, a reduced dose of antihistamine rescue medication is required.

[0085] In certain exemplary embodiments, the number of days requiring antihistamine rescue medication is reduced.

[0086] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof consists of the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0087] In certain exemplary embodiments, the antibody is dupilumab.

[0088] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0089] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0090] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0091] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0092] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0093] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0094] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0095] In another aspect, a method of treatment is provided that includes administering to a subject with chronically inducible cold urticaria (ColdU) an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, the subject is 12 to under 18 years of age, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more secondary doses, the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dose, the subject has previously failed antihistamine treatment, and the cold urticaria activity score (ColdUAS) score is improved in the subject.

[0096] In certain exemplary embodiments, the subject weighs 30 kg or greater and less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg.

[0097] In certain exemplary embodiments, the subject weighs at least 60 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

[0098] In certain exemplary embodiments, the secondary doses occur every two weeks.

[0099] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0100] In certain exemplary embodiments, an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

[0101] In certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0102] In certain exemplary embodiments, the treatment improves the clinical outcomes of patients with urticaria using a 4-item version of the Ice Cube Provocation Test score, a Likert Scale score for wheal intensity, a numerical rating scale (NRS) score for itch peak, a NRS score for pain peak, a NRS score for burning peak, a 4-item version of the Urticaria Control Test (UCT), a children's dermatology quality of life index (CDLQI) score, an infants' dermatitis quality of life index (IDQOL) score, a patient global impression of change (PGIC) score, a patient global impression of severity (PGIS) score, an acquired cold urticaria severity index (AColdUSI) score, a 5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional The objective of this study was to improve one or more ColdU-related outcomes selected from the group consisting of: questionnaire:EQ-5D-5L score, and healthcare resource utilization / productivity score.

[0103] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 12 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0104] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0105] In certain exemplary embodiments, the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

[0106] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by the subject.

[0107] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

[0108] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids.

[0109] In certain exemplary embodiments, the required oral corticosteroid dosage is reduced.

[0110] In certain exemplary embodiments, the number of days oral corticosteroid therapy is required is reduced.

[0111] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue drug.

[0112] In certain exemplary embodiments, a reduced dose of antihistamine rescue medication is required.

[0113] In certain exemplary embodiments, the number of days requiring antihistamine rescue medication is reduced.

[0114] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof consists of the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0115] In certain exemplary embodiments, the antibody is dupilumab.

[0116] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0117] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0118] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0119] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0120] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0121] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0122] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0123] In another aspect, a method of treatment is provided that includes administering to a subject with chronically inducible cold urticaria (ColdU) an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, the subject is between 6 and less than 12 years of age, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more secondary doses, the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dose, the subject has previously failed H1 antihistamine treatment, and the cold urticaria activity score (ColdUAS) score is improved in the subject.

[0124] In certain exemplary embodiments, the subject weighs at least 15 kg but less than 30 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

[0125] In certain exemplary embodiments, the secondary doses occur every four weeks.

[0126] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0127] In certain exemplary embodiments, an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

[0128] In certain exemplary embodiments, the treatment improves the clinical outcomes of patients with urticaria using a 4-item version of the Ice Cube Provocation Test score, a Likert Scale score for wheal intensity, a numerical rating scale (NRS) score for itch peak, a NRS score for pain peak, a NRS score for burning peak, a 4-item version of the Urticaria Control Test (UCT), a children's dermatology quality of life index (CDLQI) score, an infants' dermatitis quality of life index (IDQOL) score, a patient global impression of change (PGIC) score, a patient global impression of severity (PGIS) score, an acquired cold urticaria severity index (AColdUSI) score, a 5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional The objective of this study was to improve one or more ColdU-related outcomes selected from the group consisting of: questionnaire:EQ-5D-5L score, and healthcare resource utilization / productivity score.

[0129] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 12 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0130] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0131] In certain exemplary embodiments, the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

[0132] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by the subject.

[0133] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

[0134] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids.

[0135] In certain exemplary embodiments, the required oral corticosteroid dosage is reduced.

[0136] In certain exemplary embodiments, the number of days oral corticosteroid therapy is required is reduced.

[0137] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue drug.

[0138] In certain exemplary embodiments, a reduced dose of antihistamine rescue medication is required.

[0139] In certain exemplary embodiments, the number of days requiring antihistamine rescue medication is reduced.

[0140] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof consists of the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0141] In certain exemplary embodiments, the antibody is dupilumab.

[0142] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0143] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0144] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0145] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0146] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0147] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0148] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0149] In another aspect, a method of treatment is provided, comprising administering to a subject with chronically inducible cold urticaria (ColdU) an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, wherein the subject weighs 30 kg or more and less than 60 kg, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more secondary doses, wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dose, wherein the subject has previously failed H1 antihistamine treatment, and wherein the cold urticaria activity score (ColdUAS) score is improved in the subject.

[0150] In certain exemplary embodiments, the initial dose is about 400 mg and each secondary dose is about 200 mg.

[0151] In certain exemplary embodiments, the secondary doses occur every two weeks.

[0152] In certain exemplary embodiments, the subject is at least 6 years old and less than 12 years old.

[0153] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0154] In certain exemplary embodiments, an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

[0155] In certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0156] In certain exemplary embodiments, the treatment improves the clinical outcomes of patients with urticaria using a 4-item version of the Ice Cube Provocation Test score, a Likert Scale score for wheal intensity, a numerical rating scale (NRS) score for itch peak, a NRS score for pain peak, a NRS score for burning peak, a 4-item version of the Urticaria Control Test (UCT), a children's dermatology quality of life index (CDLQI) score, an infants' dermatitis quality of life index (IDQOL) score, a patient global impression of change (PGIC) score, a patient global impression of severity (PGIS) score, an acquired cold urticaria severity index (AColdUSI) score, a 5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional The objective of this study was to improve one or more ColdU-related outcomes selected from the group consisting of: questionnaire:EQ-5D-5L score, and healthcare resource utilization / productivity score.

[0157] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 12 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0158] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0159] In certain exemplary embodiments, the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

[0160] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by the subject.

[0161] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

[0162] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids.

[0163] In certain exemplary embodiments, the required oral corticosteroid dosage is reduced.

[0164] In certain exemplary embodiments, the number of days oral corticosteroid therapy is required is reduced.

[0165] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue drug.

[0166] In certain exemplary embodiments, a reduced dose of antihistamine rescue medication is required.

[0167] In certain exemplary embodiments, the number of days requiring antihistamine rescue medication is reduced.

[0168] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof consists of the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0169] In certain exemplary embodiments, the antibody is dupilumab.

[0170] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0171] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0172] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0173] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0174] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0175] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0176] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0177] In another aspect, a method of treatment is provided, comprising administering to a subject with chronically inducible cold urticaria (ColdU) an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, wherein the subject weighs 5 kg or more and less than 15 kg, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more secondary doses, wherein the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dose, wherein the subject has previously failed H1 antihistamine treatment, and wherein the cold urticaria activity score (ColdUAS) score is improved in the subject.

[0178] In certain exemplary embodiments, the initial dose is about 200 mg and each secondary dose is about 200 mg.

[0179] In certain exemplary embodiments, the secondary doses occur every four weeks.

[0180] In certain exemplary embodiments, the subject is at least 2 years old and less than 6 years old.

[0181] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0182] In certain exemplary embodiments, an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

[0183] In certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0184] In certain exemplary embodiments, the treatment improves the clinical outcomes of patients with urticaria using a 4-item version of the Ice Cube Provocation Test score, a Likert Scale score for wheal intensity, a numerical rating scale (NRS) score for itch peak, a NRS score for pain peak, a NRS score for burning peak, a 4-item version of the Urticaria Control Test (UCT), a children's dermatology quality of life index (CDLQI) score, an infants' dermatitis quality of life index (IDQOL) score, a patient global impression of change (PGIC) score, a patient global impression of severity (PGIS) score, an acquired cold urticaria severity index (AColdUSI) score, a 5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional The objective of this study was to improve one or more ColdU-related outcomes selected from the group consisting of: questionnaire:EQ-5D-5L score, and healthcare resource utilization / productivity score.

[0185] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 12 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0186] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0187] In certain exemplary embodiments, the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

[0188] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by the subject.

[0189] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

[0190] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids.

[0191] In certain exemplary embodiments, the required oral corticosteroid dosage is reduced.

[0192] In certain exemplary embodiments, the number of days oral corticosteroid therapy is required is reduced.

[0193] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue drug.

[0194] In certain exemplary embodiments, a reduced dose of antihistamine rescue medication is required.

[0195] In certain exemplary embodiments, the number of days requiring antihistamine rescue medication is reduced.

[0196] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof consists of the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0197] In certain exemplary embodiments, the antibody is dupilumab.

[0198] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0199] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0200] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0201] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0202] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0203] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0204] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0205] In another aspect, a method of treatment is provided, comprising administering to a subject with chronically inducible cold urticaria (ColdU) an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, wherein the subject weighs 15 kg or more and less than 30 kg, the subject is at least 2 years old and less than 6 years old, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more secondary doses, the antibody or antigen-binding fragment thereof is administered to the subject in weight-dependent doses, the subject has previously failed H1 antihistamine treatment, and the cold urticaria activity score (ColdUAS) score is improved in the subject.

[0206] In certain exemplary embodiments, the initial dose is about 300 mg and each secondary dose is about 300 mg.

[0207] In certain exemplary embodiments, the secondary doses occur every four weeks.

[0208] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0209] In certain exemplary embodiments, an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

[0210] In certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0211] In certain exemplary embodiments, the treatment improves the clinical outcomes of patients with urticaria using a 4-item version of the Ice Cube Provocation Test score, a Likert Scale score for wheal intensity, a numerical rating scale (NRS) score for itch peak, a NRS score for pain peak, a NRS score for burning peak, a 4-item version of the Urticaria Control Test (UCT), a children's dermatology quality of life index (CDLQI) score, an infants' dermatitis quality of life index (IDQOL) score, a patient global impression of change (PGIC) score, a patient global impression of severity (PGIS) score, an acquired cold urticaria severity index (AColdUSI) score, a 5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional The objective of this study was to improve one or more ColdU-related outcomes selected from the group consisting of: questionnaire:EQ-5D-5L score, and healthcare resource utilization / productivity score.

[0212] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 12 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0213] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0214] In certain exemplary embodiments, the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

[0215] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by the subject.

[0216] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

[0217] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids.

[0218] In certain exemplary embodiments, the required oral corticosteroid dosage is reduced.

[0219] In certain exemplary embodiments, the number of days oral corticosteroid therapy is required is reduced.

[0220] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue drug.

[0221] In certain exemplary embodiments, a reduced dose of antihistamine rescue medication is required.

[0222] In certain exemplary embodiments, the number of days requiring antihistamine rescue medication is reduced.

[0223] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof consists of the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0224] In certain exemplary embodiments, the antibody is dupilumab.

[0225] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0226] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0227] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0228] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0229] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0230] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0231] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0232] In another aspect, a method of treatment is provided that includes administering to a subject with chronically inducible cold urticaria (ColdU) an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, the subject is between 2 and less than 12 years of age, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose followed by one or more secondary doses, the antibody or antigen-binding fragment thereof is administered to the subject in a weight-dependent dose, the subject has previously failed H1 antihistamine treatment, and the cold urticaria activity score (ColdUAS) score is improved in the subject.

[0233] In certain exemplary embodiments, the subject weighs 5 kg or more and less than 15 kg, the initial dose is about 200 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every 4 weeks. In certain exemplary embodiments, the subject is at least 2 years old and less than 6 years old.

[0234] In certain exemplary embodiments, the subject weighs 15 kg or more and less than 30 kg, the initial dose is about 300 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every 4 weeks. In certain exemplary embodiments, the subject is at least 2 years old and less than 6 years old.

[0235] In certain exemplary embodiments, the subject weighs at least 15 kg but less than 30 kg, the initial dose is about 300 mg, and each secondary dose is about 300 mg. In certain exemplary embodiments, each secondary dose is administered every four weeks.

[0236] In certain exemplary embodiments, the subject weighs 30 kg or greater but less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg. In certain exemplary embodiments, each secondary dose is administered every two weeks.

[0237] In certain exemplary embodiments, the subject remains symptomatic despite use of an H1 antihistamine.

[0238] In certain exemplary embodiments, an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

[0239] In certain exemplary embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0240] In certain exemplary embodiments, the treatment improves the clinical outcomes of patients with urticaria using a 4-item version of the Ice Cube Provocation Test score, a Likert Scale score for wheal intensity, a numerical rating scale (NRS) score for itch peak, a NRS score for pain peak, a NRS score for burning peak, a 4-item version of the Urticaria Control Test (UCT), a children's dermatology quality of life index (CDLQI) score, an infants' dermatitis quality of life index (IDQOL) score, a patient global impression of change (PGIC) score, a patient global impression of severity (PGIS) score, an acquired cold urticaria severity index (AColdUSI) score, a 5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional The objective of this study was to improve one or more ColdU-related outcomes selected from the group consisting of: questionnaire:EQ-5D-5L score, and healthcare resource utilization / productivity score.

[0241] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 12 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0242] In certain exemplary embodiments, improvement in one or more ColdU-related measures occurs after 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0243] In certain exemplary embodiments, the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

[0244] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by the subject.

[0245] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

[0246] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids.

[0247] In certain exemplary embodiments, the required oral corticosteroid dosage is reduced.

[0248] In certain exemplary embodiments, the number of days oral corticosteroid therapy is required is reduced.

[0249] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with an antihistamine rescue drug.

[0250] In certain exemplary embodiments, a reduced dose of antihistamine rescue medication is required.

[0251] In certain exemplary embodiments, the number of days requiring antihistamine rescue medication is reduced.

[0252] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof consists of the heavy chain variable region (HCVR) sequence of SEQ ID NO:1 and the light chain variable region (LCVR) sequence of SEQ ID NO:2.

[0253] In certain exemplary embodiments, the antibody is dupilumab.

[0254] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

[0255] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

[0256] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0257] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0258] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0259] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0260] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0261] In another aspect, a method for treating chronically induced cold urticaria (ColdU) in a subject includes selecting a subject with ColdU and administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, and wherein the cold urticaria activity score (ColdUAS) score is improved.

[0262] In certain exemplary embodiments, the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

[0263] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by the subject.

[0264] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

[0265] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduced need for treatment of the subject with oral corticosteroids.

[0266] In certain exemplary embodiments, the ColdUAS score is measured by the number of sign- and symptom-free days on cold-exposed days, or by the severity score of signs and symptoms on cold-exposed days.

[0267] In certain exemplary embodiments, the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

[0268] In certain exemplary embodiments, the subject's total serum IgE is reduced.

[0269] In certain exemplary embodiments, 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces total serum IgE.

[0270] The foregoing and other features and advantages of the present invention will be more fully understood from the following detailed description of illustrative embodiments, taken in conjunction with the accompanying drawings. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0271] [Figure 1] The study design for the EFC16720 study is shown in Example 1. Adults and adolescents weighing 60 kg or more will receive 300 mg of dupilumab subcutaneously every 2 weeks, with each injection containing 300 mg of dupilumab (2 mL). Adolescents weighing less than 60 kg will receive 200 mg of dupilumab subcutaneously every 2 weeks, with each injection containing 200 mg of dupilumab (1.14 mL). A matching placebo will be prepared with the same formulation, but without the addition of protein (i.e., active substance). A loading dose corresponding to the assigned treatment group will be administered on Day 1. Abbreviations: EOS: end of study; EOT: end of treatment; Q2W: every 2 weeks; N: number of participants; R: randomization; SC: subcutaneous. [Figure 2]This is a table showing the Schedule of Activities (SoA) for the EFC16720 study. Abbreviations: ACUSI = acquired cold urticaria severity index, ADA = antidrug antibodies, AE = adverse event, AESI = adverse event of special interest, CDLQI = children's dermatology quality life quality index, ColdUAS = cold urticaria activity score, ColdU-QoL = Cold Urticaria Quality of Life, DLQI = Dermatology Life Quality Index, DNA = deoxyribonucleic acid, ECG = electrocardiogram, eCRF = electronic Case Report Form, e-diary = electronic diary, EOS = end of study EOT=end of treatment, EQ-5D5L=EuroQol 5-dimensional questionnaire (5-level EuroQol 5-dimensional questionnaire), HBcAb=hepatitis B core antibody, HBs Ab=hepatitis B surface antibody, HBs Ag=hepatitis B surface antigen, HBV=hepatitis B virus virus), HCRU=Healthcare resource utilization, HCV Ab=hepatitis C virus antibodies, HIV=Human immunodeficiency virus (HumanImmunodeficiency Virus, IgE = immunoglobulin E, IMP = investigational medicinal product, IVRS = interactive voice response system, IWRS = interactive web response system, NRS = numerical rating scale, OCS = oral corticosteroids, PGIC = patient global impression of change, PGIS = patient global impression of severity, PK = pharmacokinetic, q2w = every 2 weeks, RNA = ribonucleic acid, SAE = serious adverse event, SC = subcutaneous, TB = tuberculosis, UCT = urticaria control test, Ur = urine. [Figure 2-1] Same as above. [Figure 2-2] Same as above. [Figure 3] 1 shows a schematic representation of the parameters at the completion of the EFC16720 study as defined in Example 3. [Figure 4] The mean change from baseline in the proportion of days free of signs and symptoms of cold urticaria by week 24 for cold-exposed days during the 14-day observation period is plotted in the ITT population. [Figure 5] Illustrates the mean change from baseline in severity of signs and symptoms of cold urticaria to week 24 in the ITT population on cold exposure days during the 14-day observation period. [Figure 6]Illustrates the median change (with interquartile range) from baseline over time in total serum IgE (IU / mL) in the safety population. [Figure 7] Figure 1 illustrates the placebo response in patients with a Likert score of 2 at baseline. These patients had milder disease compared with other subgroups. DETAILED DESCRIPTION OF THE INVENTION

[0272] Before the present disclosure is described, it is to be understood that this disclosure is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0273] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0274] As used herein, the term "about," when used in reference to a specific recited numerical value, means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0275] As used herein, the terms "treat," "treating," and the like mean to alleviate symptoms, to eliminate the cause of symptoms, either temporarily or permanently, or to prevent or delay the onset of symptoms of the specified disorder or condition.

[0276] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, exemplary methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0277] The present disclosure provides methods and compositions for treating chronically induced urticaria (e.g., chronically induced cold urticaria (ColdU)) in a subject, e.g., a human subject.

[0278] As used herein, "urticaria" refers to a skin condition characterized by the formation of wheals (i.e., a rash) and / or the development of angioedema that lasts from minutes to hours. As used herein, "chronic urticaria" or "CU" refers to urticaria that recurs at least twice a week for six weeks.

[0279] As used herein, "chronic spontaneous urticaria" or "CSU" refers to a subset of CU in which wheals and / or angioedema are induced or induced in a subject for at least six weeks, and CSU has no specific cause or trigger.

[0280] As used herein, "chronic-induced urticaria" refers to a subset of CU in which wheals and / or angioedema are induced or provoked in subjects for at least six weeks by exposure to a specific trigger. There are nine subtypes of chronic-induced urticaria, depending on the type of trigger that induces the chronic urticaria: symptomatic dermatographia / factiac urticaria, cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria, and aquagenic urticaria. Most subtypes of chronic-induced urticaria are rare, but the most common are symptomatic dermatographia / factiac urticaria, cholinergic urticaria, and chronic-induced cold urticaria.

[0281] Subjects with chronically induced urticaria reproducibly develop wheals and / or angioedema in response to a triggering stimulus specific to their condition (e.g., cold exposure in cold contact urticaria). Chronic induced urticaria is typically diagnosed based on the subject's medical history and the results of a provocation test (e.g., wheal formation and / or angioedema development). Subjects with severe chronically induced urticaria may develop one or more systemic symptoms, including, but not limited to, dizziness, vertigo, abdominal pain, vomiting, diarrhea, gastrointestinal ulcers, shortness of breath, wheezing, rapid and irregular heartbeat, anaphylactic shock, hypotension, shock, collapse, and death.

[0282] As used herein, "chronic inducible cold urticaria" ("ColdU" or "CICU") and "cold inducible urticaria" ("CIndU") are each used interchangeably and refer to the development of itchy wheals and / or angioedema in a subject following exposure of the skin to cold. For a review of ColdU, see Magerl et al. (2016) Allergy 71:780-802 (doi:10.1111 / all.12884), which is incorporated by reference in its entirety for all purposes.

[0283] As used herein, a "wheal" refers to a raised, itchy (i.e., pruritic) area on the skin. Wheal is sometimes used interchangeably with "rash." The intensity of a wheal can be characterized using a variety of assessment tools known in the art, including those described below.

[0284] As used herein, "angioedema" refers to areas of swelling of the underlying skin or tissues immediately beneath the skin or mucous membranes. Swelling may occur in the face, tongue, larynx, abdomen, arms, or legs. Onset typically lasts from minutes to hours and typically resolves within hours to days.

[0285] How to improve ColdU-related metrics Also provided is a method of improving one or more ColdU-related measures in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an IL-4R antagonist.

[0286] Examples of clinical-reported outcome (CRO) and patient-reported outcome (PRO) measures associated with ColdU include, but are not limited to, the following: (1) ice cube provocation test score; (2) wheal intensity Likert scale score; (3) itch peak numerical rating scale (NRS) score; (4) pain peak NRS score; (5) burning peak NRS score; (6) urticaria control test (UCT) 4-item version score; (7) cold urticaria activity score (ColdUAS); (8) children's dermatology quality of life index (CDLQI) score; (9) infants' dermatitis quality of life index (IDQOL) score; and (10) patient global impression of change. (11) Patient Global Impression of Severity (PGIS) score; (12) Acquired Cold Urticaria Severity Index (AColdUSI) score; (13) 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L) score; and (14) Healthcare Resource Utilization / Productivity score.

[0287] "Improvement in ColdU-related measures" means improvement from baseline in one or more of the following: ice cube provocation test score, wheal intensity Likert scale score, NRS, peak pain NRS score, peak burning sensation NRS score, UCT 4-item score, ColdUAS score, CDLQI score, IDQOL score, PGIC score, PGIS score, AColdUSI score, EQ-5D-5L score, and healthcare resource utilization / productivity score. As used herein, the term "baseline" with respect to ColdU-related measures refers to the numerical value of the measure in a patient before or at the time of administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0288] To determine whether a ColdU-related parameter is "improved," the parameter is quantified at baseline and at time points after administration of a pharmaceutical composition described herein. For example, a ColdU-related parameter can be measured on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, or day 14, or at week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or more after initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a particular time point after initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" in the ColdU-related parameter (e.g., an increase or decrease, as the case may be, depending on the particular parameter being measured).

[0289] As used herein, the terms "obtain" or "obtaining" refer to gaining possession of a physical entity or value, e.g., a numerical value, by "directly obtaining" or "indirectly obtaining" the physical entity or value, such as a ColdU-related parameter. "Directly obtaining" means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. "Indirectly obtaining" refers to receiving the physical entity or value from another entity or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a physical entity includes performing a process that involves a physical transformation of a physical substance, e.g., a starting material. Exemplary transformations include creating a physical entity from two or more starting materials, shearing or fragmenting a material, separating or purifying a material, combining two or more separate entities into a mixture, and performing a chemical reaction that involves breaking or forming covalent or non-covalent bonds. Obtaining a value directly includes performing a process that involves a physical change of a sample or another substance, for example, performing an analytical process that involves a physical change of a substance, such as a sample, analyte, or reagent (sometimes referred to herein as a "physical analysis").

[0290] Indirectly obtained information may be provided in the form of a report, for example, provided in paper or electronic format from an online database or application ("Application"). The report or information may be provided, for example, by a medical institution, such as a hospital or clinic, or a healthcare provider, such as a doctor or nurse.

[0291] Efficacy evaluation Ice cube provocation test: In certain embodiments, administration of an IL-4R antagonist to a patient results in an improvement from baseline in the ice cube provocation test. Cold U is defined as the signs and symptoms (rash / wheals, itching, pain, and burning sensation) that appear when the skin is rewarmed after exposure to cold. The cold provocation test is used in clinical studies of patients with chronic urticaria to evaluate treatment efficacy by assessing the proportion of patients who are free of signs / symptoms in the cold provocation test after treatment or by evaluating the response to an experimental cold simulation time test. That is, the minimum time threshold required for cold stimulation to induce a confluent wheal and other Cold U signs / symptoms is evaluated.

[0292] The ice cube provocation test is the most frequently used stimulation method in the daily clinical practice of ColdU. 2 The consensus recommendations for ColdU (LEN / EDF / UNEV) define the ColdU stimulation method as follows: - Provocation testing should be performed by applying a cold stimulus (ice, ice pack) to the skin of the forearm. -Cold provocation testing should be performed on the volar side of the forearm for 1-5 minutes. -Ice cubes should be melted in a thin plastic bag to avoid direct contact with water, to avoid cold injury to the skin and to avoid confusion with aquagenic urticaria if the test is positive. -Judgment time: After removing the ice cubes, reheat for 10 minutes.

[0293] A negative test result is defined as the absence of a confluent rash / wheal at all exposed skin sites after the provocative ice cube test. In some embodiments, administration of an IL-4R antagonist to a subject in need thereof results in the subject testing negative for the ice cube provocative test.

[0294] Likert Scale for Wheal Intensity: According to certain embodiments, administration of an IL-4R antagonist to a patient results in an improvement from baseline in Likert scale scores for wheal intensity. In certain embodiments, wheal intensity is assessed using a clinician-reported Likert scale from 0 to 5, categorizing the intensity of a subject's skin reaction as follows: 0 = no wheal; 1 = multiple small, non-edematous wheals; 2 = large, regular, slightly edematous, coalescing wheals; 3 = large, moderately edematous wheals; 4 = large, regular, markedly edematous wheals without pseudopodia; and 5 = large, very edematous wheals with pseudopodia. A score of 0-1 corresponds to a negative ice cube test. A score of 2-5 corresponds to a positive ice cube test. The scale is completed at the study visit, approximately 10 minutes after a temperature provocation test (e.g., cold provocation test) is administered.

[0295] A negative provocation test is defined as the absence of a confluent rash / wheal over the entire exposed skin area (i.e., no ColdU diagnosis) after a temperature provocation test (e.g., cold provocation test) as described herein. A positive provocation test is defined as the presence of at least a confluent rash / wheal over the entire exposed skin area (i.e., a positive ColdU diagnosis) after a temperature provocation test (e.g., cold provocation test). Based on a Likert scale of wheal intensity, 0-1 indicates a negative test result (i.e., no ColdU diagnosis) and 2-5 indicates a positive test result (i.e., a ColdU diagnosis).

[0296] Methods of treatment are provided that result in a decrease in Likert scale score of wheal intensity from baseline, for example, administering an IL-4R antagonist to a subject in need thereof results in about a 1, 2, 3, 4, or 5 decrease in Likert scale score of wheal intensity from baseline.

[0297] Peak Itch Numerical Rating Scale (NRS): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in the peak itch NRS score from baseline. The peak itch NRS is a one-item PRO rated on a scale from 0 ("no itch") to 10 ("worst imaginable itch"). In certain embodiments, subjects are asked to rate the intensity of their worst localized itch (itch) 10 minutes after a temperature challenge (e.g., a cold challenge) is performed. A 24-hour version of the scale was developed, tested, and validated in patients with atopic dermatitis. A threshold of 4 has been established as a meaningful intra-individual change in score in adult and adolescent patients with atopic dermatitis.

[0298] Treatment methods are provided that result in a reduction in peak itch NRS from baseline. For example, administering an IL-4R antagonist to a subject in need thereof reduces the peak itch NRS score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 from baseline.

[0299] Peak Pain Numerical Rating Scale (NRS): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in peak pain NRS score from baseline. The peak pain NRS is a one-item PRO rated on a scale from 0 ("no pain") to 10 ("worst imaginable pain"). In certain embodiments, subjects are asked to rate the intensity of pain at the worst local site 10 minutes after a temperature provocation test (e.g., a cold provocation test) is performed.

[0300] Methods of treatment are provided that result in a reduction in peak pain NRS from baseline. For example, administering an IL-4R antagonist to a subject in need thereof reduces the peak pain NRS score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 from baseline.

[0301] Peak Burning Sensation Numerical Rating Scale (NRS): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in the Peak Burning Sensation NRS score from baseline. The Peak Burning Sensation NRS is a one-item PRO rated on a scale from 0 ("no burning sensation") to 10 ("worst imaginable burning sensation"). In certain embodiments, subjects are asked to rate the intensity of the worst localized burning sensation 10 minutes after a temperature provocation test (e.g., a cold provocation test) is performed.

[0302] Treatment methods are provided that result in a reduction in peak itch NRS from baseline. For example, administering an IL-4R antagonist to a subject in need thereof reduces the peak itch NRS score by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 from baseline.

[0303] Urticaria Control Test: According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in the Urticaria Control Test. The Urticaria Control Test (UCT) is a validated PRO measure for assessing urticaria control (Weller K, et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92.) based on four items: severity of urticaria symptoms (itch and wheal), frequency of inadequate treatment, impaired quality of life (QoL), and overall urticaria control. Each item is rated on a 5-point Likert scale (scored 0-4). Lower scores indicate higher disease activity and lower disease control. The UCT total score is calculated by adding the scores of all four individual items. Therefore, the minimum UCT score is 0 and the maximum is 16, with 16 indicating complete disease control (see Weller K, et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92.). A UCT score of 12 or greater indicates good disease control. The minimally important difference (MID) refers to the smallest change in treatment outcome that an individual patient perceives as important and that would indicate a change in the patient's management. The MID value for UCT is 3.

[0304] Treatment methods are provided that result in an increase in UCT score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof causes an increase in UCT from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 points.

[0305] Cold Urticaria Activity Score (ColdUAS): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in the ColdUAS score from baseline. The ColdUAS is a disease-specific PRO questionnaire designed to assess disease activity in cold urticaria. The ColdUAS is intended for patients aged 12 years and older with cold urticaria and has been developed and comprehensively tested in adult and adolescent cold urticaria patients. Disease activity assessment is based on daily recording of cold-induced skin reactions (wheals and swelling), skin sensations (itching, burning, pain, and burning), avoidance behaviors and trigger exposures, and overall symptom severity. Skin reactions, skin sensations, exposure to cold temperatures that typically cause ColdU symptoms, and overall symptom severity are rated on a 4-point scale from 0 ("no") to 4 ("yes, severe"). Avoidance of cold temperatures that typically cause ColdU symptoms is answered with the answers "no," "partially avoided," or "completely avoided." Daily ColdUAS scores can be summed over 7 days to calculate a ColdUAS7 score.

[0306] After each week, participants were asked about their overall disease activity in ColdU over the past week using a 4-point Likert scale ranging from "no disease activity" to "high disease activity." After each two-week period, participants were asked about their overall disease activity in ColdU over the past two weeks using a 4-point Likert scale ranging from "no disease activity" to "high disease activity." They were also asked to rate their disease activity in week 2 compared to week 1, from "significantly higher than week 1" to "significantly lower than week 1."

[0307] Therapeutic methods are provided that result in a reduction in a ColdUAS or ColdUAS7 score from baseline. For example, administration of an IL-4R antagonist to a subject in need thereof results in a reduction in a ColdUAS score from baseline of about 1, 2, 3, or 4.

[0308] Children's Dermatology Life Quality Index (CDLQI): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in CDLQI score from baseline. The Children's Dermatology Life Quality Index (CDLQI) is a validated questionnaire designed to measure the impact of skin disease on children's HRQoL (see Lewis-Jones MS, Finlay AY. The children's dermatology life quality index (CDLQI): initial validation and practical use. Br J Dermatol. 1995;132(6):942-9). Patients answer 10 questions regarding symptoms associated with the disease, leisure time, school or holidays, relationships, impact of the disease on sleep, and side effects of skin disease treatment. The device has a 7-day recall period. Nine of the 10 questions are scored on a 4-point Likert scale ranging from "0 = not at all / no answer" to "3 = very much." Question 7 has an additional answerable item (prevention group) and is worth 3 points. The CDLQI total score is the sum of the scores for each question, with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on the child's HRQoL. Patients complete the DLQI (ages 16 years and older) or the CDLQI (ages 12 years and older but younger than 16 years).

[0309] Therapeutic methods are provided that result in a reduction in CDLQI score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof causes a reduction in CDLQI score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.

[0310] Infants' Dermatitis Quality of Life Index (IDQOL): The IDQOL is a validated questionnaire for children under 4 years of age. The questionnaire is completed by the child's caregiver. The recall period for this instrument is 1 week (7 days). There are 11 questions in total: 10 focused on the quality of life index and scored on a 4-point Likert scale; and one focused on dermatitis severity and scored on a 5-point Likert scale. For questions 1 and 5–10 of the quality of life index, scores range from "always = 3" to "none = 0." Question 2 is scored as "always crying, etc. = 3," "very irritable = 2," "slightly irritable = 1," and "satisfied = 0." Question 3 is scored as "more than 2 hours = 3," "1–2 hours = 2," "15 minutes to 1 hour = 1," and "0–15 minutes = 0." Question 4 was scored as follows: 5 hours or more = 3, 3-4 hours = 2, 1-2 hours = 1, and less than 1 hour = 0. Dermatitis severity was scored on a 5-point Likert scale ranging from very severe = 4 to none = 0. The total IDQOL score was the sum of the scores for each question, with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on the child's HRQoL.

[0311] Patient Global Impression of Change (PGIC): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in PGIC score from baseline. The Patient Global Impression of Change (PGIC) is a one-item questionnaire that asks participants to self-assess their overall change in CSU on a 7-point scale compared to just before receiving study treatment. Response options are as follows: 0 = "much better," 1 = "slightly better," 2 = "slightly better," 3 = "no change," 4 = "slightly worse," 5 = "slightly worse," and 6 = "very worse." (See Guy W et al. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, 1976.)

[0312] Treatment methods are provided that result in a decrease in PGIC score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof causes a decrease in PGIC score from baseline of about 1, 2, 3, 4, 5, or 6.

[0313] Patient Global Impression of Severity (PGIS): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in PGIS scores from baseline. The Participant Global Impression of Severity (PGIS) is a one-item questionnaire that asks participants to provide an overall self-assessment of their patient's disease severity on a 4-point scale over the past week. Response options are: 1 = "none," 2 = "mild," 3 = "moderate," and 4 = "severe." (See Guy W et al. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, 1976.)

[0314] Treatment methods are provided that result in a reduction in PGIS score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in a reduction in PGIS score from baseline of about 1, 2, or 3.

[0315] Acquired Cold Urticaria Severity Index (AColdUSI) Score: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in the AColdUSI score from baseline. The AColdUSI is an index designed to assess the severity of signs / symptoms of acquired cold urticaria (ACU). It consists of four questions regarding the severity of ACU: 1) the worst problem ever caused by cold urticaria, 2) the season when it is too cold to engage in outdoor activities, 3) the maximum treatment required, and 4) the frequency of the complaint. Questions 1, 3, and 4 are scored from 1 to 4 points, and question 3 is scored from 1 to 3 points, resulting in a score of 4 to 15 points. 4 to 7 points, 8 to 11 points, and 12 to 15 points indicate low, moderate, and high severity of ACU, respectively. The fifth question assesses the overall severity of the illness on a three-point scale: mild, moderate, and severe.

[0316] Treatment methods are provided that result in a reduction in AColdUSI score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof results in a reduction in AColdUSI score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0317] Euroqol-5 Inventory (EQ-5D) and EQ-5D Youth Version (EQ-5D Y): According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in the EQ-5D or EQ-5D Y score. The Euroqol-5 Inventory (EQ-5D) is a standardized PRO measure of health status developed by the EuroQol Group to provide a simple and general measure of health for clinical and economic evaluation. The adult version of the questionnaire is adapted for patients aged 16 years and older. The EQ-5D consists of two parts: a written form and the EQ visual analog scale (EQ VAS). The EQ-5D 5L written form consists of five items: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each item has five levels of perceived problems: "no problems," "mild problems," "moderate problems," "severe problems," and "disabling" (see Herdman M, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual. Life Res. 2011;20(10):1727-36). Respondents are asked to indicate their health status by checking a box (or placing an X) for the most appropriate statement for each of the five items. This results in a single-digit number representing the level of that dimension. The five-digit number can be combined to create a five-digit number describing the respondent's health status. The EQ VAS records the respondent's self-rated health status on a vertical VAS, where the endpoints are labeled "best possible health state (100)" and "worst possible health state (0)." This information can be used as a quantitative measure of health outcomes as judged by individual respondents. The EQ-5D Youth version (EQ-5D Y) is intended for children aged 6 to 12 years and adolescents aged 12 to 15 years (Wille N, et al. Qual. Life Res. 2010; 19(6): 875-86.). The EQ-5D-Y is based on the EQ-5D-3L and basically consists of two pages: the EQ-5D essay form and the EQ VAS.The EQ-5D-Y shorthand consists of five items: mobility, taking care of oneself, performing usual activities, experiencing pain or discomfort, and feeling anxious, sad, or unhappy. Each item has three scales: no problems, some problems, and many problems. The EQ VAS is a vertical VAS labeled with endpoints "best imaginable health" and "worst imaginable health" to record young patients' self-rated health. Patients complete the EQ-5D Y or the EQ-5D questionnaire.

[0318] Therapeutic methods are provided that result in an increase in EQ VAS score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof can result in an increase in EQ VAS score from about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 1 An increase in EQ VAS from baseline of 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 is produced.

[0319] Healthcare Resource Utilization / Productivity Score: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in the number of days of absence from school or work experienced by the subject. A Healthcare Resource Utilization and Productivity Questionnaire is used to record days of absence from school (ages 3 to 18) and work (ages 18 and older). For example, administration of an IL-4R antagonist to a subject in need thereof reduces the number of days of absence from school or work experienced by the subject from baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days per month.

[0320] Pruritus-Free Days: According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in the number of pruritus-free days experienced by the subject. For example, administration of an IL-4R antagonist to a subject in need thereof results in an increase from baseline in the number of pruritus-free days experienced by the subject of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days / month.

[0321] Rash-Free Days: According to certain embodiments, administration of an IL-4R antagonist to a patient results in an increase from baseline in the number of rash-free days experienced by the subject. For example, administration of an IL-4R antagonist to a subject in need thereof causes an increase from baseline in the number of rash-free days experienced by the subject of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days per month.

[0322] Pruritus Severity Score: According to certain embodiments, administration of an IL-4R antagonist to a patient reduces the itch severity score (ISS) from baseline. ISS7 is defined as the sum of the ISS scores (ranging from 0 = none to 3 = severe) recorded at the same time each day for 7 days. ISS7 ranges from 0 to 21, with higher scores indicating worse disease. The minimally important difference (MID) for ISS7 is 4.5 to 5.

[0323] Methods of treatment are provided that result in a reduction in ISS7 score from baseline, for example, administering an IL-4R antagonist to a subject in need thereof results in a reduction from baseline in the ISS7 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 points.

[0324] Rash Severity Score: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in the rash severity score (HSS) from baseline. HSS7 is defined as the sum of the daily HSS scores (ranging from 0 = none to 3 = more than 50 rashes) recorded at the same time over 7 days. HSS7 ranges from 0 to 21, with higher scores indicating worse disease. The minimally important difference (MID) for HSS7 is 5 to 5.5.

[0325] Methods of treatment are provided that result in a reduction in HSS7 score from baseline, for example, administering an IL-4R antagonist to a subject in need thereof results in a reduction in HSS7 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 points.

[0326] Prurigo Activity Score: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction from baseline in the urticaria activity score (UAS). UAS The urticaria activity score (UAS) is a validated patient-recorded outcome (PRO) measure. The daily UAS is the sum of the daily urticaria severity score (HSS, ranging from 0 = none to 3 = more than 50 blisters) and the daily pruritus severity score (ISS, ranging from 0 = none to 3 = severe), which is the sum of the two major urticaria signs and symptoms: wheals and pruritus. The daily UAS score ranges from 0 to 6 points per day. Daily UAS scores are summed for 7 days to create the UAS7. The UAS7 ranges from 0 to 42 and is composed of components of the HSS7 and ISS7. The UAS7 is an established and widely accepted PRO tool for prospectively measuring chronic urticaria (see Mlynek A, et al. "How to assess disease activity in patients with chronic urticaria" Allergy. 2008;63(6):777-80). Recently, it has been used as the primary outcome parameter in most clinical trials of chronic urticaria and in clinical practice (see Maurer M, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368(10):924-35; Casale TB, et al. Similar efficacy with omalizumab in chronic idiopathic / spontaneous urticaria despite different background therapy. J Allergy Clin Immunol Pract. 2015;3(5):743-50).To facilitate interpretation of score changes among CSU participants, a minimally important difference (MID) value ranging from 9.5 to 10.5 was defined. (See Hollis K, et al. Comparison of urticaria activity score over 7 days (UAS7) values ​​obtained from once-daily and twice-daily versions: Results from the ASSURE-CSU study. Am J Clin Dermatol. 2018;19(2):267-74; Hawro T, et al. The urticaria activity score—validity, reliability, and responsiveness. J Allergy Clin Immunol Pract. 2018;6(4):1185-90; Mathias SD, et al. Evaluating the minimally important difference of the urticaria activity score and other measures of disease activity in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2012;108(1):20-4.) The UAS7 ranges from 0 to 42, with higher scores indicating greater disease activity. A score of 1 to 6 indicates well-controlled urticaria. A score of 7 to 15 indicates mild urticaria. A score of 16 to 27 indicates moderate urticaria activity. A score of 28 to 42 indicates severe urticaria activity. A UAS7 score of 6 or less indicates well-controlled urticaria. Complete responders (no pruritus or rash) have a UAS7 of 0.

[0327] Treatment methods are provided that result in a reduction in UAS or UAS7 score from baseline. For example, administration of an IL-4R antagonist to a subject in need thereof causes a reduction in UAS7 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 points.

[0328] Angioedema Activity Score: According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease from baseline in the angioedema activity score (AAS). The angioedema activity score (AAS) is a validated PRO measure assessing angioedema activity (see Weller K, et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy. 2013;68(9):1185-92). The AAS involves patients documenting the presence or absence of angioedema within the past 24 hours. If angioedema is present, patients answer five additional questions regarding the time of day when the edema attack occurred, the severity of the edema, and the impact of the edema on daily function and appearance. Each item on the AAS is scored between 0 and 3 points, meaning that a minimum daily AAS score of 0 points is 0, and a maximum of 15 points is 15. Daily AAS scores are compiled into a 7-day score (AAS7), which ranges from 0 to 105 (ibid.). The MID for AAS7 is established at approximately 8 points (ibid.).

[0329] Methods of treatment are provided that result in a reduction in AAS or AAS7 score from baseline. For example, administration of an IL-4R antagonist to a subject in need thereof may result in a reduction in AAS or AAS7 score from about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113 Causes a decrease in AAS or AAS7 score from baseline of 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, or 105 points.

[0330] Dermatology Life Quality Index (DLQI): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a reduction in DLQI score from baseline. The Dermatology Life Quality Index (DLQI) is a PRO developed to measure dermatology-specific HRQoL in adult participants (see Finlay AY, Khan GK. Dermatology life quality index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-6). This instrument contains 10 items that assess the impact of skin disease on the participant's health-related quality of life (HRQoL) over the previous week. Items cover symptoms, leisure activities, time at work / school or on holiday, relationships including intimacy, side effects of treatment, and emotional reactions to having a skin disease. This is a validated questionnaire used in clinical practice and clinical trials (see Chernyshov PV. The evolution of quality of life assessment and use in dermatology. Dermatology. 2019;235(3):167-74). The response scale is a 4-point Likert scale (0 = "not at all" and 3 = "very much") for nine items. The remaining item, regarding work / exams, asks whether work / exams were interfered with and then (if "no") asks how much of a problem the skin condition caused at work / exams. Items are rated on a 3-point Likert scale ("not at all" to "very much"). Total scores range from 0 to 30, with higher scores indicating poorer HRQoL. Using a distribution- and anchor-based approach-based analysis of changes in DLQI total scores and participant-rated pruritus severity scores, the median intercept (MID) for the DLQI in participants with chronic idiopathic urticaria was reported to range from 2.24 to 3.10 points.(Shikiar R,et al.Minimal important difference(MID)of the dermatology life quality index(DLQI):results from patients with chronic idiopathic urticaria.Health Qual.Life Outcomes.2005;3:36).

[0331] Therapeutic methods are provided that result in a reduction in DLQI score from baseline. For example, administering an IL-4R antagonist to a subject in need thereof causes a DLQI score reduction of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 from baseline.

[0332] Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL): According to certain embodiments, administration of an IL-4R antagonist to a patient results in a decrease in CU-Q2oL scores from baseline. The CU-Q2oL is a disease-specific scale used to assess the quality of life (QoL) of adult patients with chronic urticaria (see Baiardini I, et al. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire (CU-QoL). Allergy. 2005;60(8):1073-8). The CU-Q2oL is a 23-item self-administered questionnaire covering six QoL dimensions: itching, swelling, impact on activities of daily living, sleep disturbance, limitations, and appearance. Each item is scored on a 5-point Likert scale (1 = not at all, 5 = very much), and participants indicate how bothered they are by each dimension. Individual items are summed to produce an overall CU-Q2oL score, which is converted to a scale of 0 to 100, with higher scores indicating greater impairment of QoL.

[0333] Therapeutic methods are provided that result in a reduction in CU-Q2oL score from baseline. For example, administration of an IL-4R antagonist to a subject in need thereof can result in a reduction in CU-Q2oL score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 , causing a decrease in CU-Q2oL score of 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100.

[0334] Interleukin-4 receptor antagonist The methods featured herein involve administering to a subject in need thereof a therapeutic composition comprising an IL-4R antagonist. As used herein, an "IL-4R antagonist" is any agent that binds to or interacts with IL-4R and inhibits the normal biological signaling function of IL-4R when the IL-4R is expressed on a cell in vitro or in vivo. Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide-based IL-4R antagonists (e.g., "peptibody" molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4R. According to certain embodiments, the IL-4R antagonist comprises an anti-IL-4R antibody, which may be used in conjunction with the methods described elsewhere herein. For example, in one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R and comprises heavy and light chain (complementarity determining region) CDR sequences from the heavy chain variable region (HCVR) and light chain variable region (LCVR) of SEQ ID NOs: 1 and 2, respectively.

[0335] The term "human IL4R" (hIL-4R) refers to a human cytokine receptor that specifically binds interleukin-4 (IL-4), such as IL-4Rα.

[0336] The term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain contains a heavy chain variable region (HCVR or VL) H The heavy chain constant region comprises three domains: C H 1. C H 2, and C H Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) V H and V L The V region can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from amino to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) can be identical to human germline sequences or can be naturally or artificially modified. An amino acid consensus sequence can be defined based on a side-by-side analysis of two or more CDRs.

[0337] The term "antibody" also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like include any naturally occurring, enzymatically derived, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from intact antibody molecules using any suitable standard technique, such as, for example, proteolytic digestion or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated, for example, chemically or using molecular biology techniques, to arrange one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, etc.

[0338] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic a hypervariable region of an antibody (e.g., an isolated complementarity-determining region (CDR), such as a CDR3 peptide, or a constraining FR3-CDR3-FR4 peptide). Domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and other engineered molecules such as shark variable IgNAR domains are also encompassed by the term "antigen-binding fragment."

[0339] Antigen-binding fragments of antibodies will typically contain at least one variable domain, which may be of any size or amino acid composition and generally contains at least one CDR adjacent to or in-frame with one or more framework sequences. L V bound to domain H For antigen-binding fragments containing domains, V H Domain and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may comprise a dimer of monomer V H or V L It may contain domains.

[0340] In certain embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in the antigen-binding fragments of antibodies described herein include the following: (i) V H -C H 1, (ii) V H -C H 2, (iii) V H -C H 3, (iv) V H -C H 1-C H 2. (v) V H -C H 1-C H 2-C H 3. (vi) V H -C H 2-C H 3, (vii)V H -C L ;(viii)(V L -C H 1;(ix)V L -C H 2;(x)V L -C H 3;(xi)VL -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. A hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible link between adjacent variable and / or constant domains within a single polypeptide molecule; typically, a hinge region may consist of between 2 and 60 amino acids, typically between 5 and 50 amino acids, or typically between 10 and 40 amino acids. Furthermore, antigen-binding fragments of antibodies described herein may be linked to each other and / or to one or more monomeric V H or V L The variable domain and constant domain configurations may comprise homodimers or heterodimers (or other multimers) of any of the variable domain and constant domain configurations listed above, non-covalently associated with the domains (e.g., by disulfide bonds).

[0341] As with intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically comprise at least two different variable domains, each capable of specifically binding to a separate antigen or a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in connection with the antigen-binding fragments of antibodies described herein using routine techniques available in the art.

[0342] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the antibody isotype can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0343] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies described herein may include amino acid residues, e.g., in the CDRs, particularly CDR3, that are 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). However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0344] The term "recombinant human antibody" includes 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, e.g., Taylor et al., (1992) Nucl. Acids Res. 20:6287-6295, incorporated herein by reference in its entirety), or antibodies prepared, expressed, created, or isolated by any other means, including splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using animals transgenic for human Ig sequences, in vivo somatic mutagenesis) to thereby modify the V and constant regions of the recombinant antibody. H Area and V LThe amino acid sequence of the region is human germline V H Sequence and V L sequences that may not naturally occur within the human antibody germline repertoire in vivo.

[0345] Human antibodies can exist in two forms related to hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa in which dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked via interchain disulfide bonds, and the approximately 75-80 kDa molecule is composed of covalently linked light and heavy chains (half antibodies). These forms have been extremely difficult to separate, even after affinity purification.

[0346] The frequency of occurrence of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the antibody hinge region isotype. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form (Angal et al. (1993) Molecular Immunology 30:105) to the level typically observed using a human IgG1 hinge. Hinge, C H 2 or C H Antibodies with one or more mutations in three regions are provided, which may be desirable, for example, in manufacturing, to improve the yield of the desired antibody form.

[0347] An "isolated antibody" means 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 it naturally occurs or is naturally produced, is an "isolated antibody." Isolated antibodies also include antibodies in situ within recombinant cells. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0348] Terms such as "specifically bind" mean that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" to IL-4R includes an antibody that has a K of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM, as measured by a surface plasmon resonance assay. D However, an isolated antibody that specifically binds to human IL-4R may have cross-reactivity to other antigens, for example, IL-4R molecules from other (non-human) species.

[0349] Anti-IL-4R antibodies useful in the present methods may contain one or more amino acid substitutions, insertions, and / or deletions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 insertions and / or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 deletions) in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibody is derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. Methods are provided that include the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein in which one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 for a tetrameric antibody, or 1, 2, 3, 4, 5, or 6 for the HCVR and LCVR of the antibody) within one or more framework and / or one or more CDR regions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) have been mutated to the corresponding residue in the germline sequence from which the antibody is derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). Starting from the heavy chain and light chain variable region sequences disclosed herein, one of skill in the art can readily produce numerous antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, V H and / or V LAll of the framework and / or CDR residues within a domain are mutated back to the residue found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only mutated residues found within the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody was originally derived). Furthermore, an antibody may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., certain individual residues are mutated to the corresponding residue in a particular germline sequence, while certain other residues that differ from the original germline sequence are maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonist or agonist biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed by the present disclosure.

[0350] Methods involving the use of anti-IL-4R antibodies comprising variants of any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, the use of anti-IL-4R antibodies having HCVR, LCVR and / or CDR amino acid sequences with, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., conservative amino acid substitutions compared to any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein is provided.

[0351] The term "surface plasmon resonance" refers to an optical phenomenon that allows analysis of real-time interactions by detecting changes in protein concentration within a biosensor matrix, for example, using a BIAcore™ (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ) system.

[0352] "K D The term "antibody-antigen interaction" refers to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0353] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site within the variable region of an antibody molecule, known as the paratope. A single antigen can have two or more epitopes. Thus, different antibodies may bind to different regions on an antigen and have different biological effects. Epitopes can be either conformational or linear. Conformational epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are generated by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes can include carbohydrate, phosphoryl, or sulfonyl moieties on an antigen.

[0354] The terms "substantial identity" or "substantially identical" when referring to a nucleic acid or a fragment thereof indicates that when optimally aligned with another nucleic acid (or its complementary strand), with appropriate nucleotide insertions or deletions, there is nucleotide sequence identity of at least about 95%, or at least about 96%, 97%, 98%, or 99% of the nucleotide bases, as measured by any well-known sequence identity algorithm, such as FASTA, BLAST, or Gap, as discussed below.

[0355] When applied to polypeptides, the terms "substantial similarity" or "substantially similar" mean that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, or at least 98% or 99% sequence identity. In exemplary embodiments, non-identical residue positions differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is replaced by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Generally, conservative amino acid substitutions do not substantially alter the functional properties of a protein. When two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upward to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art (see, e.g., Pearson (1994) Methods Mol. Biol. 24:307-331, incorporated herein by reference). Examples of groups of amino acids with side chains of similar chemical properties include: (1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartic acid and glutamic acid; and (7) sulfur-containing side chains: cysteine ​​and methionine. Representative conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443 45, which is incorporated herein by reference. A "moderately conservative" substitution is any change that has a non-negative value in the PAM250 log-likelihood matrix.

[0356] Sequence similarity of polypeptides, also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions. For example, GCG software includes programs such as Gap and Bestfit, which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species or between a wild-type protein and its mutein (see, e.g., GCG version 6.1). Polypeptide sequences can also be compared using FASTA, a program in GCG version 6.1, using default or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of best overlap between the query and search sequences (Pearson (2000) supra). Another exemplary algorithm for comparing the sequences of the present disclosure to a database containing a large number of sequences from different organisms is the computer program BLAST, particularly BLASTP or TBLASTN, using default parameters (see, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402, each of which is incorporated herein by reference).

[0357] Preparation of human antibodies Methods for producing human antibodies in transgenic mice are known in the art. Any such known method can be used to produce human antibodies that specifically bind to human IL-4R.

[0358] Using VELOCIMMUNE® technology (see, e.g., U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for producing monoclonal antibodies, a high-affinity chimeric antibody against IL-4R having a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves the creation of a transgenic mouse whose genome comprises a human heavy chain variable region and a human light chain variable region operably linked to an endogenous mouse constant region locus, such that the mouse produces antibodies comprising the human variable region and the mouse constant region in response to antigenic challenge. DNA encoding the antibody heavy and light chain variable regions is isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing fully human antibodies.

[0359] Generally, VELOCIMMUNE® mice are challenged with an antigen of interest, and lymphoid cells (such as B cells) are harvested from the mice that express antibodies. Lymphoid cells can be fused with a myeloma cell line to prepare immortal hybridoma cell lines, which are then screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the heavy and light chain variable regions can be isolated and linked to the desired heavy and light chain isotype constant regions. Such antibody proteins can be produced in cells such as CHO cells. Alternatively, DNA encoding the antigen-specific chimeric antibody or the light and heavy chain variable domains can be isolated directly from antigen-specific lymphocytes.

[0360] First, high-affinity chimeric antibodies having human variable regions and mouse constant regions are isolated. The antibodies are characterized and selected for desired characteristics, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant regions are replaced with the desired human constant regions to generate the fully human antibodies described herein, such as wild-type or modified IgG1 or IgG4. The constant region selected can vary according to the particular application, but the characteristics of high-affinity antigen binding and target specificity reside in the variable regions.

[0361] Generally, antibodies that can be used in the methods have high affinity, as measured by binding to antigens immobilized on a solid phase or in solution, as described above. The mouse constant region is replaced with a desired human constant region to generate the fully human antibodies described herein. The constant region selected can vary depending on the specific application, but the characteristics of high affinity antigen binding and target specificity reside in the variable region.

[0362] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R that can be used in the context of the methods described herein comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 1. The antibody or antigen-binding fragment may comprise three light chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 2. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. Generally speaking, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989)). Public databases are also available for identifying CDR sequences within antibodies.

[0363] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from the heavy chain variable region amino acid sequence pair and light chain variable region amino acid sequence pair (HCVR / LCVR) of SEQ ID NOs: 1 and 2.

[0364] In certain embodiments, the antibody or antigen-binding fragment thereof comprises six CDRs (HCDR1 / HCDR2 / HCDR3 / LCDR1 / LCDR2 / LCDR3) having the amino acid sequences of SEQ ID NOs: 3 / 4 / 5 / 6 / 7 / 8.

[0365] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 and 2.

[0366] In a specific embodiment, the antibody is dupilumab, which comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 and 2.

[0367] In a specific embodiment, the antibody sequence is dupilumab comprising the heavy chain / light chain amino acid sequence pair of SEQ ID NOs: 9 and 10. Dupilumab HCVR amino acid sequence: [ka] Dupilumab LCVR amino acid sequence: [ka] Dupilumab HCDR1 amino acid sequence: GFTFRDYA (SEQ ID NO: 3) Dupilumab HCDR2 amino acid sequence: ISGSGGNT (SEQ ID NO: 4) Dupilumab HCDR3 amino acid sequence: AKDRLSITIRPRYYGL (SEQ ID NO: 5) Dupilumab LCDR1 amino acid sequence: QSLLYSIGYNY (SEQ ID NO: 6) Dupilumab LCDR2 amino acid sequence: LGS (SEQ ID NO: 7) Dupilumab LCDR3 amino acid sequence: MQALQTPYT (SEQ ID NO: 8) Dupilumab HC amino acid sequence: [ka] (amino acids 1-124 = HCVR; amino acids 125-451 = HC constant region) Dupilumab LC amino acid sequence: [ka] (amino acids 1-112 = LCVR; amino acids 112-219 = LC constant region)

[0368] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are SCB-VL-39 / SCB-VH-92; SCB-VL-40 / SCB-VH-92; SCB-VL-41 / SCB-VH-92; SCB-VL-42 / SCB-VH-92; SCB-VL-43 / SCB-VH-92; SCB-VL-44 / SCB-VH-92; SCB-VL-44 / SCB-VH-62; SCB-VL-44 / SCB-VH-68; SCB-VL-44 / SCB-VH-72; SCB-VL-44 / SCB-VH-82; SCB-VL-44 / SCB-VH-85; SCB-VL-44 / SCB-VH-91; SCB-VL-44 / SCB-VH-93; SCB-VL-4S / SCB-VH-92; SCB-VL-46 / SCB-VH-92; SCB-VL-47 / SCB-VH-92; SCB-VL-48 / SCB-VH-92; SCB-VL-49 / SCB-VH-92; SCB-VL-50 / SCB-VH-92; SCB-VL-51 / SCB-VH-92; SCB-VL-51 / SCB-VH-93; SCB-VL-52 / SCB-VH-92; SCB-VL-52 / SCB-VH-62; SCB-VL-52 / SCB-VH-91; SCB-VL-53 / SCB-VH-@2; SCB-VL-54 / SCB-VH-92; SCB-VL-54 / SCB-VH-62; SCB-VL-54 / SCB-VH-68; SCB-VL-54 / SCB-VH-72; SCB-VL-54 / SCB-VH-82; SCB-VL-54 / SCB-VH-85; SCB-VL-54 / SCB-VH-91; SCB-VL-55 / SCB-VH-92; SCB-VL-55 / SCB-VH-62; SCB-VL-55 / SCB-VH-6^; SCB-VL-55 / SCB-VH-72; SCB-VL-55 / SCB-VH-82; SCB-VL-55 / SCB-VH-85; SCB-VL-55 / SCB-VH-91; SCB-VL-56 / SCB-VH-92; SCB-VL-57 / SCB-VH-92; SCB-VL-57 / SCB-VH-93; SCB-VL-57 / SCB-VH-59; SCB-VL-57 / SCB-VH-60; SCB-VL-57 / SCB-VH-61; SCB-VL-57 / SCB-VH-62; SCB-VL-57 / SCB-VH-63; SCB-VL-57 / SCB-VH-64; It should be noted that there seems to be a typo in the original text where "SCB-VL-4S / SCB-VH-92" should probably be "SCB-VL-45 / SCB-VH-92", and "SCB-VL-53 / SCB-VH-@2" is likely incorrect. The above translation is based on the provided text with these potential errors.SCB-VL-57 / SCB-VH-65;SCB-VL-57 / SCB-VH-66;SCB-VL-57 / SCB-VH-67;SCB-VL-57 / SCB-VH-68;SC B-VL-57 / SCB-VH-69;SCB-VL-57 / SCB-VH-70;SCB-VL-57 / SCB-VH-71;SCB-VL-57 / SCB-VH-72;SCB- VL-57 / SCB-VH-73;SCB-VL-57 / SCB-VH-74;SCB-VL-57 / SCB-VH-75;SCB-VL-57 / SCB-VH-76;SCB-VL -57 / SCB-VH-77;SCB-VL-57 / SCB-VH-78;SCB-VL-57 / SCB-VH-79;SCB-VL-57 / SCB-VH-80;SCB-VL-5 7 / SCB-VH-81;SCB-VL-57 / SCB-VH-82;SCB-VL-57 / SCB-VH-83;SCB-VL-57 / SCB-VH-84;SCB-VL-57 / SCB-VH-85;SCB-VL-57 / SCB-VH-86;SCB-VL-57 / SCB-VH-87;SCB-VL-57 / SCB-VH-88;SCB-VL-57 / SC B-VH-89; SCB-VL-57 / SCB-VH-90; SCB-VL-57 / SCB-VH-91; SCB-VL-58 / SCB-VH-91; SCB-VL-58 / SCB-VH-92; and SCB-VL-58 / SCB-VH-93;

[0369] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises the LCVR / HCVR sequence pair of SCB-VL-44 / SCB-VH-92.

[0370] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises the LCVR / HCVR sequence pair of SCB-VL-54 / SCB-VH-92.

[0371] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises the LCVR / HCVR sequence pair of SCB-VL-55 / SCB-VH-92.

[0372] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises an HCVR comprising the HCDR1 sequence of SCB-92-HCDR1, the HCDR2 sequence of SCB-92-HCDR2, and the HCDR3 sequence of SCB-92-HCDR3, and an LCVR comprising the LCDR1 of SCB-55-LCDR1, the LCDR2 of SCB-55-LCDR2, and the LCDR3 of SCB-55-LCDR3.

[0373] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises an HCVR comprising the HCDR1 sequence of SCB-92-HCDR1, the HCDR2 sequence of SCB-92-HCDR2, and the HCDR3 sequence of SCB-92-HCDR3, and an LCVR comprising the LCDR1 of SCB-55-LCDR1, the LCDR2 of SCB-54-LCDR2, and the LCDR3 of SCB-55-LCDR3.

[0374] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises an HCVR comprising the HCDR1 sequence of SCB-92-HCDR1, the HCDR2 sequence of SCB-92-HCDR2, and the HCDR3 sequence of SCB-92-HCDR3, and an LCVR comprising the LCDR1 of SCB-55-LCDR1, the LCDR2 of SCB-54-LCDR2, and the LCDR3 of SCB-44-LCDR3.

[0375] The antibodies listed in Table 1 below are described in more detail in US Pat. No. 10,774,141, which is incorporated herein by reference in its entirety for all purposes.

[0376] [Table 1]

[0377] [Table 2]

[0378] [Table 3]

[0379] [Table 4]

[0380] [Table 5]

[0381] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises a light chain variable region (LCVR) and heavy chain variable region (HCVR) sequence pair (LCVR / HCVR) selected from the group consisting of MEDI-1-VL / MEDI-1-VH to MEDI-42-VL / MEDI-42-VH.

[0382] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises the LCVR / HCVR sequence pair MEDI-37GL-VL / MEDI-37GL-VH.

[0383] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises a HCVR comprising the HCDR1 sequence of MEDI-37GL-HCDR1, the HCDR2 sequence of MEDI-37GL-HCDR2, and the HCDR3 sequence of MEDI-37GL-HCDR3, and a LCVR comprising the LCDR1 of MEDI-37GL-LCDR1, the LCDR2 of MEDI-37GL-LCDR2, and the LCDR3 of MEDI-37GL-LCDR3.

[0384] The antibodies listed in Table 2 below are described in more detail in US Pat. No. 8,877,189, which is incorporated herein by reference in its entirety for all purposes.

[0385] [Table 6]

[0386] [Table 7]

[0387] [Table 8]

[0388] [Table 9]

[0389] [Table 10]

[0390] [Table 11]

[0391] [Table 12]

[0392] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises the LCVR / HCVR sequence pair of AJOU-90-VL / AJOU-83-VH.

[0393] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises a HCVR comprising the HCDR1 sequence of AJOU-84-HCDR1, the CHDR2 sequence of AJOU-85-HCDR2, and the HCDR3 sequence of AJOU-32-HCDR3, and a LCVR comprising the LCDR1 of AJOU-96-LCDR1, the LCDR2 of AJOU-60-LCDR2, and the LCDR3 of AJOU-68-LCDR3.

[0394] The antibodies set forth below in Table 3 are described in further detail in WO 2020 / 096381 and Kim et al. (Scientific Reports. 9:7772. 2019), which are incorporated by reference in their entireties for all purposes.

[0395] [Table 13]

[0396] [Table 14]

[0397] [Table 15]

[0398] [Table 16]

[0399] In certain embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises a light chain variable region (LCVR) and heavy chain variable region (HCVR) sequence pair (LCVR / HCVR) selected from the group consisting of 11 / 3, 27 / 19, 43 / 35, 59 / 51, 75 / 67, 91 / 83, 107 / 99, 123 / 115, 155 / 147, and 171 / 163.

[0400] The antibodies listed in Table 4 below are described in more detail in US Pat. Nos. 7,605,237 and 7,608,693, which are incorporated by reference in their entireties for all purposes.

[0401] [Table 17]

[0402] [Table 18]

[0403] [Table 19]

[0404] In a specific embodiment, the anti-IL-4Rα antibody is pembrolizumab. (i) HCVR consisting of the amino acid sequences STSA-C27-VH, STSA-C27-6-33-VH, STSA-C27-7-33-VH, STSA-C27-24-56-VH, STSA-C27-47-56-VH, STSA-C27-33-33-VH, STSA-C27-56-56-VH, STSA-C27-78-78-VH, STSA-C27-82-58-VH , STSA-C27-54-54-VH, STSA-C27-36-36-VH, STSA-C27-53-53-VH, STSA-C27-67-67-VH, STSA-C27-55- HCVR containing 55-VH, STSA-C27-59-59-VH, STSA-C27-58-58-VH, STSA-C27-52-52-VH, or STSA-C27-Y2-Y2-VH and (ii) LCVRs consisting of the amino acid sequences STSA-C27-VL, STSA-C27-6-33-VL, STSA-C27-7-33-VL, STSA-C27-24-56-VL, STSA-C27-47-56-VL, STSA-C27-33-33-VL, STSA-C27-56-56-VL, and STSA-C27-78-78-VL. 7-82-58-VL, STSA-C27-54-54-VL, STSA-C27-36-36-VL, STSA-C27-53-53-VL, STSA-C27-67-67-VL, STSA-C27-55-55-VL, STSA-C27-59-59-VL, STSA-C27-58-58-VL, TSA-C27-52-52-VL, or an LCVR comprising SEQ ID NO: 243.

[0405] The antibodies listed in Table 5 below are described in further detail in WO 2022 / 052974, which is incorporated by reference in its entirety for all purposes.

[0406] [Table 20]

[0407] [Table 21]

[0408] [Table 22]

[0409] [Table 23]

[0410] In certain embodiments, the antibodies or antigen-binding fragments thereof of the present disclosure are: Y0188-1 / Y0188-1; Y0188-2 / Y0188-2; Y0188-3 / Y0188-3; Y0188-4 / Y0188-4; Y0188-6 / Y0188-6; Y0188-8 / Y0188-8; Y0188-9 / Y0188-9; Y0188-10 / Y0188-10; Y0188-14 / Y0188-14; HV3-15-14 / Y01-14; HV3-15-14 / 164-14; HV3-15-14 / KV4-14; HV3-15-14 / KV1-27- 14;HV3-15-14 / KV1-9-14;HV3-15-14 / KV1-NL1-14;HV3-15-14 / KV1D-43-14;HV3-48-14 / Y01-14;HV3-48-14 / 164-14;HV3-48-14 / KV4-14;HV3-48-1 4 / KV1-27-14;HV3-48-14 / KV1-9-14;HV3-48-14 / KV1-NL1-14;HV3-48-14 / KV1D-43-14;HV3-73*2-14 / Y01-14;HV3-73*2-14 / 164-14;HV3-73*2-14 / K HV3-72-14 / 1 64-14;HV3-72-14 / KV4-14;HV3-72-14 / KV1-27-14;HV3-72-14 / KV1-9-14; HV3-72-14 / KV1-NL1-14;HV3-72-14 / KV1D-43-14;Y01-14 / Y01-14;Y01-14 / 164-14;Y01-14 / KV4-14;Y01-14 / KV1-27-14;Y01-14 / KV1-9-14;Y01-14 / KV1-NL1-14;Y01-14 / KV1D-43-14;162-14 / Y01-14;162-14 / 164-14;162- 14 / KV4-14;162-14 / KV1-27-14;162-14 / KV1-9-14;162-14 / KV1-NL1-14;1 62-14 / KV1D-43-1L;VH73-14 / Y01-14;VH73-14 / 164-14;VH73-14 / KV4-14;VH73-14 / KV1-27-14; VH73-14 / KV1-9-14; VH73-14 / KV1-NL1-14; VH73-14 / KV1D-43-14; comprising a heavy chain variable region (HCVR) and light chain variable region (LCVR) sequence pair (HCVR / LCVR) selected from the group consisting of: VH73-14 / KV1-27-14; VH73-14 / KV1-9-14; VH73-14 / KV1-NL1-14; VH73-14 / KV1D-43-14;

[0411] The antibodies listed in Table 6 below are described in more detail in WO 2021 / 213329, which is incorporated by reference in its entirety for all purposes.

[0412] [Table 24]

[0413] [Table 25]

[0414] [Table 26]

[0415] Pharmaceutical Composition Methods are provided that include administering to a patient an IL-4R antagonist, wherein the IL-4R antagonist is contained within a pharmaceutical composition. The pharmaceutical compositions described herein are formulated with suitable carriers, excipients, and other agents that provide suitable entry, delivery, tolerance, etc. Many suitable formulations can be found in formularies known to all medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsions of carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol. 52:238-311.

[0416] The dose of an antibody administered to a patient may vary depending on the patient's age and size, symptoms, condition, route of administration, etc. The dose is typically calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. The effective dose and schedule for administering a pharmaceutical composition containing an anti-IL-4R antibody can be determined empirically. For example, the patient's progress can be monitored by periodic evaluation, and the dose can be adjusted accordingly. Furthermore, interspecies scaling of dosages can be performed using methods well known in the art (see, for example, Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

[0417] Various delivery systems are known and can be used to administer the pharmaceutical compositions described herein, including, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The compositions can be administered by any convenient route, such as by infusion or bolus injection, or by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa), and can be administered together with other biologically active agents.

[0418] The pharmaceutical compositions described herein can be delivered subcutaneously or intravenously using a standard needle and syringe. Furthermore, for subcutaneous delivery, pen delivery devices (e.g., autoinjector pens) readily find use in delivering the pharmaceutical compositions described herein. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all of the pharmaceutical composition in the cartridge has been administered and the cartridge is emptied, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there is no replaceable cartridge. Rather, the disposable pen delivery device is pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0419] A number of reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of pharmaceutical compositions. Examples include the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), the HUMALOG MIX 75 / 25™ pen, the HUMALOG™ pen, the HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), the NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), the NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), the BD™ pen (Becton Dickinson, Franklin Lakes, NJ), the OPTIPEN™, the OPTIPEN PRO™, the OPTIPEN IV ... Examples of disposable pen delivery devices that have application in the subcutaneous delivery of the pharmaceutical compositions described herein include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and the HUMIRA™ Pen (Abbott Labs, Abbott Park, IL), to name just a few.Examples of large volume delivery devices (e.g., large volume injectors) include, but are not limited to, bolus injectors such as, for example, BD Libertas West SmartDose, Enable Injections, SteadyMed PatchPump, Sensile SenseTrial, YPsomed YpsoDose, and Bespak Lapas.

[0420] For direct administration to the paranasal sinuses, the pharmaceutical compositions described herein can be administered using, for example, a microcatheter (e.g., an endoscope and a microcatheter), an aerosolization device, a powder dispenser, a nebulizer, or an inhaler. This method includes administering an IL-4R antagonist in an aerosolized formulation to a subject in need thereof. For example, an aerosolized antibody against IL-4R can be administered to treat CSU in a patient. Aerosolized antibodies can be prepared, for example, as described in U.S. Pat. No. 8,178,098, the entire contents of which are incorporated herein by reference.

[0421] In certain circumstances, pharmaceutical compositions can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Press, Boca Raton, Florida. In yet another embodiment, a controlled release system can be placed near the target of the composition, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, supra, in Medical Applications of Controlled Release, vol. 2, pp. 115-138). For a review of other controlled release systems, see Langer, 1990, Science 249:1527-1533.

[0422] Injectable formulations include dosage forms for intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and infusion. These injectable formulations can be prepared by known methods. For example, injectable formulations can be prepared by dissolving, suspending, or emulsifying the antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injections. Aqueous injectable media include, for example, saline, isotonic solutions containing glucose and other adjuvants, and the like, which can be used in combination with appropriate solubilizers such as alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)). Oily media include, for example, sesame oil and soybean oil, which can be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. Injectable formulations prepared in this manner are typically filled into appropriate ampoules.

[0423] Preferably, the above-mentioned pharmaceutical compositions for oral or parenteral use are prepared in a dosage form suitable for a dosage of the active ingredient, such as tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0424] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used as described herein are disclosed, for example, in US Pat. No. 8,945,559.

[0425] Dosage The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) administered to a subject according to the methods described herein is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" refers to an amount of IL-4R antagonist that results in an improvement in one or more ColdU-related PRO indicators (as defined elsewhere herein). A "therapeutically effective amount" also includes an amount of IL-4R antagonist that inhibits, prevents, reduces, or delays the progression of ColdU in a subject.

[0426] In the case of an anti-IL-4R antibody, the therapeutically effective amount is about 0.05 mg to about 700 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 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 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 20 0mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, About 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410 mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about The amount of anti-IL-4R antibody may be 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg. In a specific embodiment, 200 to 300 mg of anti-IL-4R antibody is administered.

[0427] The amount of IL-4R antagonist contained in an individual dose may be expressed in milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-4R antagonist may be administered to a patient at a dose of about 0.0001 to about 10 mg / kg of the subject's body weight. For example, the IL-4R antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or 6 mg / kg.

[0428] In certain embodiments, the initial dose is about the same as the loading dose, hi certain embodiments, the initial dose is about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2.0 times, about 2.5 times, about 3.0 times or more the loading dose.

[0429] In certain embodiments, two or more (e.g., 2, 3, 4, or 5 or more) doses are administered at the beginning of a treatment regimen as an "initial dose" or "loading dose," followed by subsequent doses administered on a less frequent basis (e.g., "maintenance doses"). In one embodiment, the maintenance doses may be lower than the loading or initial doses. For example, one or more loading doses of 600 mg of an IL-4R antagonist may be administered, followed by maintenance doses of about 75 mg to about 300 mg. In certain embodiments, the method includes an initial or loading dose of about 400 mg or about 600 mg of an IL-4R antagonist. In certain embodiments, the method includes one or more secondary or maintenance doses of about 200 mg or about 300 mg of an IL-4R antagonist.

[0430] In certain exemplary embodiments, the subject is a pediatric subject weighing more than 30 kg and the IL-4R antagonist is administered at a dose of about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In certain exemplary embodiments, the subject is a pediatric subject weighing more than 30 kg and the IL-4R antagonist is administered at an initial dose of about 400 mg and one or more secondary doses of about 400 mg, the secondary doses being administered every other week (q2w). In certain exemplary embodiments, the subject is a pediatric subject weighing more than 30 kg and the IL-4R antagonist is administered at an initial dose of about 300 mg and one or more secondary doses of about 300 mg, the secondary doses being administered every other week (q2w). In certain exemplary embodiments, the subject is a pediatric subject weighing more than 30 kg and the IL-4R antagonist is administered at an initial dose of about 200 mg and one or more secondary doses of about 400 mg, with the secondary doses administered every other week (q2w). In particularly exemplary embodiments, the subject is a pediatric subject weighing more than 30 kg and the IL-4R antagonist is administered at an initial or loading dose of about 400 mg and one or more secondary or maintenance doses of about 200 mg, with the secondary doses administered every other week (q2w).

[0431] In certain exemplary embodiments, the subject is a pediatric subject weighing 30 kg or less and at least 15 kg, and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In certain exemplary embodiments, the subject is a pediatric subject weighing 30 kg or less and at least 15 kg, and the IL-4R antagonist is administered at an initial dose of about 600 mg and one or more secondary doses of about 600 mg, the secondary doses being administered every four weeks (q4w). In certain exemplary embodiments, the subject is a pediatric subject weighing 30 kg or less and at least 15 kg, and the IL-4R antagonist is administered at an initial dose of about 500 mg and one or more secondary doses of about 500 mg, with the secondary doses administered every four weeks (q4w). In certain exemplary embodiments, the subject is a pediatric subject weighing 30 kg or less and at least 15 kg, and the IL-4R antagonist is administered at an initial dose of about 400 mg and one or more secondary doses of about 400 mg, with the secondary doses administered every four weeks (q4w). In certain exemplary embodiments, the subject is a pediatric subject weighing 30 kg or less and at least 15 kg, and the IL-4R antagonist is administered at an initial dose of about 300 mg and one or more secondary doses of about 300 mg, with the secondary doses administered every four weeks (q4w). In a particularly exemplary embodiment, the subject is a pediatric subject weighing 30 kg or less and at least 15 kg, and the IL-4R antagonist is administered at an initial dose of about 600 mg and one or more secondary or maintenance doses of about 300 mg, with the secondary doses administered every four weeks (q4w).

[0432] In certain exemplary embodiments, the subject is a pediatric subject weighing less than 15 kg and at least 5 kg, and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In certain exemplary embodiments, the subject is a pediatric subject weighing less than 15 kg and at least 5 kg, and the IL-4R antagonist is administered at an initial dose of about 300 mg and one or more secondary doses of about 300 mg, the secondary doses being administered every four weeks (q4w). In certain exemplary embodiments, the subject is a pediatric subject weighing less than 15 kg but at least 5 kg, and the IL-4R antagonist is administered at an initial dose of about 250 mg and one or more secondary doses of about 250 mg, administered every four weeks (q4w). In particularly exemplary embodiments, the subject is a pediatric subject weighing less than 15 kg but at least 5 kg, and the IL-4R antagonist is administered at an initial dose of about 200 mg and one or more secondary doses of about 200 mg, administered every four weeks (q4w).

[0433] In certain exemplary embodiments, the subject is an adolescent subject weighing less than 60 kg and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In some exemplary embodiments, the subject is an adolescent subject weighing less than 60 kg and the IL-4R antagonist is administered at an initial dose of about 400 mg and one or more secondary or maintenance doses of about 200 mg, where the secondary doses are administered every other week (q2w). In certain exemplary embodiments, the subject is an adolescent subject weighing at least 30 kg but less than 60 kg, and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In some exemplary embodiments, the subject is an adolescent subject weighing at least 30 kg but less than 60 kg, and the IL-4R antagonist is administered at an initial dose of about 400 mg and one or more secondary or maintenance doses of about 200 mg, where the secondary doses are administered every other week (q2w).

[0434] In certain exemplary embodiments, the subject is an adolescent subject weighing at least 60 kg, and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In particularly exemplary embodiments, the subject is an adolescent subject weighing at least 60 kg, and the IL-4R antagonist is administered at an initial dose of about 600 mg and one or more secondary or maintenance doses of about 300 mg, where the secondary doses are administered every other week (q2w).

[0435] In certain exemplary embodiments, the subject is an adult and the IL-4R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In particularly exemplary embodiments, the subject is an adult and the IL-4R antagonist is administered at an initial dose of about 600 mg and one or more secondary or maintenance doses of about 300 mg, with the secondary doses administered every other week (q2w).

[0436] In certain exemplary embodiments, the IL-4R antagonist is administered at a concentration of 150 mg / mL using a prefilled device. In some embodiments, a 150 mg / mL solution of the IL-4R antagonist in a prefilled device is used to deliver 300 mg of the IL-4R antagonist in a 2 mL injection. In certain exemplary embodiments, the IL-4R antagonist is administered at a concentration of 175 mg / mL using a prefilled device. In some embodiments, a 175 mg / mL solution of the IL-4R antagonist in a prefilled device is used to deliver 200 mg of the IL-4R antagonist in a 1.14 mL injection.

[0437] Combination therapy Certain embodiments of the methods described herein include administering to a subject one or more therapeutic agents in combination with an IL-4R antagonist. As used herein, the term "in combination with" means that the additional therapeutic agent is administered before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. In some embodiments, the term "in combination with" includes sequential or simultaneous administration of an IL-4R antagonist and a second therapeutic agent. Methods for treating ColdU or related conditions or complications are provided, comprising administering an IL-4R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[0438] For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent can be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition comprising an IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition comprising an IL-4R antagonist. "Concurrent administration" with a pharmaceutical composition comprising an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes of (before, after, or simultaneously with) administration of the pharmaceutical composition comprising the IL-4R antagonist, or is administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the IL-4R antagonist.

[0439] In exemplary embodiments, the additional therapeutic agent administered in combination with the IL-4R antagonist is background therapy. In exemplary embodiments, the background therapy includes one or both of an antihistamine and an anti-IgE antibody. In certain embodiments, the method results in a reduced need for background therapy. For example, in certain embodiments, the method results in a reduced dose and / or frequency of background therapy.

[0440] The additional therapeutic agent may be, for example, another IL-4R antagonist (e.g., one or more suitable IL-4R antagonists listed in Tables 1-4), an IgE antagonist, an antihistamine, an IL-1 antagonist (including, for example, the IL-1 antagonists described in U.S. Pat. No. 6,927,044), an IL-5 antagonist, an IL-5R antagonist, an IL-6 antagonist, an IL-6R antagonist (including, for example, anti-IL-6R antibodies such as those set forth in U.S. Pat. No. 7,582,298), or an IL-17 antagonist.

[0441] In exemplary embodiments, the additional therapeutic agent is an H1 antihistamine, hi some embodiments, the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

[0442] In further exemplary embodiments, the additional therapeutic agent is an anti-IgE antibody. In some embodiments, the anti-IgE antibody is omalizumab. In some embodiments, the anti-IgE antibody is ligelizumab.

[0443] In some embodiments, the additional therapeutic agent administered in combination with the IL-4R antagonist is a vaccine. In certain exemplary embodiments, the vaccine is a viral vaccine or a bacterial vaccine. In certain exemplary embodiments, the vaccine is a live viral vaccine (e.g., a live attenuated vaccine) or a live attenuated bacterial vaccine (e.g., a live attenuated vaccine).

[0444] Suitable vaccines include, but are not limited to, adenovirus, anthrax (e.g., AVA vaccine (BioThrax)), cholera (e.g., Vaxchora), diphtheria (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), hepatitis B (HepB (Engerix-B, Recombivax)), HB, Heplisav-B), DTaP-HepB-IPV (Pediarix), HepA-HepB (Twinrix)), Haemophilus influenzae type b (Hib) (e.g., Hib (ActHIB, PedvaxHIB, Hiberix), DTaP-IPV / Hib (Pentacel)), human papillomavirus (HPV) (e.g., HPV9 (Gardasil 9)), influenza (flu) (e.g., IIV (also known as IIV3, IIV4, RIV3, RIV4, ccIIV4) (Afluria, Fluad, Flublok, Flucelvax, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone High-Dose, Fluzone Intradermal), LAIV (FluMist)), Japanese encephalitis (e.g., JE (Ixiaro)), measles (MMR) II), MMRV (ProQuad), etc.), meningococcal (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (MMR (MMRII), MMRV (ProQuad), etc.), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), pneumococcal (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax23)), polio (e.g., Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), rabies (e.g., Rabies (Imovax) Rabies, RabAvert), rotavirus (RV1 (Rotarix), RV5 (RotaTeq), etc.), rubella (e.g., MMR (MM-RII), MMRV (ProQuad)), shingles (ZVL (Zostavax), RZV (Shingrix), etc.), smallpox (Vaccinia (ACAM2000), etc.), tetanus, etc., DTaP (Daptacel, Vaccines include, but are not limited to, Infanrix, Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), tuberculosis, typhoid (e.g., Typhoid oral preparation (Vivotif), Typhi polysaccharide (Typhim Vi)), chickenpox (VAR (Varivax), MMRV (ProQuad), etc.), and yellow fever (YF (YF-Vax), etc.). Suitable vaccines are also listed on the US Centers for Disease Control's Vaccine List (cdc.gov / vaccines / vpd / vaccines-list.html), which is incorporated herein in its entirety for all purposes. In some embodiments, the vaccine is a tetanus, diphtheria, pertussis and / or seasonal trivalent / quadrivalent influenza vaccine.

[0445] In some embodiments, the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugate vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine. In some embodiments, the vaccine is a yellow fever vaccine. In some embodiments, a subject treated with the vaccine is simultaneously treated for CSU with an IL-4R antagonist.

[0446] In certain embodiments, treatment with the IL-4R antagonist is interrupted or terminated prior to treatment with the vaccine, hi certain embodiments, treatment with the IL-4R antagonist is interrupted about 1 to about 9 weeks (e.g., about 1, about 1 1 / 2, about 2, about 2 1 / 2, about 3, about 3 1 / 2, about 4, about 4 1 / 2, about 5, about 5 1 / 2, about 6, about 6 1 / 2, about 7, about 7 1 / 2, about 8, about 8 1 / 2, about 9 weeks or more) prior to administration of the vaccine. In some embodiments, treatment with the IL-4R antagonist is initiated about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days after administration of the vaccine. , about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days, or about 60 days before the end of the treatment period.

[0447] In certain embodiments, treatment with the IL-4R antagonist is resumed after treatment with the vaccine. In certain embodiments, treatment with the IL-4R antagonist is resumed about 1 week to about 14 weeks (e.g., about 1 week, about 1 1 / 2 weeks, about 2 weeks, about 2 1 / 2 weeks, about 3 weeks, about 3 1 / 2 weeks, about 4 weeks, about 4 1 / 2 weeks, about 5 weeks, about 5 1 / 2 weeks, about 6 weeks, about 6 1 / 2 weeks, about 7 weeks, about 7 1 / 2 weeks, about 8 weeks, about 8 1 / 2 weeks, about 9 weeks, about 9 1 / 2 weeks, about 10 weeks, about 11 weeks, about 11 1 / 2 weeks, about 12 weeks, about 12 1 / 2 weeks, about 13 weeks, about 13 1 / 2 weeks, about 14 weeks, about 14 1 / 2 weeks, or more) after administration of the vaccine. In some embodiments, treatment with the IL-4R antagonist is continued for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, or about 44 days after administration of the vaccine. , about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days, about 60 days, about 61 days, about 62 days, about 63 days, about 64 days, about 65 days, about 66 days, about 67 days, about 68 days, about 69 days, about 70 days, about 71 days, about 72 days, about 73 days, about 74 days, about 75 days, about 76 days, about 77 days, about 78 days, about 79 days, about 80 days, about 81 days, about 82 days, about 83 days, about 84 days, about 85 days, about 86 days, about 87 days, about 88 days, about 89 days, or about 90 days later.

[0448] In certain embodiments, the effectiveness of the IL-4R antagonist is not diminished by co-administration with or subsequent administration of a vaccine.

[0449] In some embodiments, the efficacy of the vaccine is not diminished by co-administration with, or prior and / or subsequent administration of, an IL-4R antagonist, hi some embodiments, subjects produce protective serum neutralizing titers to the vaccine when the vaccine is co-administered with an IL-4R antagonist.

[0450] In certain exemplary embodiments, a subject is administered a vaccine described herein, and before, during, or after administration of the vaccine, the subject is administered at least one dose of an IL-4R antagonist.

[0451] Dosing regimen According to certain embodiments, multiple doses of an IL-4R antagonist may be administered to a subject over a defined time course. Such methods include sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, "sequentially administering" means that each dose of an IL-4R antagonist is administered to a subject at a different time, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). Methods are provided that include sequentially administering a single initial dose of an IL-4R antagonist to a patient, 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.

[0452] Provided are methods that include administering to a subject a pharmaceutical composition comprising an IL-4R antagonist at a dosing frequency of about 4 times per week, twice per week, once per week (q1w), once per two weeks (every other week is used interchangeably with every other week, bi-weekly, or q2w), once per three weeks (3w or q3w), once per four weeks (monthly or q4w), once per five weeks (q5w), once per six weeks (q6w), once per seven weeks (q7w), once per eight weeks (q8w), once per nine weeks (q9w), once per ten weeks (q10w), once per eleven weeks (q11w), once per twelve weeks (q12w), or as less frequently as a therapeutic response is achieved.

[0453] In certain embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, weekly dosing in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, biweekly dosing (every two weeks is used interchangeably with every other week, bi-weekly, or q2w) in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, once every three weeks in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, dosing once every four weeks (monthly dosing) in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, dosing once every five weeks in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-4R antibody, dosing once every six weeks in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg can be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, the antibody may be administered in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg once every eight weeks. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, the antibody may be administered in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg once every twelve weeks. In certain exemplary embodiments, the route of administration is subcutaneous.

[0454] The term "week" or "weeks" refers to a period of (n x 7 days) ± 3 days, e.g., (n x 7 days) ± 2 days, (n x 7 days) ± 1 day, or (n x 7 days), where "n" indicates the number of weeks, e.g., 1, 2, 3, 4, 5, 6, 8, 12 or more.

[0455] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the temporal order of administration of an IL-4R antagonist. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also called a "baseline dose" or "loading dose"). A "secondary dose" is a dose administered after the initial dose, and a "tertiary dose" is a dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist or may differ from one another in terms of administration frequency. However, in certain embodiments, the amount of IL-4R antagonist included in the initial, secondary, and / or tertiary doses differ from one another (e.g., adjusted up or down as needed) over the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered as "loading doses" at the beginning of a treatment regimen, followed by subsequent doses (e.g., "maintenance doses") administered at a less frequent frequency. In one embodiment, the maintenance doses may be lower than the loading doses. For example, one or more initial or loading doses of 600 mg or 400 mg of the IL-4R antagonist may be administered, followed by secondary or maintenance doses of about 75 mg to about 400 mg. In one embodiment, the secondary / maintenance doses may be equal to the initial / loading dose. For example, one or more initial / loading doses of 300 mg or 200 mg of the IL-4R antagonist may be administered, followed by secondary / maintenance doses of about 300 mg or about 200 mg, respectively. In one embodiment, the loading dose may be split, e.g., two or more doses administered at different times, e.g., two loading doses, with the second loading dose administered two weeks after the first.

[0456] In certain embodiments, the initial dose is about 50 mg to about 600 mg of the IL-4R antagonist. In one embodiment, the initial dose is 600 mg of the IL-4R antagonist. In another embodiment, the initial dose is 400 mg of the IL-4R antagonist.

[0457] In certain embodiments, the secondary dose is about 50 mg to about 600 mg of the IL-4R antagonist. In one embodiment, the maintenance dose is 300 mg of the IL-4R antagonist. In one embodiment, the maintenance dose is 200 mg of the IL-4R antagonist.

[0458] In certain embodiments, the initial dose is three times the maintenance dose. In certain embodiments, the initial dose is twice the maintenance dose. In certain embodiments, the initial dose is equal to the maintenance dose.

[0459] In some embodiments, the subject is a child, weighs less than 15 kg but at least 5 kg, and the initial dose consists of 200 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every four weeks (q4w).

[0460] In some embodiments, the subject is a child, weighs less than or equal to 30 kg, but at least 15 kg, and the initial dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks (q4w).

[0461] In some embodiments, the subject is a child, weighs 30 kg or less but at least 15 kg, and the initial dose comprises 300 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every four weeks (q4w).

[0462] In some embodiments, the subject is a child weighing more than 30 kg, and the initial dose consists of 400 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses of 200 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with bi-weekly or q2w).

[0463] In some embodiments, the subject is an adolescent weighing less than 60 kg, and the initial dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses of 200 mg of the antibody or antigen-binding fragment thereof are administered every other week (every other week is used interchangeably with bi-weekly or q2w). In an exemplary embodiment, the subject is an adolescent weighing at least 30 kg but less than 60 kg, and the initial dose comprises 400 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses of 200 mg of the antibody or antigen-binding fragment thereof are administered every other week (every other week is used interchangeably with bi-weekly or q2w).

[0464] In some embodiments, the subject is an adolescent and weighs more than 60 kg, and the initial dose consists of 600 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses of 300 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every 2 weeks, bi-weekly, or q2w).

[0465] In some embodiments, the subject is an adult and the initial dose comprises 600 mg of the antibody or antigen-binding fragment thereof, and one or more secondary doses comprise 300 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every other week, bi-weekly, or q2w).

[0466] In an exemplary embodiment, each secondary and / or tertiary dose is administered 1 to 14 weeks after the immediately preceding administration (e.g., 1 week, 1 1 / 2 weeks, 2 weeks, 2 1 / 2 weeks, 3 weeks, 3 1 / 2 weeks, 4 weeks, 4 1 / 2 weeks, 5 weeks, 5 1 / 2 weeks, 6 weeks, 6 1 / 2 weeks, 7 weeks, 7 1 / 2 weeks, 8 weeks, 8 1 / 2 weeks, 9 weeks, 9 1 / 2 weeks, 10 weeks, 10 1 / 2 weeks, 11 weeks, 11 1 / 2 weeks, 12 weeks, 12 1 / 2 weeks, 13 weeks, 13 1 / 2 weeks, 14 weeks, 14 1 / 2 weeks, or more). The phrase "the immediately preceding dose" refers to the dose of an IL-4R antagonist administered to a patient prior to the administration of the very next dose in a multiple administration series, without any intervening doses.

[0467] The method can include administering any number of secondary and / or tertiary doses of an IL-4R antagonist to the patient. 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 to the patient.

[0468] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to the patient may vary over the course of the treatment regimen. The administration frequency may also be adjusted by a physician during the course of treatment based on clinical testing and the needs of the individual patient.

[0469] Methods are provided for treating Cold U (e.g., CIndU) or a related condition, comprising sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient. In some embodiments, the methods comprise administering one or more doses of an IL-4R antagonist, followed by administration of one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of a second therapeutic agent. For example, an IL-4R antagonist may be administered one or more times at a dose of about 75 mg to about 600 mg, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of a second therapeutic agent (e.g., an H1 antihistamine or an anti-IgE antibody as described elsewhere herein) to treat, alleviate, reduce, or ameliorate one or more symptoms of Cold U. In some embodiments, an IL-4R antagonist is administered in one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) to result in improvement of one or more ColdU-related parameters, followed by administration of a second therapeutic agent to prevent the recurrence of at least one symptom of ColdU. An alternative embodiment relates to simultaneous administration of an IL-4R antagonist and a second therapeutic agent. For example, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of an IL-4R antagonist are administered, and the second therapeutic agent is administered in a separate dosage at a similar or different frequency than the IL-4R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-4R antagonist.

[0470] In certain embodiments, the IL-4R antagonist is administered every other week for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 weeks or more. In other embodiments, the IL-4R antagonist is administered every four weeks for 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 weeks or more. In certain embodiments, the IL-4R antagonist is administered for at least 24 weeks.

[0471] In certain embodiments, a kit is provided comprising a dosage form of an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively, for the treatment of ColdU. In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO: 2. In certain embodiments, the antibody is dupilumab.

[0472] The kit can include a label or package insert, which includes instructions for administering the dosage form for treatment of ColdU. The instructions can recite a dosing regimen, as further described herein, for treatment of ColdU.

[0473] Treatment population The methods provided herein include administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof, where "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms or signs of or has been diagnosed with Cold U.

[0474] In certain exemplary embodiments, a subject in need thereof has a diagnosis of primary acquired ColdU, defined as recurrent cold-induced itchy wheals and / or angioedema for more than six weeks.

[0475] In certain exemplary embodiments, a subject in need thereof has a positive ice cube provocation test, ie, exhibits at least a confluent rash / wheal on exposed skin areas.

[0476] In a related embodiment, a "subject in need thereof" may be a subject who has been prescribed or is currently taking an antihistamine prior to administration of the IL-4R antagonist. In certain embodiments, the subject is currently taking an H1 antihistamine.

[0477] In certain exemplary embodiments, a subject in need thereof meets at least one of the following criteria despite the use of an H1 antihistamine: Urticaria Control Test (UCT) (4 items) <12; documented history of cold exposure that induced anaphylaxis or oropharyngeal edema; documented history of cold exposure that induced urticaria that required emergency department visit or treatment with epinephrine.

[0478] Suitable H1 antihistamines include, but are not limited to, fexofenadine, cetirizine, terfenadine, bilastine, chlorpheniramine, diphenhydramine, carbinoxamine, promatadine, desloratadine, dexchlorpheniramine, hydroxyzine, loratadine, levocetirizine, clemastine, ebastine, dexbrompheniramine, triprolidine, brompheniramine, trimeprazine, cyproheptadine, azelastine, cyproheptadine, emedastine, levocabastine, cinnarizine, rupatadine, and the like. In certain embodiments, a suitable antihistamine is selected from cinnarizine, rupatadine, bilastine, desloratadine, and ebastine. In another specific embodiment, a suitable antihistamine is selected from rupatadine, bilastine, desloratadine, and ebastine. In yet another embodiment, the suitable antihistamine is selected from loratadine, cetirizine, and desloratadine. For example, methods are provided that comprise administering an IL-4R antagonist to a patient who has been taking an H1 antihistamine regularly for at least six weeks immediately prior to administering the IL-4R antagonist (such prior treatment is referred to herein as "background treatment").

[0479] In yet another embodiment, the amount of H1 antihistamine is gradually tapered before or after administration of the IL-4R antagonist begins.

[0480] In another exemplary embodiment, the "subject in need thereof" has been diagnosed with H1 antihistamine-resistant Cold U prior to receiving the IL-4R antagonist. In some embodiments, the subject's Cold U symptoms persist despite treatment with an H1 antihistamine (i.e., the subject is refractory to treatment with an H1 antihistamine).

[0481] In some embodiments, the "subject in need thereof" is selected from the group consisting of subjects 18 years of age or older, subjects 12 years of age or older, subjects 12-17 years of age (under 12-18 years of age), subjects 6-11 years of age (under 6-12 years of age), subjects 2-11 years of age (under 2-12 years of age), and subjects 2-5 years of age (under 2-6 years of age). In some embodiments, the "subject in need thereof" is selected from the group consisting of adults, adolescents, and children. In some embodiments, the "subject in need thereof" is selected from the group consisting of adults 18 years of age or older, adolescents 12-17 years of age (under 12-18 years of age), children 6-11 years of age (under 6-12 years of age), and children 2-5 years of age (under 2-6 years of age). The subject can be under 2 years of age, e.g., 12-23 months of age, or 6-11 months of age. In particularly exemplary embodiments, the subject is a child 6-12 years of age (also referred to herein as a "child" subject). In certain embodiments, the subject in need thereof is a child between 6 and 12 years of age weighing more than 30 kg. In certain embodiments, the subject in need thereof is a child between 6 and 12 years of age weighing 30 kg or less, but at least 15 kg. In certain embodiments, the subject in need thereof is an adolescent between 12 and 18 years of age weighing at least 60 kg. In exemplary embodiments, the subject in need thereof is an adolescent between 12 and 18 years of age weighing less than 60 kg. In other exemplary embodiments, the subject in need thereof is an adolescent between 12 and 18 years of age weighing 30 kg or more but less than 60 kg.

[0482] In some embodiments, a "subject in need thereof" is a subject to be treated with a vaccine, e.g., a viral vaccine or a bacterial vaccine. In some embodiments, the vaccine is a live vaccine, e.g., a live viral vaccine (e.g., a live attenuated vaccine) or a live attenuated bacterial vaccine (e.g., a live attenuated vaccine).

[0483] Suitable vaccines include, but are not limited to, adenovirus, anthrax (e.g., AVA vaccine (BioThrax)), cholera (e.g., Vaxchora), diphtheria (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), hepatitis B (HepB (Engerix-B, Recombivax)), HB, Heplisav-B), DTaP-HepB-IPV (Pediarix), HepA-HepB (Twinrix)), Haemophilus influenzae type b (Hib) (e.g., Hib (ActHIB, PedvaxHIB, Hiberix), DTaP-IPV / Hib (Pentacel)), human papillomavirus (HPV) (e.g., HPV9 (Gardasil 9)), influenza (flu) (e.g., IIV (also known as IIV3, IIV4, RIV3, RIV4, ccIIV4) (Afluria, Fluad, Flublok, Flucelvax, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone High-Dose, Fluzone Intradermal), LAIV (FluMist)), Japanese encephalitis (e.g., JE (Ixiaro)), measles (MMR) II), MMRV (ProQuad), etc.), meningococcus (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (MMR (MMRII), MMRV (ProQuad), etc.), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), pneumococcal (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax23)), polio (e.g., Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), rabies (e.g., Rabies (Imovax) Rabies, RabAvert), rotavirus (RV1 (Rotarix), RV5 (RotaTeq), etc.), rubella (e.g., MMR (MM-RII), MMRV (ProQuad)), shingles (ZVL (Zostavax), RZV (Shingrix), etc.), smallpox (Vaccinia (ACAM2000), etc.), tetanus, etc., DTaP (Daptacel, Vaccines include, but are not limited to, Infanrix, Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), tuberculosis, typhoid (e.g., Typhoid oral preparation (Vivotif), Typhi polysaccharide (Typhim Vi)), chickenpox (VAR (Varivax), MMRV (ProQuad), etc.), and yellow fever (YF (YF-Vax), etc.). Suitable vaccines are also listed on the US Centers for Disease Control's Vaccine List (cdc.gov / vaccines / vpd / vaccines-list.html), which is incorporated herein in its entirety for all purposes.

[0484] In some embodiments, the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugate vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine. In some embodiments, the vaccine is a yellow fever vaccine. In some embodiments, a subject treated with the vaccine is simultaneously treated with CSU with an IL-4R antagonist. In some embodiments, the subject discontinues treatment with the IL-4R antagonist before administering the vaccine.

[0485] In certain embodiments, the subject discontinues treatment with the IL-4R antagonist about 1 to about 9 weeks (e.g., about 1, about 1 1 / 2, about 2, about 2 1 / 2, about 3, about 3 1 / 2, about 4, about 4 1 / 2, about 5, about 5 1 / 2, about 6, about 6 1 / 2, about 7, about 7 1 / 2, about 8, about 8 1 / 2, about 9 weeks, or more) prior to administration of the vaccine. In certain embodiments, the subject is administered the vaccine at about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about Treatment with the IL-4R antagonist is discontinued 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days, or about 60 days prior to the end of the treatment period.

[0486] In certain embodiments, the subject resumes treatment with the IL-4R antagonist after treatment with the vaccine. In certain embodiments, the subject resumes treatment with the IL-4R antagonist about 1 week to about 14 weeks (e.g., about 1 week, about 1 1 / 2 weeks, about 2 weeks, about 2 1 / 2 weeks, about 3 weeks, about 3 1 / 2 weeks, about 4 weeks, about 4 1 / 2 weeks, about 5 weeks, about 5 1 / 2 weeks, about 6 weeks, about 6 1 / 2 weeks, about 7 weeks, about 7 1 / 2 weeks, about 8 weeks, about 8 1 / 2 weeks, about 9 weeks, about 9 1 / 2 weeks, about 10 weeks, about 11 weeks, about 11 1 / 2 weeks, about 12 weeks, about 12 1 / 2 weeks, about 13 weeks, about 13 1 / 2 weeks, about 14 weeks, about 14 1 / 2 weeks, or more) after administration of the vaccine. In certain embodiments, the subject is administered the vaccine at about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about After 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days, about 60 days, about 61 days, about 62 days, about 63 days, about 64 days, about 65 days, about 66 days, about 67 days, about 68 days, about 69 days, about 70 days, about 71 days, about 72 days, about 73 days, about 74 days, about 75 days, about 76 days, about 77 days, about 78 days, about 79 days, about 80 days, about 81 days, about 82 days, about 83 days, about 84 days, about 85 days, about 86 days, about 87 days, about 88 days, about 89 days, or about 90 days, treatment with the IL-4R antagonist is resumed.

[0487] Evaluation methods for pharmacodynamic ColdU-related parameters A method for assessing one or more pharmacodynamic Cold U-related parameters in a subject in need thereof, induced by administration of a pharmaceutical composition comprising an IL-4R antagonist, is provided. A reduction in the incidence of Cold U symptoms or an improvement in a Cold U-related PRO measurement may be correlated with an improvement in one or more pharmacodynamic Cold U-related parameters. However, such a correlation may not be observed in all cases.

[0488] Examples of "pharmacodynamic ColdU-related parameters" include, for example, (a) biomarker expression levels, and (b) serum protein and RNA analysis. "Improvement of a pharmacodynamic ColdU-related parameter" refers to a decrease from baseline in one or more biomarkers, such as, for example, IgE, eosinophil levels, c-reactive protein (CRP), IL-6, D-dimer, medium platelet volume (MPV), IL-17, IL-18, IL-31, IL-33, and metalloproteinase-9. As used herein, the term "baseline" with respect to a pharmacodynamic ColdU-related parameter refers to the value of the pharmacodynamic ColdU-related parameter in a patient before or at the time of administration of a pharmaceutical composition described herein.

[0489] To assess the pharmacodynamic ColdU-related parameters, the parameters are quantified at baseline and at time points after administration of the pharmaceutical composition. For example, the pharmacodynamic ColdU-related parameters may be measured at about day 1, about day 2, about day 3, about day 4, about day 5, about day 6, about day 7, about day 8, about day 9, about day 10, about day 11, about day 12, about day 14, or at about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 11, about week 12, about week 13, about week 14, about week 15, about week 16, about week 17, about week 18, about week 19, about week 20, about week 21, about week 22, about week 23, about week 24, or more after initial treatment with the pharmaceutical composition. The difference between the value of a parameter at a specific time point after initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" or other change in the pharmacodynamic ColdU-related parameter (e.g., an increase or decrease, as the case may be, depending on the specific parameter being measured).

[0490] In certain embodiments, administration of an IL-4R antagonist to a patient causes a change, e.g., a decrease or increase, in the expression of certain biomarkers. ColdU-associated biomarkers include, but are not limited to, total IgE, c-reactive protein (CRP), IL-6, D-dimer, medium platelet volume (MPV), IL-17, IL-18, IL-31, IL-33, and metalloproteinase-9. For example, administration of an IL-4R antagonist to a ColdU patient can cause a decrease in total serum IgE levels. Such a decrease can be detected about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or more after administration of the IL-4R antagonist. Biomarker expression can be assayed by methods known in the art. For example, protein levels can be measured by enzyme-linked immunosorbent assay (ELISA). RNA levels can be measured, for example, by reverse transcription coupled to the polymerase chain reaction (RT-PCR).

[0491] As described above, biomarker expression can be assayed by detecting protein or RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers associated with response to treatment with an IL-4R antagonist or IL-4 / IL-13 signaling (e.g., by measuring soluble IL-4Rα, IL-4, IL-13, etc.). In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), e.g., RNA levels of biomarkers; in other aspects, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0492] formulation In some embodiments, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 150 mg / mL of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, ii) about 20 mM histidine, iii) about 12.5 mM acetate, iv) about 5% (w / v) sucrose, v) about 25 mM arginine hydrochloride, vi) about 0.2% (w / v) polysorbate 80, wherein the pH of the formulation is about 5.9 and the viscosity of the formulation is about 8.5 cpoise.

[0493] In an alternative embodiment, the antibody or antigen-binding fragment thereof is formulated in a composition comprising: i) about 175 mg / mL of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, ii) about 20 mM histidine, iii) about 12.5 mM acetate, iv) about 5% (w / v) sucrose, v) about 50 mM arginine hydrochloride, and vi) about 0.2% (w / v) polysorbate 80, wherein the pH of the formulation is about 5.9 and the viscosity of the formulation is about 8.5 cpoise.

[0494] In a specific embodiment, the antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:2.

[0495] In a specific embodiment, the antibody comprises dupilumab. Unless otherwise specified, the term "dupilumab" also includes any biosimilars thereof.

[0496] Suitable stabilizing formulations are also described in US Pat. No. 8,945,559, which is incorporated herein by reference in its entirety for all purposes.

[0497] The present disclosure is further illustrated by the following examples, which should not be construed as further limiting. The contents of all figures, tables, and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference for all purposes.

[0498] Furthermore, in accordance with the present disclosure there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art, such techniques being fully explained in the literature. For example, Green & Sambrook, Molecular Cloning: A Laboratory Manual, Fourth Edition (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; DNA Cloning: A Practical Approach, Volumes I and II (DN Glover ed.1985); Oligonucleotide Synthesis (MJ Gait ed.1984); Nucleic Acid Hybridization [BD Hames & S. J. Higgins eds. (1985)];Transcription And Translation[BD Hames&S.J. Higgins, eds.(1984)];Animal Cell Culture[RI Freshney, ed.(1986)];Immobilized Cells And Enzymes[IRL Press,(1986)];B.Perbal,A Practical Guide To Molecular Cloning(1984);FM Ausubel et al. (eds.), Current Protocols in Molecular Biology, John See Wiley & Sons, Inc. (1994).

[0499] The contents of articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein are incorporated by reference herein in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. Applicant reserves the right to physically incorporate into this application any and all materials and information from such articles, patents, patent applications, or other physical and electronic documents.

[0500] While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents substituted without departing from the true spirit and scope of the invention. It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods described herein, using appropriate equivalents, may be made without departing from the scope of the embodiments disclosed herein. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims. Having now described specific embodiments in detail, this will be more clearly understood by reference to the following examples, which are included for purposes of illustration only and are not intended to be limiting. [Example]

[0501] The following examples are put forth to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions featured in this disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure. While attempts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), some experimental error and deviation should be accounted for. Unless otherwise specified, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric.

[0502] The exemplary IL-4R antagonist used in each of the following examples is a human anti-IL-4R antibody called dupilumab (also referred to herein as "mAb1" or DUPIXENT®).

[0503] Example 1: A randomized, double-blind, placebo-controlled, multicenter, parallel-group study of dupilumab in patients with chronically induced cold urticaria who remain symptomatic despite H1 antihistamine treatment Research Principles Chronic inducible urticaria (ColdU) is a subtype of chronic urticaria characterized by recurrent itchy wheals, angioedema, or both, with a disease duration of at least 6 weeks. It develops only after exposure to a defined external trigger and is classified according to the stimulus that elicits the onset of signs and symptoms. Unlike chronic spontaneous urticaria (CSU), the symptoms of ColdU patients (itchy wheals and angioedema) reproducibly develop only in response to a trigger stimulus specific to the condition (e.g., cold exposure in cold urticaria (ColdU)). The triggers that elicit urticarial signs and symptoms in ColdU patients are primarily physical or chemical stimuli, resulting in two major subgroups of ColdU (physical and non-physical). Physical triggers include pressure (delayed pressure urticaria (DPU)), radiation (solar urticaria), friction (symptomatic dermatographia), temperature (cold and heat urticaria), and vibration (vibratory angioedema). Chemical triggers of ColdU reactions include water (aqueous urticaria), sweat (cholinergic urticaria (CholU)), and other urticarial chemicals (contact urticaria).

[0504] The prevalence of Cold U in the general population is estimated to be approximately 0.5% and significantly impacts the quality of life (QoL) of many patients, primarily due to the need to avoid triggers. Among Cold U subtypes, most are rare and therefore extremely difficult to study. The most common are symptomatic dermatographia, cholinergic urticaria, and Cold U (also known as chronically provoked cold urticaria), with Cold U being the second most common form of physical urticaria and estimated to have an annual incidence of 0.05%.

[0505] Cold urticaria occurs when skin cooling or cold exposure followed by rewarming releases mast cell mediators, resulting in wheals, angioedema, or both. Clinical symptoms develop within minutes of skin contact with cold air, cold liquids, cold solids, or evaporative cooling and generally persist for several hours. In severe cases, systemic involvement, including anaphylaxis, may occur. Localized angioedema affecting the lips, tongue, and pharyngeal tract has been associated with the ingestion of cold drinks or foods, and shock-like reactions have been reported after swimming in cold water. Cold urticaria can be classified as typical, atypical, or familial.

[0506] Primary acquired cold urticaria (CAU) is the most common form of cold urticaria and is considered idiopathic. Historically, the majority of patients with acquired cold urticaria (96%) have had primary cold urticaria, and secondary cold urticaria has been shown to be rare. Secondary acquired cold urticaria is extremely rare, and most cases are due to underlying cryoglobulinemia, although infectious, leukocytoclastic vasculitis, and drug-induced cases have also been reported. Both primary and secondary acquired cold urticaria have a typical positive response to cold challenge. Several other rare forms of atypical acquired cold urticaria exist, including generalized atypical acquired cold urticaria, cold-dependent dermatographia, cold-induced cold urticaria, delayed cold urticaria, and localized cold reflex urticaria, all of which have a negative immediate test response to cold stimulation. Finally, hereditary forms of ColdU have also been reported: 1) familial cold autoinflammatory syndromes caused by mutations in NLRP3 (cryopyrin) and inherited in an autosomal dominant manner (e.g., cryopyrin-associated periodic syndrome, Muckle-Wells syndrome, neonatal-onset multisystem inflammatory disease); and 2) familial atypical cold urticaria with phospholipase C-g2-associated deficiency and immune disorder (PLAID), inherited in an autosomal dominant manner.

[0507] Chronic induced urticaria is diagnosed based on the patient's medical history and the results of provocation tests. Treatment for induced urticaria involves avoidance of triggers and prophylaxis with H1 antihistamines, which block the action of histamine, a mast cell mediator, or, if antihistamines are ineffective, prophylaxis with drugs that block mast cell activation (e.g., anti-immunoglobulin E (IgE) omalizumab). Consensus recommendations for the management of cold urticaria (EAACI / GA2LEN / EDF / UNEV) are based primarily on approved treatments for chronic subacute urticaria (CSU) and some clinical data in patients with various types of cold urticaria (cholinergic, symptomatic dermatographia, and cold urticaria). In general, recommended treatments are not approved by regulatory authorities for cold urticaria; however, in select countries, antihistamines are approved for the broader indication of "urticaria." All patients are advised to avoid prolonged contact with cold objects and exposure to cold air. The first-line symptomatic treatment for cold urticaria (Cold U) is a non-sedating second-generation H1 antihistamine at the dose approved for CSU. In patients who do not achieve complete control, increasing the dose to four times the approved dose of CSU is recommended. Steps 3 and 4 of the treatment include omalizumab and cyclosporine A, respectively. All of these treatments are off-label and lack sufficient evidence of their effectiveness in cold urticaria patients. Chronic induced urticaria often poses a major treatment challenge because it persists for years and is resistant to first-line H1 antihistamine therapy. It can be debilitating, often causing systemic reactions, including anaphylaxis in severe cases, severely impacting patients' quality of life. Avoiding the problematic triggers is typically not feasible due to the significant impact on daily life. Therefore, there is a high demand for approved cold urticaria treatments, especially those with proven safety and efficacy in cold urticaria patients.

[0508] Cold U manifests as a pruritic wheal with or without angioedema secondary to the release of mediators from mast cells after skin exposure to cold air, liquids, or cold objects. Mast cell degranulation in cold U is thought to occur via activation of FcεRI (Fc epsilon receptor) through cell surface-bound IgE crosslinked by as-yet-unidentified autoallergens. Histamine and other inflammatory mediators are subsequently released, causing local tissue edema and pruritus. Many symptoms of urticaria are primarily mediated by the action of histamine (a mast cell mediator) on H1 receptors, and treatment with H1 antihistamines is the mainstay of treatment. Approximately 50% of patients achieve symptom control with conventional H1 antihistamine therapy. While increasing the dose of antihistamines can be effective in some cases, it is not effective in all cases.

[0509] Exam Overview Study EFC16720 is a 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating dupilumab in adults and adolescents (aged 12 to 18 years) with primary acquired ColdUrticaria (ColdUrticaria) whose symptoms do not improve with H1 antihistamines. Signs and symptoms of ColdUrticaria are assessed by investigators (rash / wheal intensity) and participants (itchiness, skin pain, and skin burning) after provocation testing. Additionally, ColdUrticaria disease activity is assessed daily by participants using the e-diary Cold Urticaria Activity Score (ColdUAS) questionnaire, which asks participants to report their skin reactions (wheals, swelling), skin sensations (itchiness, burning, pain, and heat), whether they have had contact with cold temperatures that typically cause skin reactions, whether they avoided exposure to triggers, and overall symptom severity. The study also evaluated the effect of dupilumab on urticaria control, participants' health-related quality of life and overall health, the proportion of patients with cold urticaria requiring emergency medical visits or treatment with epinephrine, and reduction in rescue therapy.

[0510] The total expected number of participants randomized in the study is 60. This corresponds to approximately 30 participants randomized to each intervention group (dupilumab group or placebo group). At least four participants randomized to the study will be adolescents (ages 12 to under 18) recruited in several selected countries. Randomization will be stratified by age (adolescents vs. adults), country within the adult group, and a history of cold-induced anaphylaxis or oropharyngeal edema, urticaria requiring emergency department visits, or treatment with epinephrine.

[0511] Participants who meet the inclusion and exclusion criteria will be randomized (1:1) to one of the following investigational medicinal product (IMP) treatment arms: Dupilumab: 300 mg every 2 weeks (q2w) for adults; 200 mg every 2 weeks (q2w) for adolescents with a baseline weight of 30 kg or greater but less than 60 kg; and 300 mg every 2 weeks (q2w) for adolescents with a baseline weight of 60 kg or greater. Matching placebo.

[0512] Study period (per participant) Screening period (2-4 weeks). Randomized IMP treatment duration (24 weeks). · Post-IMP treatment period (12 weeks).

[0513] Study intervention Investigational drug: Dupilumab 300 mg and matching placebo dupilumab 300 mg supplied in visually indistinguishable prefilled syringes. Dupilumab 200 mg and matching placebo dupilumab 200 mg supplied in visually indistinguishable prefilled syringes.

[0514] the purpose Main purpose To demonstrate the efficacy of dupilumab in adult and adolescent patients with primary acquired cold urticaria (ColdU) who persist with symptoms despite the use of H1 antihistamines.

[0515] Secondary Objectives To demonstrate the efficacy of dupilumab on local signs and symptoms of primary acquired ColdU (rash / wheals, itching, burning, pain) after provocation testing.

[0516] To demonstrate the efficacy of dupilumab on disease activity in primary acquired ColdU.

[0517] To demonstrate the efficacy of dupilumab in disease control of primary acquired ColdU.

[0518] Demonstrate improvement in health-related quality of life, overall disease status and severity.

[0519] To evaluate the ability of dupilumab to reduce the proportion of participants requiring rescue therapy.

[0520] To assess the proportion of participants whose urticaria was induced by cold exposure.

[0521] To evaluate safety outcome measures.

[0522] To evaluate the immunogenicity of dupilumab.

[0523] Tertiary purpose / exploratory purpose To demonstrate the effect of dupilumab on disease activity over time. To demonstrate improvements in health-related quality of life, particularly related to primary acquired ColdU. To assess the effect of dupilumab on general health status, healthcare resource utilization (HCRU), and productivity.

[0524] Pharmacokinetics (PK) / Pharmacodynamics (PD): To evaluate the PK of dupilumab and evaluate the PD effect of dupilumab.

[0525] endpoint Primary endpoint To compare the proportion of participants with a negative ice cube provocation test at week 24 with placebo. A negative ice cube provocation test result is defined as the absence of a confluent rash / wheal on all exposed skin sites after the provocation ice cube test. The provocation test reading time for all endpoints will be 15 minutes after the start of ice cube application (5 minutes after ice cube application + 10 minutes after ice cube removal and rewarming).

[0526] Secondary endpoints Change from baseline in local wheal intensity at the provocation site compared to placebo at weeks 12 and 24 using a wheal intensity Likert scale of 0 to 5 (clinician-rated). Change from baseline in local pruritus intensity at the provocation site compared to placebo at weeks 12 and 24 using a patient-reported numerical rating scale (NRS, score 0-10). Change from baseline in local skin burning sensation at the provocation site compared to placebo at weeks 12 and 24 using a patient-reported peak burning NRS. Change from baseline in local pain severity at the provocation site compared to placebo at weeks 12 and 24 using a patient-reported peak pain NRS. To compare the proportion of participants with a negative ice cube provocation test at week 12 with placebo.

[0527] Change from baseline to weeks 12 and 24 (compared to placebo) in the proportion of participants with cold exposure eliciting urticaria signs and symptoms as measured by ColdUAS7. Change from baseline to weeks 12 and 24 (compared to placebo) in the proportion of days with cold exposure eliciting urticaria signs and symptoms as measured by ColdUAS7. Change from baseline to weeks 12 and 24 (compared to placebo) in the proportion of participants with severe cold exposure eliciting urticaria signs and symptoms as measured by ColdUAS7. Change from baseline to weeks 12 and 24 (compared to placebo) in the proportion of days with severe cold exposure eliciting urticaria signs and symptoms as measured by ColdUAS7.

[0528] Change from baseline in the urticaria control test (UCT, 4 items) at week 24 compared to placebo. Proportion of participants with good control (UCT ≥ 12) at week 24 compared to placebo. Proportion of participants with an improvement of 3 or more in 4 items of the UCT from baseline to week 24 compared to placebo.

[0529] Change from baseline in health-related quality of life (HRQoL) at week 24 compared to placebo, as measured by the Dermatology Life Quality Index (DLQI) for patients aged 16 years and older and the Children's Dermatology Life Quality Index (CDLQI) for participants aged 12 to under 16 years. Change from baseline in Patient Global Impression of Primary Acquired Cold U (PGIC) at weeks 12 and 24 compared to placebo. Change from baseline in Participant Global Impression of Severity (PGIS) for Primary Acquired Cold U (PACU) at weeks 12 and 24 compared to placebo.

[0530] Time to first rescue therapy during the planned treatment period for primary acquired chronic induced ColdU compared to placebo.Proportion of participants receiving rescue therapy during the planned treatment period for primary acquired chronic induced ColdU compared to placebo.

[0531] Percentage of participants who developed urticaria induced by cold exposure and required emergency visit or treatment with epinephrine (at the time of provocation testing and / or at home).

[0532] The proportion of participants who experienced a treatment emergent adverse event (TEAE) or serious adverse event (SAE).

[0533] Incidence of treatment-emergent anti-drug antibodies (ADAs) over time to dupilumab.

[0534] Tertiary purpose / exploratory purpose Change from baseline at weeks 12 and 24 for ColdUAS7 compared to placebo. Change from baseline to week 24 for ColdUAS7 compared to placebo. Change from baseline in HRQoL measured by the Cold Urticaria Quality of Life (ColdU-QoL) questionnaire at week 24 compared to placebo. Change from baseline in the 5-point EuroQol-5D-5L (EQ-5D-5L) questionnaire at week 24 compared to placebo. Cumulative number of HCRUs compared to placebo.

[0535] Serum functional dupilumab concentrations and pharmacokinetic profile. Changes in total immunoglobulin E levels over time.

[0536] Overall study design Study EFC16720 is a 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating dupilumab in adults and adolescents (aged 12 to 18 years) with primary acquired cold urinary tract infection (Cold U) whose symptoms have not improved with H1 antihistamine therapy. These patients have active disease and have not responded to antihistamine therapy. The study aims to test the hypothesis that dupilumab increases the proportion of participants who achieve a negative ice cube provocation test compared to placebo.

[0537] A negative ice cube provocation test result is defined as the absence of a confluent rash / wheal on all exposed skin sites after the provocative ice cube test.

[0538] ColdU signs and symptoms will be assessed by investigators (rash / wheal intensity) and participants (severity of itching, skin pain, and skin burning) after provocation testing. Additionally, ColdU disease activity will be assessed daily by participants using the e-diary Cold Urticaria Activity Score (ColdUAS) questionnaire, which asks participants to report their skin reactions (wheals, swelling), skin sensations (itching, burning, pain, and heat), whether they had contact with cold temperatures that typically cause skin reactions, whether they avoided exposure to triggering contacts, and overall symptom severity. The study will also evaluate the effect of dupilumab on urticaria control, participants' health-related quality of life and overall health, the proportion of cold urticaria patients requiring emergency medical visits or treatment with epinephrine, and reduction in rescue therapy.

[0539] Scientific principles of study design In the EFC16720 study, the target population consisted of patients with primary acquired cold urticaria (Cold U), whose symptoms persist despite treatment with H1 antihistamines alone. These patients represent a significant unmet medical need. Patient treatment focuses on avoidance of triggers and symptomatic treatment. A revised international guideline for the definition, classification, diagnosis, and management of urticaria provides recommendations and a treatment algorithm. Consensus recommendations for the management of Cold U are primarily based on approved treatments for CSU and some clinical data in patients with various types of Cold U (cholinergic, symptomatic dermatographia, and Cold U). In general, recommended treatments are not approved by regulatory authorities for Cold U; only in select countries are antihistamines approved for the broader "urticaria" indication. A stepwise approach similar to that for CSU patients is recommended for Cold U. Steps 1 and 2 of this algorithm involve the use of non-sedating H1 antihistamines at approved or increased (up to fourfold) doses, respectively. Steps 3 and 4 of the treatment regimen include omalizumab and cyclosporine A, respectively. More than 50% of patients with acquired primary cold U fail to respond to H1 antihistamine treatment. Omalizumab, a monoclonal anti-immunoglobulin E (IgE) antibody, is the most commonly used off-label treatment for colds, including those resistant to antihistamines. However, approximately one-third of patients treated with omalizumab experience inadequate symptom control.

[0540] The EFC16720 trial targets patients whose symptoms are not adequately controlled with H1 antihistamine therapy and allows the use of stable doses of H1 antihistamines as background treatment, up to four times the approved dose.

[0541] The number of studies involving patients with cold urticaria is limited. As mentioned above, guideline recommendations for CSU are also adopted for patients with cold urticaria. However, there are several differences between CSU and cold urticaria. In cold urticaria, symptoms appear only after skin exposure to a physical or chemical trigger. In cold urticaria, the duration of individual wheals is relatively short, often ranging from minutes to hours. This explains why different assessment tools and endpoints are used in clinical studies of cold urticaria compared with CSU. In clinical studies of patients with chronic urticaria, cold provocation tests are primarily used to evaluate the efficacy of antihistamine treatment. However, even with treatments such as doxypine and cyproheptadine, studies also evaluate the proportion of patients who remain free of signs / symptoms in cold provocation tests after treatment, and evaluate responses to experimental cold-simulation time tests (CSTTs), i.e., the minimum time threshold of cold stimulation required to induce confluent wheals and other signs and symptoms of cold urticaria. The primary endpoint of efficacy in this study will be the proportion of patients with a negative ice cube provocation test at week 24. Patients / investigators will also score local signs and symptoms before and after provocation testing to assess the effects of the study drug on rash, itching, burning, and pain. The ice cube provocation test is a commonly used conventional test. In this study, research methods will be standardized in accordance with the international EAACI / GA2LEN / EDF / UNEV guidelines. In addition to the cold urticaria provocation test, signs and symptoms of cold urticaria will be assessed using the ColdUAS, which patients will score daily for the purpose of globally assessing disease activity.

[0542] The majority of ColdU patients (35% to 70%) experience systemic reactions, including anaphylaxis, after excessive cold exposure or exercise, respectively. Avoidance of the offending trigger is typically not feasible due to the significant impact on daily life. This significantly impacts patients' quality of life. This study evaluates the proportion of patients who develop cold-exposure-induced urticaria and require emergency medical visits and treatment with epinephrine.

[0543] Definition of Exam Completion Participants who completed all phases, including the final end-of-study (EOS) visit, were considered to have completed the study. Even if a participant discontinued the treatment period early, they were considered completers if they completed follow-up until the scheduled EOS visit. The final visit date of the last participant in the study was defined as the EOS for the entire study.

[0544] Inclusion criteria Participants were eligible for inclusion in the study only if they met all of the following criteria:

[0545] age Participants must be between 12 and 80 years of age (or the minimum legal age for minors in the country where the clinical trial site is located) at the time of signing the informed consent. In countries where local regulations do not allow the enrollment of minors (aged 12 to 18), recruitment will be limited to individuals aged 18 years or older.

[0546] Participant type and disease characteristics Participants diagnosed with primary acquired cold urticaria who had recurrent cold-induced pruritic wheals and / or angioedema for at least 6 weeks prior to the screening visit (Visit 1).

[0547] Participants who had a positive reaction to the ice cube provocation test at the screening visit (Visit 1) and the randomization visit (Visit 2), i.e., exhibited at least a confluent rash / wheals on exposed skin areas, were included.

[0548] Participants who met at least one of the following criteria despite using H1-AH: urticaria control test (UCT) (4 items) less than 12 times at the screening visit (visit 1) and randomization visit (visit 2), anaphylaxis or oropharyngeal edema due to cold exposure within 6 months of the screening visit, or a documented history of emergency room visit or urticaria requiring epinephrine treatment due to cold exposure within 6 months of the screening visit.

[0549] Participants taking an H1 antihistamine for primary acquired ColdU, as defined by the study. Note: Participants must maintain the non-sedating H1 antihistamine dose used at pre-test. A maximum of four times the recommended dose is permitted. If a participant is receiving more than four times the recommended dose at screening, the investigator may adjust the participant's dose to within the specified range at the screening visit (Visit 1), if clinically appropriate. The H1 antihistamine dose must be maintained stable for at least three consecutive days prior to the screening visit (Visit 1).

[0550] Weight and gender Weight over 30kg, male or female.

[0551] female participants Female contraceptive use must comply with local regulations regarding contraceptive methods for people participating in clinical trials. Female participants are eligible to participate if they are not pregnant or lactating and at least one of the following conditions applies: they are not women of childbearing age (WOCBP); or they are WOCBP and agree to use a highly effective method of contraception with a failure rate of less than 1%. WOCBP must have a negative high-sensitivity pregnancy test (urine or serum, as required by local regulations) one day before the first dose of study intervention. If the negative urine test on the first day cannot be confirmed (e.g., if the result is equivocal), a serum pregnancy test is required. In such cases, a positive serum pregnancy test result must exclude the participant from participation.

[0552] Informed consent Be able to provide a signed informed consent form (ICF) that includes adherence to the requirements and limitations described in this protocol. In countries where the legal age of majority is 18 years or older, a specific ICF must also be signed by the participant's legally authorized representative. For adolescents, a specific ICF must be signed by both the participant and a parent or legal representative.

[0553] Exclusion criteria Participants were excluded from the study if any of the following criteria applied:

[0554] medical conditions A well-defined underlying condition of urticaria other than primary acquired Cold U. This includes, but is not limited to, the following: acute urticaria, chronic spontaneous urticaria, provoked urticaria; all other types of Cold U (acquired secondary Cold U, atypical acquired Cold U, hereditary Cold U syndrome), solar, cholinergic, febrile, aquagenic, vibratory angioedema, symptomatic dermatographia, delayed pressure, and contact; conditions that may present with urticaria or angioedema: systemic lupus erythematosus, urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, or systemic cancer.

[0555] Systemic hypersensitivity reactions, including anaphylaxis, associated or suspected to be associated with ice cube provocation testing at the screening visit (Visit 1) and the randomization visit (Visit 2).

[0556] The presence of any skin disease or itch-related disease other than primary acquired ColdU that may interfere with the evaluation of the results of this study.

[0557] Participants with active atopic dermatitis.

[0558] Diagnosed with active helminth infection; suspected or at high risk for helminth infection, unless active infection has been ruled out by clinical examination and (if necessary) laboratory evaluation before randomization.

[0559] History of human immunodeficiency virus (HIV) infection or positive HIV1 / 2 serology at screening (Visit 1).

[0560] Serious comorbidities that the investigator determines may adversely affect the participant's participation in the study. Examples include, but are not limited to, participants with a shortened life expectancy, participants with poorly controlled diabetes (hemoglobin A1c ≥ 9%), participants with cardiovascular disease (e.g., New York Heart Association Class III or IV heart failure), severe renal disease (e.g., participants undergoing dialysis), hepatobiliary disease (e.g., Child-Pugh Class B or C), neurological disease (e.g., demyelinating disease), active major autoimmune disease (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis), other serious endocrine, gastrointestinal, metabolic, pulmonary, or lymphatic disease. Specific justification for participants excluded based on this criterion will be provided in study documentation (e.g., medical record notes, case report form [CRF], etc.).

[0561] Known or suspected immunodeficiency, as determined by the investigator, including, for example, a history of invasive opportunistic infection (e.g., tuberculosis (TB), histoplasmosis, listeriosis, coccidioidomycosis, pneumococcosis, and aspergillosis) despite resolution of the infection, or recurrent infections of unusual frequency or prolonged duration, is indicative of an immunocompromised state.

[0562] Participants with a history of active TB or nontuberculous mycobacterial disease, or incompletely treated TB, will be excluded from the study unless, in the medical judgment of the investigator and / or infectious disease specialist, it is satisfactorily certified by a specialist that the participant is adequately treated and currently eligible to start biologic therapy. TB testing will be performed on a country-by-country basis, in accordance with local guidelines, if required by regulatory authorities or ethics committees.

[0563] Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks prior to the screening visit and during the screening period.

[0564] A history of malignant tumors within 5 years prior to the first day of visit, except for cases in which in situ carcinoma of the cervix has been cured or nonmetastatic squamous cell carcinoma or basal cell carcinoma of the skin has been cured.

[0565] Known or suspected alcohol and / or drug abuse.

[0566] Those with a history of systemic hypersensitivity or anaphylaxis to other biological products or their excipients.

[0567] Participants are scheduled to undergo major surgical procedures while they are participating in this study.

[0568] Participants with any other medical or psychological condition, including relevant laboratory or electrocardiogram abnormalities at screening, that, in the judgment of the investigator, may suggest a new and / or poorly understood disease, that participation in this clinical trial may pose an unreasonable risk to the participant, that may make the participant's participation unreliable, or that may interfere with study assessments. Specific justification for participants excluded based on this criterion will be provided in the study documentation (e.g., medical record notes, CRFs, etc.).

[0569] Previous Therapy / Concomitant Therapy Those who have previously participated in a clinical trial of dupilumab or been treated with commercially available dupilumab.

[0570] Subjects who have been exposed to other systemic or topical investigational drugs (monoclonal antibodies and small molecule compounds) within a period prior to the screening visit (Visit 1) as defined as follows: for investigational monoclonal antibodies, 6 months or less than 5 PK half-lives, whichever is longer; for investigational small molecules, 30 days or less than 5 PK half-lives, whichever is longer.

[0571] Received any of the following treatments within 4 weeks prior to the screening visit (Visit 1): immunosuppressants / immunomodulators (e.g., systemic corticosteroids (oral or parenteral—intravenous, intramuscular, or SC), cyclosporine, mycophenolate mofetil, interferon gamma, Janus kinase inhibitors, azathioprine, methotrexate, hydroxychloroquine, sulfasalazine, dapsone, colchicine, etc.); antifibrinolytic agents tranexamic acid and epsilon aminocaproic acid; leukotriene receptor antagonists (LTRAs), and H2 receptor antagonists. Note: Patients taking stable LTRAs and / or H2 receptor antagonists for conditions other than CSU (e.g., asthma or gastroesophageal reflux disease) are permitted to continue using phototherapy, including tanning beds.

[0572] Treatment with biologics such as: cell depleting agents, including but not limited to rituximab, within 6 months prior to the screening visit (Visit 1); anti-immunoglobulin E therapy (omalizumab) within 4 months prior to the screening visit (Visit 1); other monoclonal antibodies (biological response modifiers), within 5 half-lives (if known) or 16 weeks prior to the screening visit (Visit 1), whichever is longer.

[0573] Received a live (attenuated) vaccine within 4 weeks prior to the screening visit (Visit 1). Note: For participants scheduled to receive a live attenuated vaccine during the study (based on national immunization schedules / local guidelines), in consultation with their physician, it will be determined whether the vaccination can be postponed until after EOS or before the start of the study without compromising the participant's health: Participants who can safely postpone receiving a live (attenuated) vaccine will be eligible to participate in the study. Participants who postpone vaccination will be eligible to participate in the study after a 4-week interval following vaccination.

[0574] Subjects who received regular doxepin (daily or every other day for 5 or more consecutive days) within 14 days prior to the screening visit (Visit 1).

[0575] Planned or anticipated use of prohibited medications and procedures during screening and study treatment.

[0576] Subjects who received either intravenous immunoglobulin (IVIG) therapy and / or plasmapheresis within 30 days prior to the screening visit (Visit 1).

[0577] Diagnostic evaluation Participants had one of the following results at the screening visit (Visit 1): hepatitis B virus surface antigen (HBs Ag) HBs Ag positive (or indeterminate), or hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive confirmed hepatitis B core antibody (HBc Ab) positive, or hepatitis C virus (HCV) ribonucleic acid (RNA) positive confirmed hepatitis C antibody (HCV Ab) positive.

[0578] Failure to comply with e-diary Participants will be considered to be OK with completing their e-diary if they complete it on fewer than 4 days out of the 7 days immediately preceding the baseline visit (Visit 2).

[0579] Other Exclusions An individual held in an institution because of a regulatory or legal order; an inmate or participant who is legally held in an institution.

[0580] Certain country-related regulations that prevent participants from participating in the study.

[0581] Participants who, in the opinion of the investigator, are unsuitable to participate for any reason, including a medical or clinical condition, or who may be at risk of non-compliance with study procedures. Participants may be employees of the clinical trial center or other individuals directly involved in the conduct of the study, or the immediate family members of such individuals.

[0582] Specific situations in which ethical concerns may arise during the conduct / process of the study.

[0583] Sensitivity to any of the study interventions or components thereof, or to any drug or other allergy that, in the opinion of the investigator, contraindicates participation in the study.

[0584] Lifestyle Considerations Participants did not try to avoid known cold triggers.

[0585] Those who failed screening A screen failer is defined as a participant who consented to participate in a clinical trial but was not subsequently randomized to the study intervention or enrolled in the trial. A minimum set of screen failer information is required to ensure transparent reporting of screen failing participants to meet Consolidated Standards of Reporting Trials (CONSORT) publication requirements and to respond to inquiries from regulatory authorities. This minimum information includes demographics, reasons for screen failure, eligibility criteria, and SAEs.

[0586] Those who do not meet the study inclusion criteria (screen failures) may be rescreened once. Participants who are rescreened will be assigned a new participant number that will be different from the number they received at the initial screening visit (Visit 1).

[0587] Study intervention investigational drug Dupilumab 300 mg and matched placebo dupilumab 300 mg delivered in visually indistinguishable prefilled syringes. Dupilumab 200 mg and matched placebo dupilumab 200 mg delivered in visually indistinguishable prefilled syringes.

[0588] Dupilumab formulation Dupilumab 300 mg: A 150 mg / mL dupilumab solution is loaded into a prefilled syringe and administered as a 2 mL injection to deliver 300 mg. Dupilumab 200 mg: A 175 mg / mL dupilumab solution is loaded into a prefilled syringe and administered as a 1.14 mL injection to deliver 200 mg.

[0589] Dosing regimen All adults and adolescents weighing 60 kg or more will receive a 600 mg loading dose (two 300 mg injections) on day 1, followed by one 300 mg subcutaneous injection every other week. Adolescent participants weighing 30 kg or more but less than 60 kg will receive a 400 mg loading dose (SC injection), followed by one 200 mg SC injection every other week (two 200 mg injections).

[0590] placebo formulation Placebo corresponding to dupilumab 300 mg: Placebo will be administered in a 2 mL injection solution filled in a pre-filled syringe with the same formulation as the active 300 mg formulation, but without dupilumab. Or placebo corresponding to dupilumab 200 mg: Placebo will be administered in a 1.14 mL injection solution filled in a pre-filled syringe with the same formulation as the active 200 mg formulation, but without dupilumab.

[0591] Dosing regimen All adult participants and adolescent participants weighing 60 kg or more will receive an initial matching placebo loading dose of 600 mg (two 300 mg matching placebo injections), followed by one 300 mg matching placebo injection every other week.Adolescent participants weighing 30 kg or more but less than 60 kg will receive an initial matching placebo loading dose of 400 mg (two 200 mg matching placebo injections), followed by one 200 mg matching placebo injection every other week.

[0592] Packaging and Labeling Each dose of dupilumab will be provided as one prefilled glass syringe packaged in a participant kit box. Both the glass prefilled syringe and the box will be labeled according to country requirements. Each dose of placebo will be provided as one prefilled glass syringe packaged in a participant kit box. Both the glass prefilled syringe and the box will be labeled according to country requirements.

[0593] IMP was administered every 14 ± 3 days (q2w) for a 24-week treatment period, with the final dose at week 22.

[0594] The first IMP administration must be administered at the study center. Subsequent IMP administrations can be administered at home by the participant (or parent / legal representative or caregiver). If the participant (or parent / legal representative or caregiver) is unable or unwilling to prepare and inject the IMP, an unscheduled visit can be made to administer the injection at the study center; or arrangements can be made for qualified study center staff and / or health care professionals (e.g., visiting nurse services) to administer the IMP in the participant's home.

[0595] For doses not administered at the study center, participants will be provided with a paper diary to record injection-related information, which will be kept as source data in the participant's study file.

[0596] At Visit 2, the investigator or his / her representative will prepare and inject the first dose of IMP in the presence of the participant (or parent / legal representative / caregiver). If home administration is planned, the participant (or parent / legal representative / caregiver) will prepare and inject the second dose of IMP under the supervision of the investigator or his / her representative. Training must be documented in the participant's study file. In the event of an emergency (e.g., natural disaster, pandemic), different training methods (e.g., virtual training via video call) can be implemented (and will be documented in the participant's study file).

[0597] Subcutaneous injection sites should alternate between the upper thigh, the four quadrants of the abdomen, or the upper arm, and the same site should not be injected twice during consecutive doses. Injections into the upper arm may only be administered by a trained individual (parent / legal representative / caregiver trained by the investigator or surrogate) or healthcare professional, but not by the participant themselves.

[0598] Participants must be monitored for at least 30 minutes. The monitoring period may be extended according to country-specific or local research center-specific requirements.

[0599] Participants / guardians / legal representatives / caregivers must be trained by study center staff to recognize potential signs and symptoms of a hypersensitivity reaction, to self-monitor at home for at least 30 minutes after injection (or longer as required by different countries or institutions), and in case of hypersensitivity symptoms, participants should contact their healthcare professional or emergency contact.

[0600] The following contingencies may be implemented to ensure clinical supplies are available to participants during emergency periods (after sponsor consent is obtained): In the event of an emergency (natural disaster, pandemic, etc.), IMP may be supplied to participants from the study center via an investigator-approved courier if permitted by local regulations and approved by the participant (or guardian / legal representative); if the participant has a study visit, IMP will be administered in accordance with clinical procedures and blood draws.

[0601] Non-clinical drug Participants should continue their established standard of care with background therapy with a long-acting, non-sedating H1 antihistamine, up to four times the recommended dose. If a participant is taking more than four times the recommended dose at the screening visit (Visit 1), the investigator may adjust the participant's dose within the range specified at the screening visit (Visit 1). Participants must continue taking the same dose daily for the duration of the study unless they experience a flare, at which point rescue therapy may be initiated. The following list of H1 antihistamines is permitted and listed with recommended doses: cetirizine 10 mg once daily (qd); levocetirizine dihydrochloride 5 mg once daily (qd); ebastine 10 mg twice daily (qd); fexofenadine 60 mg twice daily or 180 mg once daily (qd); loratadine 10 mg once daily (qd); desloratadine 5 mg once daily (qd); bilastine 20 mg once daily (qd); rupatadine 10 mg once daily (qd); other H1 antihistamines in consultation with the sponsor.

[0602] How patients were assigned to treatment groups A randomization intervention kit number list will be centrally generated by Sanofi, and the IMPs (dupilumab 300 mg, dupilumab 200 mg, or their corresponding placebos) will be packaged according to this list. Randomization and intervention assignment will be performed centrally by Interactive Response Technology (IRT). The IRT will generate a participant randomization list and assign participants their intervention number and corresponding intervention kit accordingly.

[0603] Study interventions will be dispensed at study visits outlined in the Schedule of Activities (SoA) (see Figure 2). Returned study interventions should not be re-prescribed to participants.

[0604] Figure 2: a The randomization / baseline visit will be defined as Day 1. All assessments at Visit 2 (Day 1) will be performed prior to IMP administration, except for the assessment of local tolerability of the SC injection. b ACUSI will be recorded on the eCRF. c Concomitant medications, including rescue OCS, taken since the last visit will be recorded throughout the study period. d A loading dose will be administered on the first day (Visit 2): Adults and adolescents ≥60 kg will receive a 600 mg / matching placebo (2 SC injections) with a 300 mg / matching placebo every 2 weeks (q2w) regimen; or adolescents ≥30 kg but <60 kg will receive a 400 mg / matching placebo (2 SC injections) with a 200 mg / matching placebo every 2 weeks (q2w) regimen. Study drug will be administered every other week. The final dose is scheduled for Week 22. Participants will be allowed to self-inject IMP at home after appropriate training of the participant (or parent / legal representative or caregiver). eAn electronic diary will be used to record daily ColdUAS and antihistamine use from screening through week 24. The device, along with instructions for use, will be dispensed at the screening visit (Visit 1). At EOT, the e-diary will be returned to the study center. For UCT, DLQI (ages 16 years and older) / CDLQI (ages under 16 years), ColdQoL, and EQ-5D-5L, participants will complete questionnaires in the e-diary during study visits. The e-diary will also be used to complete the peak itch NRS, peak pain NRS, and peak burning NRS after provocation testing. After completing the peak itch NRS, peak pain NRS, and peak burning NRS, participants will complete the PGIS and PGIC on the e-diary. f EpiPens or equivalent will be provided locally. g Assessments / procedures should occur in the following order: patient-reported outcomes, investigator assessment, safety and laboratory assessments (including ADA, PK, biomarkers, optional DNA and RNA sampling), ice cube challenge test, participant and investigator assessment of signs and symptoms after challenge test, and administration of IMP. h The physical examination includes examination of the skin, nasal passages, eyes, ears, respiratory system, circulatory system, digestive system, nervous system, lymphatic system, and musculoskeletal system. i Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats / min), temperature (°C), and respiratory rate, will be measured at each visit before and after provocation testing. Height (cm) will be measured only at the screening visit (Visit 1). Weight (kg) will be measured at the screening visit (Visit 1) and at the EOT / EOS visits. j Electrocardiograms are recorded and interpreted on-site. kBlood tests include hemoglobin, hematocrit, platelet count, total white blood cell count, differential count, and total red blood cell count. Serum chemistry tests include creatinine, blood urea nitrogen, glucose, lactate dehydrogenase, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. Urinalysis includes specific gravity, pH, glucose, ketones, blood, protein, nitrates, leukocyte esterase, urobilinogen, and bilirubin. If the urine dipstick test is abnormal, a urine sample should be sent to a central laboratory for microscopic examination. l Laboratory tests at the screening visit (Visit 1) include HBs Ag, HBs Ab, HBc Ab, HCV Ab, and HIV screening (anti-HIV-1 and HIV-2 antibodies). If the result is HBs Ag (negative) or HBc Ab (positive), an HBV DNA test must be performed and confirmed as negative before randomization. If the result is HCV Ab (positive), an HCV RNA test must be performed and confirmed as negative before randomization. m Only women of childbearing potential are eligible. Pregnancy will result in confirmed treatment discontinuation in all cases. Pregnancy testing will be required monthly, but no visits to the study center will be scheduled and female participants will be provided with a few months' worth of dipsticks. Pregnancy testing for female participants who discontinue the study intervention will need to continue for a minimum of 12 weeks after the last dose of study intervention. Home urine pregnancy tests will be required between visits. n Serum dupilumab concentration and ADA samples will be collected and stored prior to IMP administration. In the event of an SAE, a serious injection site reaction lasting ≥24 hours, or an AESI involving an anaphylactic or systemic allergic reaction requiring medical treatment related to IMP, PK and ADA samples will be collected at the time of the event or shortly thereafter for further analysis, if needed, or for archiving. oParticipants (excluding adolescents) who decided to participate and provided specific written informed consent for any basophil activation testing. p Participants (excluding adolescents) who decide to participate and provide specific written informed consent for optional archival serum and plasma samples. Optional archival serum and plasma samples will be collected for future analysis of drug response, disease activity, safety, and potential biomarkers of the type 2 inflammatory pathway. q Participants (excluding adolescents) who decide to participate and provide specific written informed consent for any genomic substudy (DNA sample collection). DNA samples must be collected at the Day 1 visit, but can be collected at any visit during the study period. r Participants (excluding adolescents) who decide to participate and provide specific written informed consent for any genomic substudy (RNA sample collection). RNA samples must be collected before the first dose of IMP and at week 24 of treatment. s A positive challenge was defined as the presence of at least a confluent rash / wheal over the entire exposed skin area after ice cube challenge. t The Likert scale of wheal intensity after provocation testing will be completed by the investigator after provocation testing and entered into the eCRF. u Participants will complete the DLQI (ages 16 and over) or the CDLQI (ages 12 to under 16). v HCRU (Days Absent from School / Work) baseline version will be administered at baseline and post-baseline version at subsequent visits. This will be entered into the eCRF.

[0605] Blinding method Dupilumab 300 mg / 200 mg and matching placebo will be provided in identical 2 mL / 1.14 mL prefilled syringes to ensure visual indistinguishability for each dose. Syringes and boxes will be labeled with the treatment kit number. While the study is double-blinded with respect to dupilumab or placebo treatment, it is not blinded to weight-based dose levels due to the different volumes (2 mL vs. 1.14 mL) of dupilumab dose levels (300 mg / matching placebo or 200 mg / matching placebo) used for each weight category of adolescent patients.

[0606] Combination therapy Any medications or vaccines (including over-the-counter or prescription drugs, vitamins, and / or herbal supplements) that participants are receiving at the time of enrollment or received during the study must be recorded along with the following: reason for use, dates of administration including start and end dates, and dosage information including dose and frequency.

[0607] Non-sedating H1 antihistamines are permitted as background and, if necessary, rescue medications at doses up to four times the CSU-approved dose. See Sections 6.1.2 and 6.5.1 for further details.

[0608] Concomitant use of the following therapies is prohibited throughout the study. Participants receiving these therapies must discontinue study treatment: systemic immunosuppressants (immunosuppressants / immunomodulators), e.g., systemic corticosteroids (oral or parenteral (intravenous, intramuscular, or subcutaneous)), cyclosporine, mycophenolate mofetil, interferon gamma, Janus kinase inhibitors, azathioprine, methotrexate, hydroxychloroquine, dapsone, sulfasalazine, and colchicine. Note: Short courses of OCS are permitted as rescue therapy; cytodepleting agents, including but not limited to rituximab; monoclonal antibodies (which are biological response modifiers), including anti-immunoglobulin E therapy (omalizumab); treatment with live (attenuated) vaccines; IVIG; plasmapheresis; and other investigational medications.

[0609] Concomitant use of the following treatments is prohibited during the study, but participants receiving these treatments against the protocol are not required to discontinue study treatment: topical corticosteroids; topical calcineurin inhibitors; topical and oral antihistamines (except those permitted as background therapy); routine administration of doxepin (daily or every other day for 5 or more consecutive days); LTRAs and H2 receptor antagonists (except when stable and taken for illness other than Cold U); antifibrinolytic drugs tranexamic acid and epsilon-aminocaproic acid; and phototherapy, including tanning beds.

[0610] Rescue medication All participants taking one to three times the dose of an approved non-sedating H1 antihistamine (maintenance dose used at screening) will be permitted to take an additional H1 antihistamine as rescue therapy during the screening, treatment, and follow-up periods, as long as the dose does not exceed four times the approved dose. If symptoms are not controlled after increasing the H1 antihistamine to the maximum tolerated dose, or if the participant is already taking four times the approved dose of an H1 antihistamine, the participant may switch to another antihistamine up to four times the approved dose or receive a short course of OCS during the treatment and follow-up periods. To ensure consistency, if possible, we recommend starting with oral prednisone 40 mg (or a clinically equivalent OCS) for 5 to 7 days, followed by tapering at the investigator's discretion.

[0611] In the event of a cold-induced systemic hypersensitivity reaction, participants may require epinephrine administration. EpiPens (or local equivalents) will be provided to participants at the start of the study, and participants must be properly trained on how and when to use them. Use of EpiPens must be in accordance with locally approved product labeling.

[0612] The initial antihistamine maintenance dose must remain stable throughout the study, and participants should continue their initial H1 antihistamine maintenance dose once rescue treatment is no longer required. If possible, permitted rescue medication should be deferred for at least 8 weeks after initiating study drug administration. The date and time of rescue medication administration, as well as the name and method of administration, should be recorded.

[0613] Discontinuation of study intervention In rare instances, it may be necessary for a participant to permanently discontinue the study intervention. If the study intervention is permanently discontinued, the participant must undergo all scheduled assessments at end of treatment (EOT) and complete the early treatment discontinuation visit. See Figure 2 for data to be collected upon discontinuation of the study intervention.

[0614] Participants may discontinue treatment with the IMP at any time for any reason, which may be at the discretion of the investigator. Every effort should be made to document the reason for discontinuation and record it on the eCRF.

[0615] Participants must be permanently withdrawn from study treatment for the following reasons: at their own request or at the request of their legally authorized representative (a legally authorized representative is an individual or judicial or other institution that has the authority under applicable law to consent on behalf of a prospective participant to participation in procedures involving the patient in a research study); if the investigator determines that continuation in the study would be hazardous to the participant's health, at the specific request of the sponsor, or if there is a deviation from the protocol at the discretion of the investigator or sponsor; pregnancy requested by the investigator; anaphylactic or generalized allergic reaction related to IMP that requires treatment; diagnosis of malignancy during the study period, other than non-invasive carcinoma of the cervix, squamous cell carcinoma or basal cell carcinoma of the skin; opportunistic infection or other infection of a nature or course suggestive of an immunocompromised state. Infection; participation in the study will be permanently discontinued if the immunization period is broken; pregnancy; anaphylactic or systemic allergic reaction related to IMP requiring treatment; diagnosis of malignancy during the study period, except for noninvasive carcinoma of the cervix or squamous or basal cell carcinoma of the skin; opportunistic infection or other infection whose nature or course suggests an immunocompromised state; serum alanine aminotransferase (ALT) >3 × upper limit of normal (ULN) and total bilirubin >2 × ULN; serum ALT >5 × ULN if baseline ALT ≤2 × ULN, or ALT >8 × ULN if baseline ALT >2 × ULN; a medical condition requiring the use of a prohibited medication; a participant misses three or more consecutive doses of IMP; or a systemic hypersensitivity reaction, including anaphylaxis, related to or suspected to be related to ice cube provocation testing. Subjects who experience such a reaction should not undergo further ice cube provocation testing during the study period.

[0616] Any abnormalities in clinical laboratory values ​​or electrocardiogram parameters will be immediately re-checked within a reasonable timeframe as assessed by the investigator before a decision is made to definitively discontinue the participant from IMP.

[0617] If clinically significant ECG findings are identified at screening (including, but not limited to, a change from baseline in the QT interval corrected using the Bazett formula (QTcB) or Fridericia formula (QTcF)), the investigator or qualified designee will determine whether the participant is eligible for the study. This review of the printed ECG at the time of collection must be documented. Any new clinically relevant findings should be reported as an AE.

[0618] Participants will be followed up according to the study procedures specified in the study protocol until the planned completion date of the study, or after completion of the study until the AEs covered by the follow-up specified in the study protocol have resolved or stabilized, whichever occurs first.

[0619] Participants who discontinue the study intervention early (before the end of the 24-week treatment period) will have an early treatment discontinuation visit with all assessments normally scheduled at the EOT visit (Visit 4) as soon as possible to ensure a complete clinical evaluation can be performed close in time to the early discontinuation of study treatment.

[0620] Additionally, participants will be asked and encouraged to complete all remaining study treatment and participate in safety follow-up visits according to the visit schedule, with a ±3-day window, so that participant outcomes can be assessed during the specified study period. In exceptional circumstances where a participant is unable to come to the study center for a scheduled visit, telephone contact is possible. At a minimum, information regarding AEs, concomitant medications, and urticaria status should be collected during telephone contact.

[0621] If an AE is suspected, the investigator may consider temporarily discontinuing the intervention.

[0622] Additionally, if a patient develops an infection while receiving dupilumab treatment and does not respond to anthelmintic treatment, dupilumab treatment should be temporarily discontinued until the infection resolves.

[0623] If a participant missed three or more consecutive doses, they would be discontinued from study treatment entirely.

[0624] For all temporary intervention interruptions, the duration should be recorded by the investigator on the appropriate page of the eCRF.

[0625] If the investigator determines, based on their best medical judgment, that IMP is unlikely to have been involved in the occurrence of the event and the patient still meets the inclusion criteria for the trial, administration of IMP will be resumed under close and appropriate clinical and laboratory monitoring.

[0626] Efficacy evaluation The e-diary will be used to record daily ColdUAS questionnaires; record daily use of H1 antihistamines; assess DLQI (ages 16 years and over) / CDLQI (ages 12 years and over but under 16 years), UCT, ColdU-QoL and EQ-5D-5L at study site visits; assess peak itch NRS, peak burning NRS and peak pain NRS after provocation testing; and assess PGIS and PGIC after participants have completed the NRS.

[0627] The timing of the assessments is specified in Figure 2.

[0628] The device will be dispensed with instructions for use at the screening visit (Visit 1), and participants will be instructed on using the device.

[0629] The recorded information is downloaded from this device daily. At the EOT visit, the e-diary is downloaded and returned to the testing center.

[0630] Study center staff should periodically and when alerted, check compliance with background therapy and the entire e-diary, including ColdUAS. Study centers should follow up with participants as necessary.

[0631] The wheal intensity Likert scale and absence / absence days questionnaire will be completed by the investigator / study center staff on the eCRF.

[0632] Various test types Ice cube provocation test Cold urticaria is defined as the appearance of signs and symptoms (rash / wheals, itching, pain, and burning sensation) after contact cooling and rewarming of the skin. Chronic provocative urticaria, including primary acquired Cold U, is diagnosed based on the patient's medical history and the results of provocation tests. Furthermore, in clinical studies of patients with chronic urticaria, cold provocation tests are primarily used to evaluate the efficacy of antihistamine treatment. However, studies also evaluate the proportion of patients who remain free of signs / symptoms in cold provocation tests after treatment with doxypine, cyproheptadine, and other drugs, and evaluate experimental cold shock tests (CSTTs), i.e., the minimum time threshold for cold stimulation required to induce confluent wheals and other signs and symptoms of Cold U.

[0633] The ice cube provocation test was proposed for this clinical study because it is the most frequently used method for provoking ColdU in daily clinical practice.

[0634] ColdU(EAACI / GA 2 The consensus recommendations for the LEN / EDF / UNEV (Labour Council for Emergency Medicine) define the method of provocation for ColdU as follows: The provocation test should be performed by applying cold to the skin of the forearm. The traditional provocation test should be performed on the volar forearm for 5 minutes. The ice cube should be melted in a thin plastic bag to avoid cold damage to the skin, and if the test is positive, it should not come into direct contact with water to avoid confusion with aquagenic urticaria; the evaluation period is 10 minutes after removing the ice cube and rewarming it.

[0635] If a severe hypersensitivity reaction occurs during ice cube provocation testing, emergency procedures should be available at the testing center to be administered by trained testing center staff.

[0636] The procedure for the ice cube provocation test will be described in a separate document.

[0637] The primary endpoint will be the proportion of participants with a negative ice cube challenge, defined as the absence of a confluent rash / wheal over the exposed skin area after ice cube challenge at Week 24. Assessment will be performed by the investigator 10 minutes after ice cube removal. Results will be recorded on the eCRF.

[0638] Likert scale of wheal intensity The wheal intensity Likert scale (ranging from 0 to 5) is a clinician-reported outcome measure using a single item to assess the intensity of the patient's skin reaction as follows: 0 = no wheals; 1 = numerous small, non-edematous wheals; 2 = large, regular, slightly edematous, coalescing wheals; 3 = large, moderately edematous wheals; 4 = large, regular, markedly edematous wheals without pseudopodia; and 5 = large, very edematous wheals with pseudopodia.

[0639] The investigator will complete the scale at the study visit, 10 minutes after removing the ice cube from the participant's arm. The investigator will complete the wheal intensity Likert scale on the eCRF, as depicted in Figure 2.

[0640] Peak pruritus numerical rating scale (NRS), peak pain NRS, peak burning NRS Upon arrival at the study site, participants will undergo a thermal provocation test using an ice cube. Ten minutes after removing the ice cube from their arm, participants will be asked to rate the severity of local itching, pain, and burning sensations on the skin at the provocation site using an NRS.

[0641] The Peak Pruritus NRS is a single-item PRO rated on a scale ranging from 0 ("no itch") to 10 ("worst itch imaginable"). Participants are asked to rate the intensity of their worst localized itch 10 minutes after removing the ice cube. This 24-hour version of the scale was developed, tested, and validated in patients with atopic dermatitis (AD). A meaningful threshold for intra-individual change in score was established at 4 in adults and adolescents with AD.

[0642] The Peak Pain NRS is a one-item PRO rated on a scale from 0 ("no pain") to 10 ("worst pain imaginable"). Participants are asked to rate the intensity of their worst localized pain 10 minutes after removing the ice cube.

[0643] The Peak Burning Sensation NRS is a single-item PRO rated on a scale from 0 ("no burning") to 10 ("the worst burning sensation imaginable"). Participants are asked to rate the intensity of the worst local skin burning sensation 10 minutes after removing the ice cube.

[0644] Participants completed the NRS as outlined in Figure 2.

[0645] Urticaria Control Test (UCT) 4-item version The UCT is a PRO questionnaire for assessing urticaria control. The questionnaire was developed and validated for CSU and ColdU patients. It consists of four items: severity of urticaria physical symptoms (itching, rash, and / or swelling), QoL impairment, frequency of treatments that do not adequately control urticaria, and overall urticaria control. The recall period is "the past 4 weeks." Each item is rated on a 5-point Likert scale (scored 0 to 4 points). Lower scores indicate higher disease activity and lower disease control. The UCT total score is calculated by adding the scores of all four individual items. Therefore, the minimum UCT score is 0 and the maximum is 16, with 16 indicating complete disease control.

[0646] UCT's MID is set at 3.

[0647] Participants complete the UCT as described in Figure 2.

[0648] Cold Urticaria Activity Score (ColdUAS) The ColdUAS is a disease-specific PRO questionnaire designed to assess disease activity in cold urticaria. It is intended for patients aged 12 years and older and has been developed and comprehensively tested in both adult and adolescent cold urticaria patients. Disease activity assessment is based on daily recording of cold-induced skin reactions (wheals and swelling), skin sensations (itching, burning, pain, and burning), avoidance behaviors and trigger exposures, and overall symptom severity. Skin reactions, skin sensations, exposure to cold temperatures that typically cause ColdU symptoms, and overall symptom severity are rated on a 4-point scale from 0 ("no") to 4 ("yes, severe"). Avoidance of cold temperatures that typically cause ColdU symptoms is answered with the following responses: "no," "partially avoided," or "completely avoided."

[0649] After each week, participants were asked about their overall disease activity in ColdU over the past week using a 4-point Likert scale ranging from "no disease activity" to "high disease activity." After each two-week period, participants were asked about their overall disease activity in ColdU over the past two weeks using a 4-point Likert scale ranging from "no disease activity" to "high disease activity." They were also asked to rate their disease activity in week 2 compared to week 1, from "significantly higher than week 1" to "significantly lower than week 1."

[0650] Daily ColdUAS will be summed over 7 days to form ColdUAS7, which will be assessed at baseline, week 12, and week 24.

[0651] Participants complete the ColdUAS as described in Figure 2.

[0652] Dermatology Life Quality Index and Pediatric Dermatology Life Quality Index (DLQI) The DLQI is a PRO developed to measure dermatology-specific HRQoL in adult participants. The instrument includes 10 items assessing the impact of skin disease on participants' HRQoL over the previous week. Items cover symptoms, leisure activities, time spent at work / school or on holidays, relationships including intimacy, side effects of treatment, and emotional reactions to having a skin disease. It is a validated questionnaire used in clinical practice and clinical trials. The response scale is a 4-point Likert scale (0 = "not at all" and 3 = "very much") for 9 items. The remaining item, related to work / exams, asks whether work / exams were interfered with and then (if "no") asks how much the skin condition caused problems at work / exams. Items are rated on a 3-point Likert scale ("not at all" to "very much"). The total score ranges from 0 to 30, with higher scores indicating poorer HRQoL. Using a pooled analysis of distribution- and anchor-based approaches using changes in DLQI total scores and participant-rated pruritus severity scores, the MID of the DLQI in participants with chronic idiopathic urticaria was reported to range from 2.24 to 3.10 points. To date, the MID value for ColdU patients has not been determined.

[0653] Participants will complete the DLQI (ages 16 and over) described in Figure 2.

[0654] Pediatric Dermatology Life Quality Index (CDLQI) The CDLQI is a validated questionnaire designed to measure the impact of skin diseases on children's HRQoL. Participants answer 10 questions (symptoms associated with the disease, leisure time, school or holidays, relationships, impact of the disease on sleep, and side effects of skin disease treatment). The recall period for this instrument is 7 days. Nine of the 10 questions are scored on a 4-point Likert scale ranging from "0 = not at all / not answered" to "3 = very much." Question 7 includes an additional answerable item (prevention group), worth 3 points. The total CDLQI score is the sum of the scores for each question, with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on the child's HRQoL.

[0655] Participants complete the CDLQI (ages 12 to 16 years) as described in Figure 2.

[0656] Cold Urticaria Quality of Life Questionnaire (ColdU-QoL) The ColdU-QoL questionnaire is a newly developed disease-specific PRO questionnaire to assess the impact of cold urticaria on patients' health-related quality of life. It has been developed and comprehensively tested in adult and adolescent cold urticaria patients. The questionnaire contains 19 items, each rated on a 5-point Likert scale ranging from 0 (not at all / not at all) to 4 (very much / very much), with a recall period of "past 2 weeks." The sum of the ColdU-QoL raw scores is converted to a scale of 0 to 100, with higher scores indicating greater ColdU-related quality of life impairment.

[0657] Participants completed the ColdU-QoL as described in Figure 2.

[0658] Patient Global Impression of Change (PGIC) and Participant Global Impression of Severity (PGIS) The PGIC is a one-item questionnaire that asks participants to globally self-assess their change in ColdU compared to just before they started receiving study treatment on a 7-point scale. Response options are as follows: 0 = "much better," 1 = "slightly better," 2 = "slightly better," 3 = "no change," 4 = "slightly worse," 5 = "slightly worse," and 6 = "very worse."

[0659] The PGIS is a one-item questionnaire that asks participants to globally self-assess the severity of their current cold on a four-point scale, with response options as follows: 1 = "none," 2 = "mild," 3 = "moderate," and 4 = "severe."

[0660] Participants completed two items after answering the Peak Itch NRS, Pain NRS, and Skin Burning NRS, as outlined in Figure 2.

[0661] Acquired Cold Urticaria Severity Index (ACUSI) The ACUSI is an index designed to assess the severity of signs / symptoms of acquired cold urticaria (ACU). It consists of four questions regarding the severity of ACU: 1) the worst ever problem caused by cold urticaria, 2) the season when outdoor activity is problematic due to cold, 3) the maximum treatment required, and 4) the frequency of the complaint. Questions 1, 3, and 4 are scored 1–4 points, and question 3 is scored 1–3 points, resulting in a score of 4–15 points. 4–7 points, 8–11 points, and 12–15 points indicate low, moderate, and high severity of ACU, respectively. The fifth question assesses the overall severity of the illness as mild, moderate, or severe.

[0662] The ACUSI questionnaire will be recorded on the eCRF.

[0663] EuroQol-5 Dimensions Questionnaire (EQ-5D) The EQ-5D is a standardized PRO measure of health status developed by the EuroQol Group to provide a simple and general measure of health for clinical and economic evaluation. The EQ-5D consists of two parts: a narrative system (EQ-5D-5L) and a EuroQol visual analog scale (EQ-VAS). The EQ-5D 5L narrative consists of five items: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each item has five levels of perceived problems: "no problems," "mild problems," "moderate problems," "severe problems," and "extremely serious problems." Respondents are asked to indicate their health status by checking a box (or crossing out) the most appropriate statement for each of the five items. This results in a single-digit number representing the level of that dimension. The five item numbers can be combined to form a five-digit number describing the respondent's health status. The EQ VAS records respondents' self-rated health status on a vertical visual analog scale (VAS), where endpoints are labeled "best possible health state (100)" and "worst possible health state (0)." This information can be used as a quantitative measure of health outcomes as judged by individual respondents.

[0664] The recall period is "today."

[0665] Participants will fill out the questionnaire as described in Figure 2.

[0666] Medical resource utilization / productivity Questionnaires regarding healthcare resource utilization and productivity (number of days absent [12–17 years] / number of days worked [18 years and older]) will be collected by the investigator for all participants throughout the study via eCRF.

[0667] Participants will fill out the questionnaire as described in Figure 2.

[0668] Adverse events and serious adverse events Definition of AE An AE is any untoward medical occurrence in a patient or clinical trial participant temporally related to the use of the study intervention, whether or not considered related to the study intervention. Note: Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) temporally related to the use of the study intervention.

[0669] Definition of SAE An SAE is defined as any event at any dose that results in death, is life-threatening, requires hospitalization or prolongs existing hospitalization, results in persistent disability / disability, is a congenital anomaly / birth defect, or is medically unexpected.

[0670] AEs will be reported by the participant (or, where appropriate, by a caregiver, parent, surrogate, or legally authorized representative of the participant).

[0671] The investigator and qualified designee are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE, and for tracking serious AEs that are considered related to the study intervention or study procedures, or that cause a participant to discontinue the study intervention.

[0672] AE and SAE information collection period and frequency All AEs, both serious and non-serious, will be collected at the time points specified in Figure 2 from the time the ICF was signed until the EOS visit.

[0673] All SAEs and AESIs will be recorded and reported to the Sponsor or designee promptly, but in no event more than 24 hours. The Investigator will provide updated SAE / AESI data to the Sponsor within 24 hours of its availability.

[0674] The investigator is under no obligation to actively investigate AEs or SAEs after study participation has ended. However, if the investigator learns of an SAE, including death, at any time after a participant has left the study and determines that the event is reasonably related to the study intervention or participation, the investigator must promptly notify the sponsor.

[0675] AE and SAE detection methods It describes how to record, evaluate, and assess causality of AEs and SAEs, as well as procedures for completing and submitting SAE reports.

[0676] Care should be taken to avoid bias when detecting AEs and / or SAEs. Open-ended, non-leading verbal questions are preferred when inquiring about the occurrence of AEs.

[0677] AE and SAE follow-up After the first AE / AESI / SAE report, investigators are expected to actively follow up each participant at subsequent visits / contacts. At the pre-specified study end date, all SAEs and non-serious AESIs will be followed until they have resolved, stabilized, the event is explained, or the participant is lost to follow-up.

[0678] Disease-related events and / or disease-related outcomes that are not AEs or SAEs ColdU episodes should only be reported as an AE or SAE if the investigator determines that the severity and / or frequency unexpectedly worsened or changed in nature. If a participant has a history of angioedema and the condition worsens during the study, it should be reported as an AE or SAE. New-onset angioedema in a participant with no prior history of angioedema should also be reported as an AE or SAE.

[0679] IBs or other AEs not listed as expected in this protocol will be considered unexpected.

[0680] Adverse events of special interest An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the sponsor's product or program that requires ongoing monitoring and immediate notification by the investigator to the sponsor. Such events may require further investigation to characterize and understand them. Adverse events of special interest may be added, modified, or removed by protocol amendment during the trial.

[0681] AESIs are as follows: anaphylactic reaction; systemic hypersensitivity reaction; helminth infection; any severe conjunctivitis or blepharitis; keratitis; clinically symptomatic eosinophilia (or clinically symptomatic eosinophilia); significant ALT elevation (ALT >5 x ULN in participants with baseline ALT ≤2 x ULN; or ALT >8 x ULN if baseline ALT >2 x ULN); pregnancy in female participants in studies with IMP, and pregnancy in female partners of male participants in studies with IMP (pregnancy in female participants in clinical trials or female partners of male participants in clinical trials). Only if one of the severity criteria is met will it be considered an SAE; if a female participant becomes pregnant, the IMP must be discontinued; pregnancy in a female participant or the female partner of a male participant requires mandatory follow-up until outcome is known; symptomatic overdose (serious or non-serious) with an IMP / non-investigational medicinal product (NIMP) (an overdose (accidental or intentional) with an IMP is an event suspected by the investigator or spontaneously notified by the participant (not based on systematic pill counts) in which an underdose of the intended dose occurs less than 11 days apart. An overdose is defined as at least twice the prescribed maximum daily dose administered. The circumstances of the overdose (i.e., accidental or intentional) must be clearly specified on the overdose form. An overdose (accidental or intentional) with any NIMP is defined as an event suspected by the investigator or spontaneously reported by the participant (not based on systematic pill counts) in which at least twice the prescribed maximum daily dose is administered within the intended treatment interval. The circumstances of the overdose (i.e., accidental or intentional) must be clearly specified on the overdose form.

[0682] anaphylactic reaction A serious feature of ColdU is anaphylaxis: 35% to 70% of patients who use ColdU experience systemic reactions, including anaphylaxis in severe cases.

[0683] Anaphylaxis is defined as a severe, potentially life-threatening, systemic hypersensitivity reaction characterized by a rapid onset of life-threatening airway, respiratory, and circulatory compromise, usually, but not always, accompanied by changes to the skin and mucous membranes.

[0684] If a diagnosis of anaphylaxis is made, the basis for suspecting the diagnosis must be documented. Reports of anaphylaxis will be captured in the eCRF as AESIs.

[0685] All participants with ColdU and their parents / legal guardians / caregivers should be warned about the risk of anaphylaxis and provided with an epinephrine autoinjector.

[0686] To assess the proportion of participants whose cold exposure induced urticaria and required emergency visits or treatment with epinephrine (after provocation testing and / or at home).

[0687] Pharmacodynamics Venous blood samples will be collected from all participants for measurement of total serum IgE using a validated quantitative method. No other pharmacodynamic parameters will be assessed in this study.

[0688] Determining sample size To obtain sufficient statistical power to compare the proportion of participants with a negative ice-cube challenge test at week 24, the primary endpoint, between the two groups, the sample size was calculated based on the following assumptions: in the placebo group, 15% of participants had a negative ice-cube challenge test at week 24, and in the dupilumab group, 55% had a negative ice-cube challenge test at week 24; the dropout rate was 15% in both groups; the statistical test was a Z-test based on the difference between the two proportions, with a non-pooled variance estimate and a two-sided 5% significance level; participants were equally randomly assigned to the dupilumab and placebo groups.

[0689] Using these assumptions, a total of 60 patients (30 in each group) would provide 90% power to detect a difference in response rate between 55% in the dupilumab group and 15% in the placebo group. Sample size calculations were performed using nQuery+nTerim 4.0.

[0690] Analysis population The analysis population is defined in Table 7.

[0691] [Table 27]

[0692] Example 2. A multicenter, single-arm study investigating the pharmacokinetics and safety of dupilumab in male and female participants aged 2 to 12 years with uncontrolled chronically inducible cold urticaria (ColdU). Research Principles Chronic urticaria is defined as the appearance of itchy wheals (rash) with or without angioedema for more than 6 weeks. Chronic urticaria is divided into chronic provoked urticaria (also called physical urticaria, including chronic provoked cold urticaria (ColdU)) and chronic spontaneous urticaria (CSU), in which no provoking factor has been identified.

[0693] Antihistamines are the mainstay of treatment, but up to 50% of patients may not be controlled with antihistamines alone. Treating pediatric Cold U patients remains challenging. The pathophysiology of these conditions is thought to be similar across all age groups, making antihistamines the first-line treatment. However, there remains a significant unmet need for novel treatments for these indications, particularly in children.

[0694] Study design The PKM16982 study is a phase 3, multicenter, single-arm, 24-week treatment trial evaluating the PK and safety of dupilumab in patients with ColdU aged 2 to less than 12 years who are not adequately controlled with H1 antihistamine therapy and / or appropriate prophylaxis.

[0695] The primary objective of this study is to characterize the PK profile, and the secondary objective is to evaluate the safety profile of dupilumab in children aged 2 to 12 years with uncontrolled Cold U. The study will also collect clinical information on treatment effects in this age group, but all efficacy analyses will be descriptive.

[0696] In this study, all enrolled participants will receive dupilumab injections in a weight / age-stratified dosing regimen for 24 weeks, followed by a 12-week post-treatment observation period at the end of the study intervention.

[0697] The study consists of three periods: -Screening period (2-4 weeks) -Study intervention period (24 weeks) -Follow-up period (12 weeks) -The study duration is 38-40 weeks (including screening and follow-up). The number of clinical trial visits will be 8.

[0698] Screening Period Prior to screening, participants must be receiving treatment with a non-sedating H1 antihistamine for CSU or ColdU. ColdU participants must have confirmed active disease at the time of the screening visit, such as a positive ice cube provocation test.

[0699] The screening period is 2 to 4 weeks.

[0700] Treatment duration Participants who successfully complete the screening period will enter the treatment period. All participants will receive dupilumab subcutaneously (SC) every 4 weeks (Q4W) or every 2 weeks (Q2W) with or without a loading dose based on their weight and age.

[0701] Post-treatment period After completing the treatment period, all participants will complete a 12-week post-treatment follow-up period without any study intervention.

[0702] the purpose primary purpose To characterize dupilumab serum concentrations over time.

[0703] Secondary Objectives -To evaluate the safety of dupilumab. -To evaluate the immunogenicity of dupilumab. To evaluate the improvement in health-related quality of life in dupilumab-treated subjects with Cold U who remain symptomatic despite the use of H1 antihistamines. To assess the effect of dupilumab on urticaria activity in ColdU participants who remain symptomatic despite the use of H1 antihistamines or appropriate preventive measures.

[0704] endpoint -C at 12 and 24 weeks trough Changes in serum dupilumab concentrations over time, including: - Safety and tolerability assessment: incidence of TEAEs or SAEs. - Changes in the incidence of ADAs in response to dupilumab over time. Change from baseline in C-DLQI at week 24 in children aged 4 to <12 years Change from baseline in IDQOL (at 24 weeks) in children aged 2 to less than 4 years. - Percentage of participants with a negative ice cube challenge test at week 24. Change from baseline in wheal intensity Likert scale at week 24.

[0705] Inclusion criteria Participants were eligible for inclusion in the study only if all of the following criteria were met:

[0706] Age and weight Participants must be between 2 and 12 years of age and weigh between 5 and 60 kg at the time of signing the informed consent.

[0707] Participant type and disease characteristics Participants with a ColdU diagnosis from 6 months prior to the screening visit.

[0708] ColdU participants Participants with symptoms of ColdU (cold-induced angioedema with or without recurrent pruritic wheals lasting for 6 weeks or more) who remain symptomatic at screening despite regular or as-needed use of H1 antihistamines or appropriate preventive measures.

[0709] At the screening visit, one ColdU participant had a positive reaction to ice cube provocation testing and presented with a confluent rash / wheals over the exposed skin area.

[0710] compliance The participant / parent / carer / participant's legal representative (if applicable) is willing and able to comply with the study visit and related procedures.

[0711] Exclusion criteria Participants were excluded from the study if any of the following criteria applied:

[0712] medical conditions Underlying chronic urticaria other than CSU.

[0713] The presence of skin diseases other than CSU that may affect the assessment of study results.

[0714] Participants diagnosed with both CSU and ColdU.

[0715] Participants with active AD.

[0716] Serious comorbidities that may adversely affect a patient's participation in the study.

[0717] Participants with a history of active tuberculosis (TB) or nontuberculous mycobacterial infection, or inadequately treated TB.

[0718] Those who have been diagnosed with, are suspected of having, or are at high risk of having an internal parasitic infection.

[0719] Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks of the screening visit (V1) or during the screening period.

[0720] Known or suspected immunodeficiency.

[0721] Active or history of malignancy within 5 years prior to the baseline visit.

[0722] History of systemic hypersensitivity or anaphylaxis to dupilumab (including excipi...

Claims

1. 1. A method of treating a subject with chronic-induced cold urticaria (ColdU), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; The method, wherein the subject has an improved Cold Urticaria Activity Score (ColdUAS).

2. 10. The method of claim 1, wherein the subject remains symptomatic despite use of an H1 antihistamine.

3. 3. The method of claim 1 or 2, wherein an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

4. 4. The method of claim 3, wherein the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

5. The method of any one of claims 1 to 4, wherein the subject is an adult.

6. 6. The method of claim 5, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses.

7. 7. The method of claim 6, wherein the initial dose is about 600 mg and each secondary dose is about 300 mg.

8. 8. The method of claim 7, wherein each secondary dose is administered every two weeks.

9. The method of any one of claims 1 to 4, wherein the subject is aged between 12 and 18 years.

10. 10. The method of claim 9, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses.

11. 11. The method of claim 10, wherein the subject weighs 30 kg or greater but less than 60 kg, the initial dose is about 400 mg, and each secondary dose is about 200 mg.

12. 12. The method of claim 11, wherein each secondary dose is administered every two weeks.

13. 13. The method of claim 12, wherein the subject weighs at least 60 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

14. 14. The method of claim 13, wherein each secondary dose is administered every two weeks.

15. The method of any one of claims 1 to 4, wherein the subject is 6 to under 12 years old.

16. The method of any one of claims 1 to 4, wherein the subject is between 2 and under 12 years old.

17. 17. The method of claim 15 or 16, wherein the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses.

18. 18. The method of claim 17, wherein the subject weighs 30 kg or more, the initial dose is about 400 mg, and each secondary dose is about 200 mg.

19. 20. The method of claim 18, wherein each secondary dose is administered every two weeks.

20. 20. The method of claim 19, wherein the subject weighs greater than or equal to 15 kg and less than 30 kg, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

21. 21. The method of claim 20, wherein each secondary dose is administered every four weeks.

22. 22. The method of claim 21, wherein the subject weighs greater than or equal to 15 kg and less than 30 kg, the initial dose is about 300 mg, and each secondary dose is about 300 mg.

23. 23. The method of claim 22, wherein each secondary dose is administered every four weeks.

24. 24. The method of claim 23, wherein the subject is at least 2 years old but less than 6 years old.

25. 18. The method of claim 17, wherein the subject weighs greater than or equal to 5 kg and less than 15 kg, the initial dose is about 200 mg, and each secondary dose is about 200 mg.

26. 26. The method of claim 25, wherein each secondary dose is administered every four weeks.

27. 27. The method of claim 26, wherein the subject is at least 2 years old but less than 6 years old.

28. 1. A method of treating a subject with chronic-induced cold urticaria (ColdU), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; the subject is 12 to under 18 years of age; the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses; the antibody or antigen-binding fragment thereof is administered to the subject at a weight-dependent dose; and The method, wherein the subject has an improved Cold Urticaria Activity Score (ColdUAS).

29. 29. The method of claim 28, wherein the subject weighs at least 30 kg but less than 60 kg, and the initial dose is about 400 mg and each secondary dose is about 200 mg.

30. 29. The method of claim 28, wherein the subject weighs 60 kg or more, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

31. 31. The method of claim 29 or 30, wherein each secondary dose is administered every two weeks.

32. 32. The method of any one of claims 28 to 31, wherein an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

33. 1. A method of treating a subject with chronic-induced cold urticaria (ColdU), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; the subject is 12 to under 18 years of age; the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses; the antibody or antigen-binding fragment thereof is administered to the subject at a weight-dependent dose; the subject has previously been treated ineffectively with antihistamine therapy; and The method, wherein the subject has an improved Cold Urticaria Activity Score (ColdUAS).

34. 34. The method of claim 33, wherein the subject weighs 30 kg or greater but less than 60 kg, and the initial dose is about 400 mg and each secondary dose is about 200 mg.

35. 34. The method of claim 33, wherein the subject weighs 60 kg or more, the initial dose is about 600 mg, and each secondary dose is about 300 mg.

36. 36. The method of claim 34 or 35, wherein each secondary dose is administered every two weeks.

37. 37. The method of any one of claims 33 to 36, wherein the subject remains symptomatic despite the use of an H1 antihistamine.

38. 38. The method of any one of claims 33 to 37, wherein an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

39. 39. The method of claim 37 or 38, wherein the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

40. 1. A method of treating a subject with chronic-induced cold urticaria (ColdU), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; the subject is between 6 and 12 years of age; the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses; the antibody or antigen-binding fragment thereof is administered to the subject at a weight-dependent dose; the subject has previously been treated ineffectively with H1 antihistamine therapy; and The method, wherein the subject has an improved Cold Urticaria Activity Score (ColdUAS).

41. 41. The method of claim 40, wherein the subject weighs at least 15 kg but less than 30 kg, and the initial dose is about 600 mg and each secondary dose is about 300 mg.

42. 42. The method of claim 41, wherein each secondary dose is administered every four weeks.

43. 43. The method of any one of claims 40 to 42, wherein the subject remains symptomatic despite the use of an H1 antihistamine.

44. 44. The method of any one of claims 40 to 43, wherein an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

45. 1. A method of treating a subject with chronic-induced cold urticaria (ColdU), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; The subject weighs 30 kg or more and less than 60 kg, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses; the antibody or antigen-binding fragment thereof is administered to the subject at a weight-dependent dose; the subject has previously been treated ineffectively with H1 antihistamine therapy; and The method, wherein the subject has an improved Cold Urticaria Activity Score (ColdUAS).

46. 46. ​​The method of claim 45, wherein the initial dose is about 400 mg and each secondary dose is about 200 mg.

47. 46. ​​The method of claim 45, wherein each secondary dose is administered every two weeks.

48. 46. ​​The method of claim 45, wherein the subject is at least 6 years old but less than 12 years old.

49. 49. The method of any one of claims 45 to 48, wherein the subject remains symptomatic despite the use of an H1 antihistamine.

50. 50. The method of any one of claims 45 to 49, wherein an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

51. 51. The method of claim 49 or 50, wherein the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

52. 1. A method of treating a subject with chronic-induced cold urticaria (ColdU), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; The subject weighs 5 kg or more and less than 15 kg, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses; the antibody or antigen-binding fragment thereof is administered to the subject at a weight-dependent dose; the subject has previously been treated ineffectively with H1 antihistamine therapy; and The method, wherein the subject has an improved Cold Urticaria Activity Score (ColdUAS).

53. 53. The method of claim 52, wherein the initial dose is about 200 mg and each secondary dose is about 200 mg.

54. 53. The method of claim 52, wherein each secondary dose is administered every four weeks.

55. 53. The method of claim 52, wherein the subject is at least 2 years old but less than 6 years old.

56. 56. The method of any one of claims 52 to 55, wherein the subject remains symptomatic despite the use of an H1 antihistamine.

57. 57. The method of any one of claims 52 to 56, wherein an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

58. 58. The method of claim 56 or 57, wherein the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

59. 1. A method of treating a subject with chronic-induced cold urticaria (ColdU), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; The subject weighs 15 kg or more and less than 30 kg, The subject is 2 years old or older but younger than 6 years old, the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses; the antibody or antigen-binding fragment thereof is administered to the subject at a weight-dependent dose; the subject has previously been treated ineffectively with H1 antihistamine therapy; and The method, wherein the subject has an improved Cold Urticaria Activity Score (ColdUAS).

60. 60. The method of claim 59, wherein the initial dose is about 300 mg and each secondary dose is about 300 mg.

61. 60. The method of claim 59, wherein each secondary dose is administered every four weeks.

62. 62. The method of any one of claims 59 to 61, wherein the subject remains symptomatic despite the use of an H1 antihistamine.

63. 63. The method of any one of claims 59 to 62, wherein an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

64. 64. The method of claim 62 or 63, wherein the H1 antihistamine is selected from the group consisting of cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine, bilastine, and rupatadine.

65. 1. A method of treating a subject with chronic-induced cold urticaria (ColdU), comprising administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; the subject is between 2 and under 12 years of age; the antibody or antigen-binding fragment thereof is administered to the subject as an initial dose, followed by one or more secondary doses; the antibody or antigen-binding fragment thereof is administered to the subject at a weight-dependent dose; the subject has previously been treated ineffectively with H1 antihistamine therapy; and The method, wherein the subject has an improved Cold Urticaria Activity Score (ColdUAS).

66. 66. The method of claim 65, wherein the subject weighs at least 5 kg but less than 15 kg, the initial dose is about 200 mg, and each secondary dose is about 200 mg.

67. 67. The method of claim 66, wherein each secondary dose is administered every four weeks.

68. 66. The method of claim 65, wherein the subject is at least 2 years old but less than 6 years old.

69. 69. The method of claim 65 or 68, wherein the subject weighs greater than or equal to 15 kg and less than 30 kg, the initial dose is about 300 mg, and each secondary dose is about 300 mg.

70. 70. The method of claim 69, wherein each secondary dose is administered every four weeks.

71. 66. The method of claim 65, wherein the subject is at least 6 years old but less than 12 years old.

72. 72. The method of claim 65 or 71, wherein the subject weighs greater than or equal to 15 kg and less than 30 kg, and the initial dose is about 600 mg and each secondary dose is about 300 mg.

73. 73. The method of claim 72, wherein each secondary dose is administered every four weeks.

74. 66. The method of claim 65, wherein the subject weighs greater than or equal to 30 kg and less than 60 kg, and the initial dose is about 400 mg and each secondary dose is about 200 mg.

75. 75. The method of claim 74, wherein each secondary dose is administered every two weeks.

76. 76. The method of any one of claims 65 to 75, wherein the subject remains symptomatic despite the use of an H1 antihistamine.

77. 77. The method of any one of claims 65 to 76, wherein an H1 antihistamine is administered in combination with the antibody or antigen-binding fragment thereof.

78. 78. The method of any one of claims 1-77, wherein said treatment improves one or more ColdU-related outcomes selected from the group consisting of ice cube provocation test score, wheal intensity Likert scale score, pruritus peak Numerical Rating Scale (NRS) score, pain peak NRS score, burning peak NRS score, Urticaria Control Test (UCT) 4-item score, Pediatric Dermatology Life Quality Index (CDLQI) score, Infant Dermatitis Quality of Life Index (IDQOL) score, Patient Global Impression of Change (PGIC) score, Participant Global Impression of Severity (PGIS) score, Acquired Cold Urticaria Severity Index (AColdUSI) score, 5-item 5-point questionnaire (EQ-5D-5L) score, and healthcare resource utilization / productivity score.

79. 79. The method of claim 78, wherein the improvement in the one or more measures associated with ColdU occurs with 12 weeks of treatment with the antibody or antigen-binding fragment thereof.

80. 79. The method of any one of claims 1-78, wherein the improvement in the one or more measures related to ColdU occurs with 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

81. 81. The method of any one of claims 1 to 80, wherein the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

82. 82. The method of any one of claims 1-81, wherein said treatment with said antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by said subject.

83. 83. The method of any one of claims 1-82, wherein treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

84. 84. The method of any one of claims 1 to 83, wherein treatment with the antibody or antigen-binding fragment thereof reduces the subject's need for treatment with oral corticosteroids.

85. 85. The method of claim 84, wherein the required oral corticosteroid dosage is reduced.

86. 86. The method of claim 84 or 85, wherein the number of days oral corticosteroid therapy is required is reduced.

87. 87. The method of any one of claims 1 to 86, wherein treatment with the antibody or antigen-binding fragment thereof reduces the subject's need for treatment with an antihistamine rescue drug.

88. 88. The method of claim 87, wherein the required dosage of antihistamine rescue drug is reduced.

89. 89. The method of claim 87 or 88, wherein the number of days requiring antihistamine rescue medication is reduced.

90. 90. The method of any one of claims 1 to 89, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) sequence of SEQ ID NO:

2.

91. 91. The method of any one of claims 1 to 90, wherein the antibody is dupilumab.

92. 92. The method of any one of claims 1 to 91, wherein the antibody or antigen-binding fragment thereof is administered using an autoinjector, a needle and syringe, or a pen.

93. 93. The method of any one of claims 1 to 92, wherein the antibody or antigen-binding fragment thereof is administered using a pre-filled device.

94. 94. The method of any one of claims 1 to 93, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

95. 1. A method of treating chronically induced cold urticaria (ColdU) in a subject, comprising: Selecting a subject for ColdU; administering to the subject an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R); the antibody or antigen-binding fragment thereof comprises three heavy chain CDR sequences comprising SEQ ID NOs: 3, 4, and 5, respectively, and three light chain CDR sequences comprising SEQ ID NOs: 6, 7, and 8, respectively; The method, wherein the subject has an improved Cold Urticaria Activity Score (ColdUAS).

96. 96. The method of claim 95, wherein the subject has angioedema prior to treatment with the antibody or antigen-binding fragment thereof.

97. 96. The method of claim 95, wherein said treatment with said antibody or antigen-binding fragment thereof results in an increase in the number of pruritus-free days experienced by said subject.

98. 96. The method of claim 95, wherein treatment with the antibody or antigen-binding fragment thereof results in an increase in the number of rash-free days experienced by the subject.

99. 96. The method of claim 95, wherein said treatment with said antibody or antigen-binding fragment thereof reduces the subject's need for treatment with oral corticosteroids.

100. 100. The method of any one of claims 1 to 99, wherein the ColdUAS score is measured as the number of sign and symptom-free days on cold-exposed days or by a severity score of signs and symptoms on cold-exposed days.

101. 101. The method of claim 100, wherein the ColdUAS score is reduced by 24 weeks of treatment with the antibody or antigen-binding fragment thereof.

102. 102. The method of any one of claims 1 to 101, wherein total serum IgE is reduced in the subject.

103. 103. The method of claim 102, wherein 24 weeks of treatment with the antibody or antigen-binding fragment thereof reduces the total serum IgE.

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