Methods for treating atopic dermatitis by administering il-4r antagonist

Abstract

To provide pharmaceutical compositions for novel target therapy for treating and / or preventing atopic dermatitis (AD).SOLUTION: Disclosed is a pharmaceutical composition comprising an anti-interleukin-4 receptor (IL-4R) antibody or antigen binding fragment thereof for use in a method for reducing AD-associated biomarker levels in a patient with atopic dermatitis (AD), where the AD associated biomarker is a biomarker associated with type 2 helper T cell (Th2) induced inflammation, the patient shows an elevated level of the AD associated biomarker before or at the start of the treatment, the antibody or antigen binding fragment thereof comprises three heavy chain CDRs (HCDRs) of specific sequences and three light chain CDRs (LCDRs) of specific sequences.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the treatment and / or prevention of atopic dermatitis and related conditions. More particularly, the present invention relates to the administration of an interleukin-4 receptor (IL-4R) antagonist to treat or prevent atopic dermatitis in a patient in need thereof. [Background technology]

[0002] Atopic dermatitis (AD) is a chronic / relapsing inflammatory skin disease characterized by intense pruritus (e.g., intense itching) and scaly and dry eczema lesions. AD is often associated with other atopic disorders such as allergic rhinitis and asthma. Severe disease can be extremely disabling due to major psychological problems, significant sleep loss, and reduced quality of life, resulting in high socio-economic costs.

[0003] The pathophysiology of AD is influenced by a complex interplay between immunoglobulin E (IgE) sensitization, the immune system, and environmental factors. The primary skin defect may be an immune disorder causing IgE sensitization, with epithelial barrier dysfunction resulting from both genetic mutations and local inflammation. AD often begins in children before the age of 5 and may continue into adulthood. Summary of the Invention [Problem to be solved by the invention]

[0004] Typical treatments for AD include topical lotions and moisturizers, topical corticosteroid ointments, creams or injections.However, many treatment options only provide temporary, incomplete, symptomatic relief.In addition, many patients with moderate to severe AD become resistant to topical corticosteroid or calcineurin inhibitor treatment.Thus, there is a need in the art for novel targeted therapies for the treatment and / or prevention of AD. [Means for solving the problem]

[0005] According to certain aspects of the present invention, methods are provided for treating, preventing, and / or reducing the severity of symptoms of atopic dermatitis (AD), including moderate to severe AD. Certain embodiments of the present invention relate to methods for treating, ameliorating, or preventing moderate to severe AD in patients who are resistant to treatment with topical corticosteroids or calcineurin inhibitors. In some embodiments, the present invention discloses a method for treating a patient with moderate to severe AD that is uncontrolled despite treatment with topical corticosteroids or calcineurin inhibitors. The method of the present invention comprises administering to a subject or patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL-4R) antagonist. According to certain embodiments of the present invention, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. Exemplary anti-IL-4R antibodies that can be used in the context of the methods of the present invention are described elsewhere herein, such as in Example 1. In certain embodiments, the IL-4R antagonist is an anti-IL-4R antibody having the binding characteristics of a reference antibody referred to herein as "mAb1" (an antibody or antigen-binding fragment thereof comprising the complementarity determining regions of mAb1). In one embodiment, the antibody or antigen-binding fragment thereof that binds to IL-4R comprises complementarity determining regions (CDRs) in the heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair of SEQ ID NO: 162 / 164.

[0006] Some embodiments of the present invention are directed to a method for treating, alleviating, improving, or preventing pruritus in a patient, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.In one embodiment, the patient suffers from moderate to severe AD.In some embodiments, the patient suffering from AD is resistant to treatment with either topical corticosteroids or calcineurin inhibitors.

[0007] In certain embodiments, the present invention includes a method of treating moderate to severe AD in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that binds to IL-4R, and determining an improvement in an AD-related parameter. The improvement can be determined or assayed or quantified by methods well known in the art. AD-related parameters and their improvement are discussed elsewhere herein, for example, in Example 7.

[0008] According to certain exemplary embodiments, the present invention provides a method for improving one or more AD-related parameters in a subject in need thereof.Improvement of AD-related parameters includes, for example, lowering Investigator's Global Assessment (IGA) score; lowering Body Surface Area Involvement of Atopic Dermatitis (BSA) score; lowering Eczema Area and Severity Index (EASI) score; lowering SCORAD score; lowering 5-D Pruritus Scale; and / or lowering Pruritus Numeric Rating Scale (NRS) score. In exemplary embodiments, the improvement in an AD-related parameter is selected from the group consisting of: (i) at least a 25% decrease from baseline in IGA score; (ii) at least a 35% decrease from baseline in BSA score; (iii) at least a 45% decrease from baseline in EASI score; (iv) at least a 30% decrease from baseline in SCORAD score; (v) at least a 15% decrease from baseline in 5-D itch scale; (vi) at least a 25% decrease from baseline in itch NRS score; and (vii) the percentage of responders showing greater than or equal to a 50% improvement in EASI (EASI50).

[0009] In some embodiments, the improvement in the AD-related parameter comprises at least a 25% decrease from baseline in IGA from day 22 to at least day 85 after administration of the pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that binds IL-4R. In some embodiments, the improvement in the AD-related parameter comprises at least a 40% decrease from baseline in BSA score from day 29 to at least day 85 after administration of the pharmaceutical composition. In some embodiments, the improvement in the AD-related parameter comprises at least a 50% decrease from baseline in EASI score from day 29 to at least day 85 after administration of the pharmaceutical composition. In certain embodiments, the improvement in the AD-related parameter comprises at least a 50% decrease from baseline in EASI score at day 29 in at least 70% of the subjects administered the pharmaceutical composition. In some embodiments, the improvement in the AD-related parameter comprises at least a 30% decrease from baseline in SCORAD score from day 29 to at least day 85 after administration of the pharmaceutical composition. In some embodiments, the improvement in the AD-related parameter comprises at least a 15% decrease from baseline in 5-D itch scale from day 15 to at least day 85 after administration of the pharmaceutical composition. In some embodiments, the improvement in AD-related parameters comprises at least a 25% decrease from baseline in NRS score at the end of the second week through at least the end of the tenth week after administration of the pharmaceutical composition.

[0010] In some embodiments, the improvement in the AD-related parameter comprises at least a 45% decrease from baseline in IGA from 85 days to at least 197 days after administration of a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist. In some embodiments, the improvement in the AD-related parameter comprises at least a 50% decrease from baseline in BSA score from 85 days to at least 197 days after administration of a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist. In some embodiments, the improvement in the AD-related parameter comprises at least a 60% decrease from baseline in EASI score from 85 days to at least 197 days after administration of a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist. In some embodiments, the improvement in the AD-related parameter comprises at least a 45% decrease from baseline in SCORAD score from 85 days to at least 197 days after administration of a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist. In some embodiments, the improvement in an AD-related parameter comprises at least a 30% decrease from baseline in the 5-D itch scale from day 85 to at least day 197 after administration of a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist. In some embodiments, the improvement in an AD-related parameter comprises at least a 50% decrease from baseline in the NRS score from day 85 to at least day 197 after administration of a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0011] According to another exemplary embodiment, the present invention provides a method for treating AD in a subject, comprising: (a) selecting a subject exhibiting an elevated level of at least one AD-associated biomarker; and (b) administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist. In certain embodiments, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that binds to IL-4R. Exemplary AD-associated biomarkers that can be assessed and / or measured in the context of the present invention include, but are not limited to, thymus and activation-regulated chemokine (TARC; also known as CCL17), immunoglobulin E (IgE), eotaxin-3, lactate dehydrogenase (LDH), eosinophils, antigen-specific IgE (e.g., Phadiatop™ test), and periostin. In some embodiments, the method of the present invention comprises determining the level of an AD-associated biomarker in a patient in need thereof, selecting a patient with an elevated level of an AD-associated biomarker, and administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In some embodiments, the patient is selected by obtaining information regarding the level of AD-associated biomarkers in the patient. In some embodiments, the level of AD-associated biomarkers is determined by an assay or test known in the art or disclosed elsewhere herein. In one embodiment, the patient is selected based on exhibiting an IgE level greater than about 1500 kU / L prior to or at the time of treatment. In one embodiment, the patient is selected based on exhibiting a TARC level greater than about 1000 pg / mL prior to or at the time of treatment. According to a related aspect of the invention, a method for treating AD is provided, comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist, wherein administration of the pharmaceutical composition to the subject results in a decrease in at least one AD-associated biomarker in the subject by 4, 8, 15, 22, 25, 29, 36 days or more following administration.In certain embodiments, patients exhibit a 5% to 20% decrease in IgE levels from baseline on or after day 36 after administration, in certain embodiments, patients exhibit a 25% to 70% decrease in TARC levels from baseline on or after day 4 after administration.

[0012] The present invention also provides a method for reducing the level of one or more AD-related biomarkers in a subject or improving one or more AD-related parameters in a subject, comprising administering to a subject a single initial dose of a pharmaceutical composition comprising an IL-4R antagonist. and then sequentially administering to a subject in need thereof one or more second doses of a pharmaceutical composition comprising an IL-4R antagonist.

[0013] According to certain embodiments, the present invention provides a method for reducing the level of one or more AD-related biomarkers in a subject or improving one or more AD-related parameters in a subject, comprising administering to the subject about 50 mg to about 600 mg of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. In certain embodiments, the first dose and the one or more second doses each comprise about 75 mg to about 300 mg of the antibody or antigen-binding fragment thereof. According to this aspect of the invention, the pharmaceutical composition may be administered to the subject with a dosing frequency of, for example, once a week. In some embodiments, each second dose is administered 1 to 8 weeks after the immediately preceding dose. In certain embodiments, at least four doses of the antibody or antigen-binding fragment thereof are administered. In one embodiment, each second dose is administered 1 week after the immediately preceding dose. In certain embodiments, the first dose comprises a first amount of the antibody or antigen-binding fragment thereof, and each of the one or more second doses comprises a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or fragment thereof is 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times the second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition is administered subcutaneously or intravenously.

[0014] In some embodiments, the present invention provides a method for treating moderate to severe AD, comprising co-administration of an IL-4R antagonist and a topical corticosteroid (TCS). In some embodiments, the method further comprises assaying for improvement of an AD-related parameter. In certain embodiments, the present invention provides a method for improving one or more AD-related parameters, comprising co-administration of an IL-4R antagonist and a TCS, wherein the improvement of the AD-related parameter is selected from the group consisting of: (i) at least 45% reduction in IGA score from baseline; (ii) at least 40% reduction in BSA score from baseline; (iii) at least 65% reduction in EASI score from baseline; (iv) at least 50% reduction in SCORAD score from baseline; (v) at least 25% reduction in 5-D itch scale from baseline; and (vi) at least 60% reduction in itch NRS score from baseline. In some embodiments, the improvement in the AD-related parameter is at least a 50% decrease from baseline in IGA at 29 days after administration of the antibody or antigen-binding fragment thereof that binds IL-4R. In some embodiments, the improvement in the AD-related parameter is at least a 65% decrease from baseline in NRS at 29 days after administration. In some embodiments, the improvement in the AD-related parameter is at least a 70% decrease from baseline in EASI at 29 days after administration. In some embodiments, the improvement in the AD-related parameter is at least a 60% decrease from baseline in SCORAD at 29 days after administration.

[0015] In certain embodiments, the TCS is selected from the group consisting of Group I TCS, Group II TCS, and Group III TCS. In some embodiments, the TCS is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate, and hydrocortisone butyrate.

[0016] In a related embodiment, the invention provides a method for reducing dependency on TCS in a patient with moderate to severe AD, comprising co-administration of an IL-4R antagonist with TCS, where the dose of TCS is reduced by 50% compared to a subject not administered an IL-4R antagonist. In one embodiment, the invention provides a method for treating moderate to severe AD, comprising administering an IL-4R antagonist simultaneously with a reduced dose of TCS. The present invention provides a method for reducing the dose of TCS in a patient with IL-4R. The dose of TCS can be reduced, for example, by more than 10%, 20%, 30%, 40%, or 50%. In one embodiment, the dose of TCS can be reduced, for example, by more than 10%, 20%, 30%, 40%, or 50%, compared to the dose used by the subject prior to treatment with an IL-4R antagonist.

[0017] The present invention also includes IL-4R antagonists as disclosed herein for use in treating or preventing AD, improving AD-associated parameters, reducing the level of at least one AD-associated biomarker, and / or treating any of the other indications or conditions disclosed herein.

[0018] In certain embodiments, the IL-4R antagonist of the methods of the present invention specifically binds to IL-4R and is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 148, 150 / 152, 154 / 156, 158 / 158, 159 / 160, 162 / 164, 164 / 166, 166 / 168, 170 / 172, 174 / 176, 178 / 178, 179 / 180, 182 / 184, 186 / 188, 188 / 189, 190 / 191, 192 / 193, 193 / 194, 194 / 195, 195 / 196, 196 / 197, 197 / 198, 198 / 199, 199 / 200, 200 / 201, 200 / 201, 201 / 202, 201 / 203, 201 / 204, 201 / 205, 201 / 206, 201 / 207, 201 / 208, 201 / 209, 210 / 211, 211 / 212, 212 / 213, and 262 / 264. In one embodiment, the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NO: 162 / 164. In one embodiment, an antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

[0019] In some embodiments, the pharmaceutical composition is administered subcutaneously or intravenously to a patient. In some embodiments, the pharmaceutical composition comprises about 50 mg to about 600 mg of an antibody or antigen-binding fragment thereof that binds to IL-4R. In further embodiments, the pharmaceutical composition comprises about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg of an antibody or antigen-binding fragment thereof that binds to IL-4R.

[0020] In certain embodiments, the pharmaceutical composition is administered to the patient before, after, or simultaneously with a second therapeutic agent. In some embodiments, the second therapeutic agent is a topical corticosteroid (TCS) or a calcineurin inhibitor.

[0021] In another embodiment, the present invention provides a method for monitoring the effectiveness of treatment of moderate to severe AD in a subject with an IL-4R antagonist, comprising the steps of: (a) determining an expression level of an AD-related biomarker, such as TARC or serum IgE, in a biological sample obtained from the subject prior to treatment with the IL-4R antagonist; (b) determining an expression level of one or both of TARC and serum IgE in a biological sample obtained from the subject after treatment with the IL-4R antagonist; (c) comparing the level determined in step (a) with the level determined in step (b); and (d) concluding that the treatment is effective if the level determined in step (b) is lower than the level determined in step (a), or concluding that the treatment is not effective if the level determined in step (b) is the same as or higher than the level determined in step (a). In one embodiment, the level in step (b) is determined 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks after determining the level in step (a). In one embodiment, the biomarker is TARC and the TARC level is IL-4. If the IL-4R antagonist is administered, the treatment with the IL-4R antagonist is determined to be effective. In one embodiment, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, and is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 150 / 152, 154 / 156, 158 / 158, 160 / 162, 162 / 164, 164 / 166, 166 / 168, 170 / 172, 174 / 176, 178 / 178, 178 / 179, 180 / 182, 182 / 184, 182 / 186, 182 / 18 ... 4, 146 / 154, 162 / 164, 166 / 168, 170 / 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

[0022] The expression level of the biomarker can be determined, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or more after administration of the IL-4R antagonist, and compared with the expression level before administration of the antagonist. The dose or dosing regimen of the IL-4R antagonist (e.g., anti-IL4R antibody) can be adjusted after said determination. For example, if the expression of the biomarker cannot be reduced within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or longer after administration of the antagonist, treatment with the antagonist can be stopped or the dose of the antagonist can be increased. If the expression of the biomarker is reduced after administration of the antagonist, the dose of the antagonist can be maintained or reduced to identify the minimum effective dose. In some embodiments, treatment is maintained at the minimum effective dose.

[0023] In another aspect, the present invention provides a method for monitoring a subject's response to treatment with an IL-4R antagonist, the method comprising: (a) obtaining information on the expression levels of one or both of TARC and IgE in a biological sample from the subject after administration of an IL-4R antagonist to the subject; and (b) providing instructions that treatment should be continued if the expression levels of TARC or IgE are decreased compared to the levels before treatment with an IL-4R antagonist. In one embodiment, the biomarker is TARC, and if it is determined that the TARC level is decreased after administration of the antagonist, instructions are provided to continue treatment with an IL-4R antagonist.

[0024] The present invention also includes the IL-4R antagonists disclosed herein for use in the manufacture of a medicament for the treatment and / or prevention of atopic dermatitis (AD) (e.g., moderate to severe eosinophilic AD, extrinsic AD, intrinsic AD, etc.), or for treating any of the other indications or conditions disclosed herein.

[0025] The present invention also includes the IL-4R antagonists disclosed herein for use in the treatment and / or prevention of AD (such as, for example, moderate to severe eosinophilic AD), or for treating and / or preventing any of the other indications or conditions disclosed herein.

[0026] In one embodiment, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof.

[0027] The present invention includes pharmaceutical compositions comprising anti-IL4R antibody antagonists or antigen-binding fragments thereof for use in the treatment and / or prevention of AD and related conditions.

[0028] The present invention also provides an anti-IL4R antibody antagonist or an antigen-binding fragment thereof for use in improving one or more AD-related parameters in a subject in need thereof. Also included is a pharmaceutical composition comprising:

[0029] Furthermore, the present invention includes a pharmaceutical composition comprising an anti-IL4R antibody antagonist or an antigen-binding fragment thereof for use in reducing the level of one or more AD-associated biomarkers in a subject in need thereof.

[0030] The present invention includes a pharmaceutical composition comprising an anti-IL-4R antibody antagonist or an antigen-binding fragment thereof for use in treating AD in patients with elevated levels of a biomarker selected from the group consisting of thymus and activation-regulated chemokine (TARC), IgE, eotaxin-3, lactate dehydrogenase (LDH), and periostin.

[0031] The present invention further includes a pharmaceutical composition comprising an anti-IL-4R antibody antagonist or an antigen-binding fragment thereof for use in treating AD in a subject, wherein the treatment results in a decrease in an AD-associated biomarker in the subject by 4, 8, 15, 22, 25, 29 or 36 days after treatment, compared to the level of the biomarker in the subject before treatment. In certain embodiments, the AD-associated biomarker is one or both of TARC and IgE.

[0032] The present invention further includes a pharmaceutical composition comprising an anti-IL-4R antibody antagonist or an antigen-binding fragment thereof for use in improving AD-related parameters or for reducing the level of an AD-related biomarker in a subject in need thereof, administered sequentially to a subject as a single initial dose followed by one or more secondary doses.

[0033] In one embodiment, the one or more second doses are administered weekly.

[0034] In some embodiments, the pharmaceutical composition comprises 75 mg to 600 mg of an anti-IL-4R antibody or antigen-binding fragment thereof. In one embodiment, the pharmaceutical composition comprises 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof.

[0035] In another aspect, the present invention provides a method for monitoring whether a therapeutic dose of an interleukin-4 receptor (IL-4R) antagonist administered to a human subject is safe, the method comprising obtaining information regarding the safety of the antagonist after administration to a human, the information including the occurrence of one or more events selected from the group consisting of an anaphylactic or acute allergic reaction requiring immediate treatment, a severe injection site reaction lasting longer than 24 hours, a severe infection, any parasitic infection, an increase in alanine aminotransferase (ALT) 2-fold or more above the upper limit of normal (ULN), a QTc≧500 ms, pregnancy, an overdose, and a herpes simplex type II virus infection; determining that one or more of the events have occurred, determining that the therapeutic dose is unsafe, and optionally advising to discontinue or reduce the therapeutic dose.

[0036] In a related embodiment, the invention provides a method for monitoring whether a therapeutic dose of an interleukin-4 receptor (IL-4R) antagonist administered to a human subject is safe, the method comprising: obtaining information regarding the safety of the antagonist after administration to a human, the information including the occurrence of one or more events selected from the group consisting of an anaphylactic or acute allergic reaction requiring immediate treatment, a severe injection site reaction lasting longer than 24 hours, a severe infection, any parasitic infection, an increase in alanine aminotransferase (ALT) greater than or equal to two times the upper limit of normal (ULN), a QTc≧500 ms, pregnancy, overdose, and herpes simplex virus type II infection; determining that one or more of the events have not occurred; and determining that the therapeutic dose is safe.

[0037] In one embodiment, the infection is an upper respiratory tract infection, pharyngitis, or sinusitis. In one embodiment, the injection site reaction is erythema, pain, nodules, hematoma, or itching. In one embodiment, the pain is greater than 2 mm VAS, for example, 3 mm to 30 mm VAS. In one embodiment, the diameter of the erythema is 9 mm or more.

[0038] In one embodiment, the safe therapeutic dose is 500 mg or less. In one embodiment, the safe therapeutic dose is selected from the group consisting of 75 mg, 150 mg, and 300 mg.

[0039] In another aspect, the present invention provides a method for quantifying or monitoring the amount of anti-drug antibodies in the serum of a human subject following administration of a drug, where the drug is an interleukin-4 receptor (IL-4R) antagonist, the method comprising: (a) obtaining a sample of said serum from a human subject who has been administered a dose of said IL-4R antagonist; and (b) determining the amount of anti-drug antibodies in said serum sample.

[0040] In another embodiment, the present invention provides a method for comparing interleukin-4 receptor (IL-4R) antagonists produced by a first method and a proposed equivalent second method, comprising obtaining safety information for the antagonists following administration of the antagonist produced by the first method to a first human and following administration of the antagonist produced by the second method to a second human, the information including the occurrence of anaphylactic or acute allergic reactions requiring immediate treatment, severe injection site reactions lasting more than 24 hours, severe infections, any parasitic infections, alanine aminotransferase (ALT) levels greater than or equal to two times the upper limit of normal (ULN), wherein the information is determined to be significantly different for the antagonist produced by the first method and the antagonist produced by the second method, the two methods are determined to be acceptable for producing equivalent antagonists; and wherein the information is determined to be significantly different for the antagonist produced by the first method and the antagonist produced by the second method, the two methods are determined to be unacceptable for producing equivalent antagonists.

[0041] In a related aspect, the invention provides a method for comparing an interleukin-4 receptor (IL-4R) antagonist produced by a first method and a proposed equivalent second method, comprising obtaining information regarding the therapeutic dose of the antagonist following administration to a first human of a dose of the antagonist produced by the first method, and following administration to a second human of a dose of the antagonist produced by the second method, the information comprising (a) an area under the plasma concentration versus time curve (AUC) calculated using the trapezoidal method from time zero to real time of about 4 mg·h / ml to about 20 mg·h / ml; last (b) maximum observed plasma concentrations (C max (c) the time to reach the first maximum plasma concentration (t max );(d) Approximately 5,000,000ng / h * mL~approx. 25,000,000ng / h * (e) the area under the plasma concentration versus time curve (AUC) extrapolated to infinity in mL and (f) the time to terminal half-life (t 1 / 2 Z ), wherein if the information is not significantly different for the antagonist produced by the first method and the antagonist produced by the second method, the two methods are determined to be acceptable for producing an equivalent antagonist; and if the information is determined to be significantly different for the antagonist produced by the first method and the antagonist produced by the second method, the two methods are determined to be unacceptable for producing an equivalent antagonist.

[0042] In another embodiment, the present invention provides an interleukin-4 receptor (IL-4R) antagonist. 2. A therapeutic dosage form of a pharmaceutical composition comprising a sucrose ester, the sucrose ester being administered to a human subject, the sucrose ester being administered to a human subject in a manner that satisfies the requirements of the present invention, the sucrose ester being administered to a human subject in a manner that satisfies the requirements of the present invention, the sucrose ester being administered to a human subject in a manner that satisfies the requirements of the present invention, the last (b) maximum observed plasma concentrations (C max(c) the time to reach the first maximum plasma concentration (t max );(d) Approximately 5,000,000ng / h * mL~approx. 25,000,000ng / h * (e) the area under the plasma concentration versus time curve (AUC) extrapolated to infinity in mL and (f) the time to terminal half-life (t 1 / 2 Z The therapeutic dosage form provides one or more of the following:

[0043] In one embodiment, the safe therapeutic dose is 500 mg or less. In one embodiment, the safe therapeutic dose is selected from the group consisting of 75 mg, 150 mg, and 300 mg.

[0044] Certain aspects of the present invention relate to methods and compositions that are useful in vaccine applications. The present invention provides a method for enhancing or strengthening an immune response to an antigen in a subject. In some embodiments, the method for enhancing or strengthening an immune response to an antigen in a subject comprises administering a pharmaceutical composition comprising an antigen and an IL-4R antagonist. Some embodiments relate to a method comprising: (a) administering to a subject a vaccine composition comprising an antigen; and (b) administering an IL-4R antagonist before, simultaneously with, and / or after administering the vaccine composition to the subject. The present invention also provides a pharmaceutical composition for enhancing or strengthening an immune response to said antigen in a subject, comprising: (a) an antigen; and (b) an IL-4R antagonist. In one exemplary embodiment, the IL-4R antagonist is an anti-IL-4R antibody (exemplified in Example 1 herein). In certain embodiments, the IL-4R antagonist is an anti-IL-4R antibody having the binding characteristics of a reference antibody referred to herein as "mAb1" (e.g., an antibody or antigen-binding fragment thereof comprising the complementarity determining regions of mAb1).

[0045] Other embodiments of the present invention will become apparent from a review of the following detailed description. [Brief description of the drawings]

[0046] [Figure 1] FIG. 1 shows Cartesian plots of mean (SD) serum functional mAb1 concentration-time profiles following a single subcutaneous dose. [Diagram 2] FIG. 1 is a diagrammatic representation of the injection procedure and pain assessment described in Example 5. [Diagram 3] FIG. 1 shows the IGA score responder rate (score of 0 or 1)-last observation carried forward (LOCF) for the study in Example 6. [Figure 4] FIG. 1 shows the change in mean IGA score from baseline to LOCF for the study in Example 6. [Diagram 5] FIG. 1 shows the percent change in mean IGA score from baseline to LOCF for the study in Example 6. [Figure 6] FIG. 1 shows the change in mean EASI score from baseline to LOCF for the study in Example 6. [Figure 7] FIG. 1 shows the percent change in mean EASI score from baseline to LOCF for the study in Example 6. [Figure 8] FIG. 1 shows EASI50 responder rates up to LOCF for the study in Example 6. [Figure 9] FIG. 1 shows the mean BSA change from baseline to LOCF for the study in Example 6. [Figure 10] FIG. 1 shows the mean percent change in BSA from baseline to LOCF for the study in Example 6. [Figure 11] FIG. 1 shows the mean 5-D change from baseline to LOCF for the study in Example 6. [Figure 12] FIG. 1 shows the mean 5-D percent change from baseline to LOCF for the study in Example 6. [Figure 13]FIG. 1 shows the mean NRS change from baseline to LOCF for the study in Example 6. [Figure 14] FIG. 1 shows the percent change in mean NRS from baseline to LOCF for the study in Example 6. [Figure 15] FIG. 13 shows the percent change from baseline in BSA in patients receiving 75 mg, 150 mg, or 300 mg of anti-IL-4R antibody versus placebo for the study in Example 8. [Figure 16] FIG. 1 shows the percent change from baseline in IGA in patients receiving 75 mg, 150 mg, or 300 mg of anti-IL-4R antibody versus placebo for the study in Example 8. [Figure 17] FIG. 13 shows the percent change from baseline in EASI in patients receiving 75 mg, 150 mg, or 300 mg of anti-IL-4R antibody versus placebo for the study in Example 8. [Figure 18] FIG. 13 shows the percent change from baseline in pruritus NRS in patients receiving 75 mg, 150 mg, or 300 mg of anti-IL-4R antibody versus placebo for the study in Example 8. [Figure 19] FIG. 1 shows the EASI response time course in patients with moderate to severe AD to 300 mg of anti-IL-4R antibody for the study in Example 8. [Figure 20] FIG. 1 shows the responder rates by EASI score receiving 75 mg, 150 mg or 300 mg of anti-IL-4R antibody versus placebo for the study in Example 8. [Figure 21] FIG. 13 shows EASI responses at week 4 (day 29) to anti-IL-4R antibody administered at doses of 75 mg, 150 mg or 300 mg versus placebo for the study in Example 8. [Figure 22] FIG. 1 shows the proportion of patients achieving an IGA of 1 or less for the study in Example 8. [Figure 23]FIG. 1 shows the percentage change in mean EASI score from baseline to last observation carried forward (LOCF) for the study in Example 10. [Figure 24] FIG. 1 shows IGA score responder rates (score of 0 or 1) up to LOCF for the study in Example 10. [Diagram 25] FIG. 1 shows IGA score responder rates (decrease in score of 2 or more) up to LOCF for the study in Example 10. [Figure 26] FIG. 1 shows EASI score responder rate (50% score reduction from baseline) up to LOCF for the study in Example 10. [Figure 27] FIG. 1 shows the change in mean EASI score from baseline to LOCF for the study in Example 10. [Figure 28] FIG. 1 shows the change in mean IGA score from baseline to LOCF for the study in Example 10. [Figure 29] FIG. 1 shows the percent change in mean IGA score from baseline to LOCF for the study in Example 10. [Diagram 30] FIG. 1 shows the mean BSA change from baseline to LOCF for the study in Example 10. [Diagram 31] FIG. 1 shows the change in mean SCORAD score from baseline to LOCF for the study in Example 10. [Diagram 32] FIG. 1 shows the change in mean NRS score from baseline to LOCF for the study in Example 10. [Diagram 33] FIG. 1 shows the change in mean 5-D pruritus score from baseline to LOCF for the study in Example 10. [Diagram 34] FIG. 1 shows the percent change in mean EASI score from baseline to censored LOCF for the study in Example 11. [Diagram 35]FIG. 1 shows the change in mean EASI score from baseline to censored LOCF for the study in Example 11. [Diagram 36] FIG. 1 shows EASI50 responder rates up to censoring LOCF for the study in Example 11. [Figure 37] FIG. 1 shows a Kaplan-Meier plot of time to first EASI50 up to censoring LOCF for the study in Example 11. [Figure 38] FIG. 1 shows the percent change in mean IGA score from baseline to censored LOCF for the study in Example 11. [Figure 39] FIG. 1 shows the change in mean IGA score from baseline to censored LOCF for the study in Example 11. [Diagram 40] FIG. 1 shows IGA score responder rates (score of 0 or 1) up to censoring LOCF for the study in Example 11. [Diagram 41] FIG. 1 shows a Kaplan-Meier plot of time to first IGA ≦1 to censoring LOCF for the study in Example 11. [Diagram 42] FIG. 1 shows the proportion of patients with an IGA of ≦1 at each visit who remain relapse-free up to censoring LOCF for the study in Example 11. [Diagram 43] FIG. 1 shows the proportion of patients with a decline from baseline of 2 or more IGAs at each visit until censoring LOCF for the study in Example 11. [Diagram 44] FIG. 1 shows the percent change in mean SCORAD score from baseline to censored LOCF for the study in Example 11. [Diagram 45] FIG. 1 shows the change in mean SCORAD score from baseline to censoring LOCF for the study in Example 11. [Figure 46] FIG. 1 shows the percent change in mean pruritus NRS from baseline to censored LOCF for the study in Example 11. [Figure 47] FIG. 1 shows the change in mean pruritus NRS from baseline to censored LOCF for the study in Example 11. [Figure 48A] FIG. 1 shows serum IgE levels at baseline (A) for the study in Example 12. [Figure 48B] FIG. 13 shows the median percent change in response to various doses of mAb1 or placebo (B) for the study in Example 12. [Figure 49A] FIG. 1 shows serum TARC levels at baseline (A) for the study in Example 12. [Figure 49B] FIG. 13 shows the mean percent change in response to various doses of mAb1 or placebo (B) for the study in Example 12. [Figure 50] FIG. 13 shows the change in TARC levels for the pooled mAb1 group compared to placebo for the study in Example 12. [Figure 51A] FIG. 1 shows the distribution of baseline levels of (A) TARC in patients in the study of Example 12, Section B. [Figure 51B] FIG. 1 shows the distribution of baseline levels of (B) total serum IgE in patients in the study in Section B of Example 12. [Figure 51C] FIG. 1 shows the distribution of baseline levels of lactate dehydrogenase (LDH) in patients (C) in the study of Example 12, Section B. [Figure 52] FIG. 1 shows the median percent change in IgE from baseline for the studies in Example 12, Section B. [Diagram 53] FIG. 1 shows the median percent change in LDH from baseline for the study in Section B of Example 12. [Figure 54] FIG. 1 shows the median percent change in TARC from baseline for the study in Section B of Example 12. [Figure 55] FIG. 1 shows the median percent change in IgE from baseline for the studies in Example 12, Section C. [Figure 56] FIG. 1 shows the median percent change in TARC from baseline for the study in Section C of Example 12. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] Before describing the invention, it is to be understood that the invention 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 invention will be limited only by the appended claims.

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs. As used herein, the term "about" when used in reference to a specific stated value means that the value may vary from the stated value by 1% or less. 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.). As used herein, the terms "treat", "treating" and the like mean to alleviate symptoms, eliminate the cause of symptoms on a temporary or permanent basis, or prevent or delay the onset of symptoms of a named disorder or condition.

[0049] The present invention includes methods comprising administering a therapeutic composition comprising an IL-4R antagonist to a subject in need thereof. As used herein, the phrase "subject in need thereof" refers to a human or non-human animal exhibiting one or more symptoms or signs of atopic dermatitis and / or diagnosed with atopic dermatitis. In certain embodiments, the methods of the present invention can be used to treat patients exhibiting elevated levels of one or more AD-related biomarkers (described elsewhere herein). For example, the methods of the present invention include administering an IL-4R antagonist to patients with elevated levels of IgE or TARC or periostin. In some embodiments, the methods of the present invention can be used to treat AD in children aged 1 year or younger. For example, the methods of the present invention can be used to treat infants aged less than 1 month, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In other embodiments, the methods of the present invention can be used to treat children and / or adolescents aged 18 years or younger. For example, the methods of the invention can be used to treat children or adolescents under the age of 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2 years old.

[0050] In the context of the present invention, a "subject in need thereof" may include a subject who, prior to treatment, exhibits (or has exhibited) one or more AD-related parameters, such as, for example, elevated IGA, BSA, EASI, SCORAD, 5D-pruritus, and / or NRS scores, and / or elevated levels of one or more AD-related biomarkers, such as, for example, IgE and / or TARC (described elsewhere herein). In certain embodiments, a "subject in need thereof" may include a subset of a population that is more susceptible to AD or may exhibit elevated levels of AD-related biomarkers. For example, a "subject in need thereof" may include a subset of a population defined by the race or ethnicity present in the population.

[0051] As used herein, "atopic dermatitis" (AD) refers to an inflammatory skin disease characterized by intense pruritus (e.g., intense itching) and scaly and dry eczema lesions. The term "atopic dermatitis" includes, but is not limited to, AD caused by or associated with epithelial barrier dysfunction, allergies (e.g., allergies to certain foods, pollen, mold, dust mites, animals, etc.), radiation exposure, and / or asthma. The present invention encompasses methods of treating patients with mild, moderate to severe AD. As used herein, "moderate to severe AD" is characterized by widespread, diffuse skin lesions with intense pruritus, often exacerbated by persistent bacterial, viral or fungal infections. Moderate to severe AD also includes chronic AD in patients. Often, chronic lesions include thickened skin patches, lichenification, and fibrous papules. Patients with moderate to severe AD also generally have more than 20% of the skin of the body affected, or 10% of the skin area affected, in addition to the lesions of eyes, hands and body wrinkles.Moderate to severe AD is also considered to be present in patients who need frequent treatment with topical corticosteroids.Patient can also be said to have moderate to severe AD if the patient is resistant or refractory to treatment with topical corticosteroids or calcineurin inhibitors or any other commonly used therapeutic agent known in the art.

[0052] The present invention includes methods for treating both extrinsic and intrinsic AD. Extrinsic AD, associated with IgE sensitization and increased levels of Th2 cytokines, comprises 70%-80% of patients with AD. Intrinsic AD, lacking IgE sensitization, comprises 20%-30% of patients with AD; these patients have lower levels of IL-4 and IL-13 than extrinsic AD.

[0053] The present invention includes a method of treating AD in patients who are resistant, unresponsive, or inadequately responsive to treatment with topical corticosteroids (TCS) or calcineurin inhibitors. As used herein, the term "resistant, unresponsive, or inadequately responsive to treatment with TCS or calcineurin inhibitors" refers to subjects or patients with AD who are treated with TCS or calcineurin inhibitors and for whom the TCS / calcineurin inhibitors have no therapeutic effect. In some embodiments, the term refers to poor patient compliance and / or toxicity and side effects and / or ineffectiveness of TCS / calcineurin inhibitors administered to alleviate, improve, or reduce symptoms of AD. In some embodiments, the term refers to patients suffering from moderate to severe AD who are refractory to treatment with TCS / calcineurin inhibitors. In some embodiments, the term refers to patients with AD that is uncontrolled despite treatment with TCS and / or calcineurin inhibitors. In some embodiments, a patient who is "resistant, non-responsive, or insufficiently responsive to treatment with TCS or calcineurin inhibitor" may not show improvement in one or more AD-related parameters. Examples of AD-related parameters are described elsewhere herein. For example, treatment with TCS / calcineurin inhibitor may not result in a decrease in pruritus or EASI score or BSA score. In some embodiments, the present invention includes a method of treating moderate to severe AD in a patient who was previously treated with TCS / calcineurin inhibitor for more than one month but does not show a decrease in one or more AD-related parameters. For example, the method of the present invention can be used to treat a patient with chronic AD who was on a stable regimen of TCS / calcineurin inhibitor but has a BSA score of 10% or more and an IGA score of 3 or more.

[0054] In alternative embodiments, the term "subject in need thereof" refers to a subject who has been in need thereof for more than 6 months, more than 1 year, more than 2 years, more than about 5 years, more than about 7 years, or more than about 10 years. The present invention includes a patient with moderate to severe AD who has been administered one or more TCSs, and who may wish to minimize or avoid the adverse side effects of TCS. The present invention includes a method for safer and more effective long-term management of moderate to severe AD in a patient, comprising administering an IL-4R antagonist concurrently with TCS, the dose of which is adjusted to minimize or prevent the adverse side effects of TCS. In certain embodiments, the present invention includes a method for reducing dependency on TCS in a patient with moderate to severe AD, comprising administering a therapeutically effective amount of an IL-4R antagonist concurrently with a potent TCS, whereby the amount of TCS used by the patient is reduced by about 50% compared to a patient not administered an IL-4R antagonist. In certain embodiments, the invention includes a method of reducing dependency on TCS in a patient with moderate to severe AD, comprising administering a therapeutically effective amount of an IL-4R antagonist concomitantly with a potent TCS, wherein the amount of TCS used by the patient is reduced by about 50% compared to the amount used by the patient prior to treatment with the IL-4R antagonist. In certain embodiments, administration of an IL-4R antagonist and a TCS provides additive or synergistic activity in treating AD when compared to monotherapy.

[0055] The term "TCS" as used herein includes Group I, Group II, Group III and Group IV topical corticosteroids. According to the World Health Organization Anatomical Therapeutic Classification, corticosteroids are classified as weak (Group I), moderately potent (Group II) and potent (Group III) and very potent (Group IV) based on their activity compared to hydrocortisone. Group IV TCS (very potent) are up to 600 times more potent than hydrocortisone and include clobetasol propionate and halcinonide. Group III TCS (potent) are 50-100 times more potent than hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Class II TCS (moderately potent) are 2-25 times more potent than hydrocortisone and include, but are not limited to, clobetasone butyrate, and triamcinolone acetonide. Class I TCS (mild) include hydrocortisone.

[0056] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0057] Methods for improving atopic dermatitis (AD)-related parameters - Patents.com The present invention includes a method for improving one or more atopic dermatitis (AD) associated parameters in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist.

[0058] Examples of "AD-related parameters" include (a) Investigator Global Assessment (IGA); (b) Atopic Dermatitis Body Surface Area Lesions (BSA); (c) Eczema Area and Severity Index (EASI); (d) SCORAD; (e) 5-D Pruritus Scale; and (f) Numerical Rating Scale for Pruritus (NRS). "Improvement of AD-related parameters" refers to a reduction from baseline in one or more of IGA, BSA, EASI, SCORAD, 5-D Pruritus Scale, or NRS. The term "baseline" as used herein with respect to AD-related parameters refers to the numerical value of the AD-related parameter for a subject before or at the time of administration of the pharmaceutical composition of the present invention.

[0059] To determine whether an AD-related parameter has been "improved," the parameter is Quantification is performed at baseline and at one or more time points after administration of the pharmaceutical composition of the present invention.For example, AD-related parameters can be measured at the 1st day, 2nd day, 3rd day, 4th day, 5th day, 6th day, 7th day, 8th day, 9th day, 10th day, 11th day, 12th day, 14th day, 15th day, 22nd day, 25th day, 29th day, 36th day, 43rd day, 50th day, 57th day, 64th day, 71st day, 85th day after the first treatment with the pharmaceutical composition of the present invention; or at the end of the 1st week, 2nd week, 3rd week, 4th week, 5th week, 6th week, 7th week, 8th week, 9th week, 10th week, 11th week, 12th week, 13th week, 14th week, 15th week, 16th week, 17th week, 18th week, 19th week, 20th week, 21st week, 22nd week, 23rd week, 24th week or longer. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (eg, a decrease) of the AD-related parameter.

[0060] Investigator Global Assessment (IGA). IGA is a rating scale used in clinical settings to determine the severity of AD and clinical response to treatment based on a 6-point scale ranging from 0 (clear) to 5 (very severe). According to certain embodiments of the present invention, administration of an IL-4R antagonist to a patient results in a reduction in IGA score. For example, the present invention includes a method of treatment that results in at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more reduction in IGA score from baseline at 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 days or more after administration of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the invention, administration of an IL-4R antagonist to a subject results in at least a 25% reduction in IGA from baseline. In one embodiment of the invention, administration of an IL-4R antagonist to a subject results in at least a 25% reduction in IGA from baseline by day 15 after administration. In one embodiment of the invention, administration of an IL-4R antagonist to a subject results in at least a 35% reduction in IGA from baseline by day 22 after administration. In other embodiments, administration of an IL-4R antagonist to a subject results in at least a 40% or at least a 45% reduction in IGA from baseline by day 85 of treatment.

[0061] Body surface area lesions (BSA) of atopic dermatitis. BSA is assessed for each major part of the body (head, trunk, arms and legs) and reported as a percentage of all major body parts combined. According to certain embodiments of the present invention, administration of an IL-4R antagonist to a patient results in a reduction in BSA score. For example, the present invention includes a method of treatment that results in at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more reduction in BSA score from baseline at 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 days or more after administration of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the invention, administration of an IL-4R antagonist to a subject results in at least a 35% decrease in BSA score from baseline. In one embodiment of the invention, administration of an IL-4R antagonist to a subject results in at least a 35% decrease in BSA score from baseline by day 29 after administration. In one embodiment of the invention, administration of an IL-4R antagonist to a subject results in at least a 40% decrease in BSA score from baseline by day 29 after administration. In some embodiments, administration of an IL-4R antagonist to a subject results in at least a 40% or at least a 50% decrease in BSA score from baseline by day 85 of treatment.

[0062] Eczema Area and Severity Index (EASI). EASI is a validated scale used in clinical settings to assess the severity and extent of AD (Hanifin et al., 2001, Exp. Dermatol. 10:11-18). Four AD disease characteristics are assessed for severity by a physician or other qualified medical professional on a scale from 0 (none) to 3 (severe). Furthermore, the area of ​​AD lesions is assessed as a percentage by body area of ​​the head, trunk, arms and legs and converted into a score of 0-6. According to certain embodiments of the present invention, administration of an IL-4R antagonist to a patient results in a decrease in EASI score. For example, the present invention includes a method of treatment that results in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in EASI score from baseline at 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or more days after administration of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the present invention, administration of an IL-4R antagonist to a subject results in at least a 45% decrease in EASI score from baseline. In one embodiment of the present invention, administration of an IL-4R antagonist to a subject results in at least a 45% decrease in EASI score from baseline by 15 days after administration. In one embodiment of the invention, administration of an IL-4R antagonist to a subject results in at least a 50% decrease in EASI score from baseline by day 29 after administration. In some embodiments, administration of an IL-4R antagonist to a subject results in at least a 55% or at least a 60% decrease in EASI score from baseline by day 85 of treatment.

[0063] SCORAD. The Scoring System for Atopic Dermatitis (SCORAD) is a European It is a clinical assessment of the severity (e.g., extent or intensity) of atopic dermatitis developed by the Task Force on Atopic Dermatitis (Consensus Report of the European Task Force on Atopic Dermatitis, 1993, Dermatology (Basel) 186(1):23-31). The extent of AD is assessed as a percentage of each defined body area and reported as a sum of the total area, with a maximum score of 100% (assigned "A" in the overall SCORAD calculation). The severity of six specific symptoms of AD is assessed using the following scale: none (0), mild (1), moderate (2), or severe (3) (assigned "B" in the overall SCORAD calculation, for a maximum total score of 18). Subjective assessment of itch and insomnia is recorded by the patient for each symptom or relatively on a visual analog scale (VAS) (0 being no itch (or insomnia), 10 being the worst itch (or insomnia) imaginable, with a maximum possible score of 20). This parameter is assigned a "C" in the overall SCORAD calculation. SCORAD is calculated as A / 5+7B / 2+C. According to certain embodiments of the present invention, administration of an IL-4R antagonist to a patient results in a decrease in the SCORAD score. For example, the present invention includes a method of treatment that results in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more decrease in SCORAD score from baseline at 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or more days after administration of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the present invention, administration of an IL-4R antagonist to a subject results in at least a 30% decrease in SCORAD score from baseline. In one embodiment of the present invention, administration of an IL-4R antagonist to a subject results in at least a 30% decrease in SCORAD score from baseline by 29 days after administration.In one embodiment of the invention, the administration of the IL-4R antagonist to the subject is 29 days after administration. In some embodiments, administration of an IL-4R antagonist to a subject results in at least a 35% decrease in SCORAD score from baseline by day 85 of treatment. In some embodiments, administration of an IL-4R antagonist to a subject results in at least a 40% or at least a 45% decrease in SCORAD score from baseline by day 85 of treatment.

[0064] 5-D Pruritus Scale. The 5-D Pruritus Scale is a one-page, five-question tool used in clinical settings to assess five dimensions of background itch: severity, duration, direction, disability, and distribution (Elman and Hynan, 2010, Brit. J. Dermatol. 162:587-593). Each question corresponds to one of the five dimensions of itch; patients rate their symptoms as "present" or on a scale of 1 to 5, with 5 being most affected. According to certain embodiments of the present invention, administration of an IL-4R antagonist to a patient results in a decrease in the 5-D Pruritus Scale. For example, the present invention includes methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more reduction from baseline in the 5-D pruritus scale at or after days 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85 or more following administration of an IL-4R antagonist (e.g., following subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the present invention, administration of an IL-4R antagonist to a subject results in at least a 15% reduction from baseline in the 5-D pruritus scale. In one embodiment of the invention, administration of an IL-4R antagonist to a subject results in at least a 15% reduction from baseline in the 5-D pruritus scale by day 15 after administration. In one embodiment of the invention, administration of an IL-4R antagonist to a subject results in at least a 20% reduction from baseline in the 5-D pruritus scale by day 15 after administration. In some embodiments, administration of an IL-4R antagonist to a subject results in at least a 25% or at least a 30% reduction from baseline in the 5-D pruritus scale by day 85 of treatment.

[0065] Pruritus Numeric Rating Scale (NRS). The Pruritus NRS is a single question assessment tool used to rate a subject's worst itch as a result of AD in the previous 12 hours on a scale of 1 to 10. According to certain embodiments of the invention, administration of an IL-4R antagonist to a patient results in a decrease in the NRS score. For example, the present invention includes methods of treatment that result in at least about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more reduction in NRS score from baseline at the end of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more after administration of an IL-4R antagonist (e.g., after subcutaneous administration of about 75 mg, 150 mg, or 300 mg of an anti-IL-4R antibody or antigen-binding fragment thereof). In certain exemplary embodiments of the present invention, administration of an IL-4R antagonist to a subject results in at least a 25% reduction in NRS score from baseline. In one embodiment of the invention, administration of an IL-4R antagonist to a subject results in at least a 25% decrease in NRS score from baseline by the end of the second week after administration. In one embodiment of the invention, administration of an IL-4R antagonist to a subject results in at least a 30% decrease in NRS score from baseline by the end of the second week after administration. In some embodiments, administration of an IL-4R antagonist to a subject results in at least a 45% or at least a 50% decrease in NRS score from baseline by day 85 of treatment.

[0066] Global Individual Signs Score (GISS). The individual components of AD lesions (erythema, infiltrates / clusters, excoriation, and lichenification) were scored on a 4-point scale (ranging from 0=none to 3=severe) using the EASI severity grading criteria. ) and assess globally (i.e., assess the entire body, not by anatomical region).

[0067] Pruritus Categorical Scale: The Pruritus Categorical Scale is a 4-point scale used to assess symptoms used in clinical trials for AD, with less than "moderate" effectiveness (Kaufmann, 2006). The scale is rated as follows: 0: no pruritus; 1: mild pruritus (occasional slight itching / scratching); 2: moderate pruritus (constant or intermittent itching / scratching that does not interfere with sleep) and 3: severe pruritus (intrusive itching / scratching that interferes with sleep).

[0068] Patient Oriented Eczema Measure (POEM). The POEM is a seven-item validated questionnaire used in clinical practice and clinical trials to assess disease symptoms in children and adults (Charman, 2004). The format is a response to seven items (dryness, itching, peeling, cracking, loss of sleep, bleeding, and weeping) with a scoring system of 0 to 28, with higher scores indicating impaired quality of life.

[0069] Dermatology Life Quality Index (DLQI). The DLQI is a 10-item validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatments on QOL (Badia, 1999). The format is a simple response to 10 items assessing QOL over the past week, with a global scoring system of 0 to 30, with higher scores indicating poorer QOL.

[0070] Itchy QOL. Itchy QOL is a validated itch-specific instrument that addresses the symptomatic, emotional, and functional impact of itch. There is a global score as well as subscale scores to address three types of impact. It is a reliable, valid, and responsive questionnaire (Desai, 2008).

[0071] EQ-5D. The EQ-5D is a standard measure of health status developed by the EuroQOI Group to provide a simple and generic measure of health for clinical and economic evaluation. The EQ-5D, as a measure of health-related quality of life, defines health in terms of five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has three normal levels of severity: "no problems" (1), "some problems" (2), and "severe problems" (3). The overall health status is defined as a five-digit number. The health status defined by the classification of the five dimensions can be converted into a corresponding index score that quantifies the health status, where 0 represents "death" and 1 represents "perfect health."

[0072] HADS. The HADS is a common Likert scale used to detect states of anxiety and depression (Bjelland, 2002). The 14 items on the questionnaire include 7 items related to anxiety and 7 items related to depression. Each item on the questionnaire is scored; a person can have a score between 0 and 21 for either anxiety or depression.

[0073] Patient Global Assessment of Disease Status and Treatment Effect. Patients rate their overall well-being on a 5-point Likert scale ranging from poor to excellent. Patients are asked, "Considering all the ways your eczema affects you, please indicate how well you think it is." Response options are "poor"; "well"; "good"; "very good"; "excellent."

[0074] Regarding the effectiveness of treatment, patients rate their satisfaction with the study treatment on a 5-point Likert scale ranging from poor to excellent. Patients are asked, "How would you rate the way your eczema responded to the study medication?" Response options are: "poor"; "fair"; "good"; "very good"; "excellent."

[0075] Methods for the long-term management of atopic dermatitis - Patents.com The present invention includes a method for the long-term management of moderate to severe AD in a patient. In certain embodiments, the method includes administering an IL-4R antagonist simultaneously with a conventional treatment, such as topical corticosteroids (TCS). In further embodiments, the IL-4R antagonist may be an anti-IL-4R antibody as described herein.

[0076] The term "conventional therapeutic agents" as used herein refers to therapeutic agents and drugs commonly or routinely used to treat AD in patients. Conventional therapeutic agents include systemic as well as topical therapeutic agents. For example, the most commonly or frequently prescribed drug is topical corticosteroids (TCS). Other examples of such agents include, but are not limited to, topical calcineurin inhibitors, antihistamines, oral immunosuppressants, and glucocorticoids, systemic immunosuppressants such as methotrexate, cyclosporine, and azathioprine. Conventional therapeutic agents are used to alleviate the symptoms of AD, but have several and significant adverse side effects, including diabetes, hypertension, osteoporosis, bone marrow suppression, nephrotoxicity, hepatotoxicity, leukopenia, and increased risk of microbial infection. Topical agents such as corticosteroids and calcineurin inhibitors are not recommended for long-term application due to the risk of irreversible skin atrophy, pigmentation, acneiform rash, and the risk associated with systemic absorption, including skin malignancies and lymphomas. Also, repeated application of any topical treatment over an extended period of time can reduce patient compliance.

[0077] The term "long-term management of AD" as used herein refers to the treatment or containment of one or more symptoms or disease states of AD for an extended period of time, typically more than about 2 years, more than about 5 years, more than about 10 years, or more than about 20 years. Long-term management of AD includes methods for treating or improving one or more AD-related parameters for a period of more than 6 months, more than 1 year, more than 2 years, or more than about 5 years, comprising administering an anti-IL-4R antagonist together with a conventional therapeutic agent such as TCS. The administration regimen and dose of the IL-4R antibody and TCS are adjusted or changed so that one or more AD-related parameters are significantly improved and toxicity due to the conventional agent is prevented or minimized. In some embodiments, the IL-4R antibody may be administered at a higher loading dose for significant improvement of AD-related parameters, followed by a lower regular dose to sustain or maintain the improvement. Concomitantly administered TCS may be administered at a lower dose, typically about 20%, about 30%, about 40%, about 50% or about 60% reduced compared to patients not treated with IL-4R antibody. Administration regimens and dosages are described elsewhere herein. In some embodiments, the present invention includes methods for reducing dependency on TCS in patients with moderate to severe AD.

[0078] In certain embodiments, the present invention includes a method for treating a patient who has had AD for more than 1 year, more than about 5 years, more than about 10 years, or more than about 15 years, comprising administering a therapeutically effective amount of an IL-4R antagonist along with a conventional therapeutic agent, such as TCS.

[0079] In another aspect, the present invention provides a method for the treatment of moderate to severe AD in patients with AD. The present invention includes methods for safer and / or more effective treatment. The term "safer and / or more effective treatment" as used herein refers to a treatment method comprising administering an IL-4R antagonist together with a conventional therapeutic agent, such as TCS, such that one or more AD-related parameters are significantly improved and side effects and toxicity caused by the conventional agent are minimized or prevented. In certain embodiments, the improvement in AD-related parameters is selected from the group consisting of: (a) at least a 50% reduction in Investigator Global Assessment (IGA) score from baseline; (b) at least a 65% reduction in Numerical Rating Scale for Pruritus (NRS) score from baseline; (c) at least a 70% reduction in Eczema Area and Severity Index (EASI) score from baseline; and (d) at least a 60% reduction in SCORAD score from baseline. In some embodiments, the dose of the conventional agent is reduced or lowered to minimize adverse side effects. In some embodiments, the treatment method described herein can reduce or eliminate the risk of rebound after reduction or cessation of steroids.

[0080] The present invention includes methods for more effective and safer treatments in the long-term management of AD in patients such as children or young adults who may be more sensitive or susceptible to conventional therapeutic agents.

[0081] In another aspect of the present invention, a method is provided for reducing or eliminating the dependency of AD patients on conventional therapeutic agents such as TCS during the treatment of moderate to severe AD. In one embodiment of the present invention, the method comprises: selecting a patient with moderate to severe AD that is uncontrolled or partially controlled on background treatment; administering to the patient a prescribed dose of an IL-4R antagonist, preferably an anti-IL-4R antibody, for an initial treatment period while maintaining the patient's background treatment for the initial treatment period; and gradually decreasing the dose of one or more components of the background treatment over subsequent treatment periods while continuing the administration of the IL-4R antagonist. The term "background treatment" as used herein refers to standard or conventional therapeutic agents known in the art (as described elsewhere herein) used to treat AD. In certain embodiments, the background treatment comprises a TCS, or a topical calcineurin inhibitor. In one embodiment, the background treatment is a potent group III TCS, such as mometasone furoate or methylprednisolone aceponate. In some embodiments, the dose of a conventional therapeutic agent such as TCS is removed or completely withdrawn during the initial treatment period. For example, TCS is administered during the initial treatment period and then stopped or completely withdrawn during the subsequent treatment period. In certain embodiments, the dose of TCS is reduced by about 10%, about 20%, about 30%, about 40%, about 50% or more compared to the dose during the initial treatment period.

[0082] In one example of a treatment regimen for patients with moderate to severe AD, an IL-4R antagonist is administered to a patient with moderate to severe AD during an initial treatment period (also called the "stable period"), and a conventional therapeutic agent such as TCS is administered to the patient as background treatment. During subsequent treatment periods (also called the "withdrawal period"), administration of TCS is gradually reduced by about 5-60% compared to the initial treatment period. In one embodiment, the TCS is stopped, i.e., the TCS is gradually reduced over subsequent treatment periods until it is weaned or removed.

[0083] In a related aspect of the invention, a method of treating AD is provided that includes add-on therapy to background therapy with systematic background therapy withdrawal. In certain embodiments of the invention, the IL-4R antagonist is administered for a certain period of time (e.g., 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 5 months, 12 months, 18 months, 24 months, or more). The TCS is administered as an add-on therapy to AD patients who have been on background therapy (also called a "stable period") for a period of 10-12 weeks or more. In some embodiments, the background therapy comprises TCS. After the stable period, there is a background therapy withdrawal period, in which one or more components comprising the background therapy are withdrawn or reduced or eliminated while the add-on therapy continues. In some embodiments, the background therapy can be reduced by about 5%, about 10%, about 20%, about 30%, about 40%, about 50% or more during the withdrawal period. The withdrawal period may last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more.

[0084] Atopic dermatitis-related biomarkers The present invention also includes methods involving the use, quantification, and analysis of AD-associated biomarkers. As used herein, the term "AD-associated biomarker" refers to any biological response, cell type, parameter, protein, polypeptide, enzyme, enzyme activity, metabolite, nucleic acid, carbohydrate, or other biomolecule that is present or detectable in AD patients at a level or amount that is different (e.g., higher or lower) than the level or amount of the marker that is present or detectable in non-AD patients. In some embodiments, the term "AD-associated biomarker" includes biomarkers associated with type 2 helper T cell (Th2)-induced inflammation. Exemplary AD-associated biomarkers include, but are not limited to, thymus and activation-regulated chemokine (TARC; also known as CCL17), immunoglobulin E (IgE), eotaxin-3 (also known as CCL26), lactate dehydrogenase (LDH), eosinophils, antigen-specific IgE (e.g., Phadiatop™ test), and periostin. The term "AD-related biomarker" also includes genes or gene probes known in the art that are differentially expressed in subjects with AD compared to subjects without AD.For example, genes that are significantly upregulated in subjects with AD include, but are not limited to, type 2 helper T cell (Th2)-related chemokines, such as CCL13, CCL17, CCL18 and CCL26, markers of epidermal proliferation, such as K16, Ki67, and T cell and dendritic cell antigens CD2, CD1b and CD1c (Tintle et al., 2011; J. Allergy Clin. Immunol. 128:583-593).Alternatively, "AD-related biomarker" also includes genes that are downregulated due to AD, such as terminal differentiation proteins (e.g., loricrin, filaggrin and involucrin) (Tintle et al., 2011; J. Allergy Clin. Immunol. 128:583-593). Certain embodiments of the invention relate to the use of these biomarkers to monitor disease reversal with administration of an IL-4R antagonist.Methods for detecting and / or quantitating such AD-associated biomarkers are known in the art; kits for measuring such AD-associated biomarkers are available from a variety of commercial sources; and various clinical testing companies offer services to provide measurement of such biomarkers as well.

[0085] According to certain aspects of the present invention, a method for treating AD is provided, comprising: (a) selecting a subject exhibiting a level of at least one AD-associated biomarker prior to or at the time of treatment indicative of a disease state; and (b) administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist. In certain embodiments, the patient is selected by determining whether the level of the AD-associated biomarker is elevated. The level of the AD-associated biomarker is determined or quantified by obtaining a sample from the patient for a biomarker assay known in the art. In certain embodiments, the patient is selected by obtaining information regarding the elevated level of the AD-associated biomarker from the patient. In certain embodiments of this aspect of the present invention, the subject is selected based on an elevated level of IgE or TARC or periostin.

[0086] For purposes of the present invention, a normal IgE level in a healthy subject is less than about 114 kU / L (e.g., as measured using the ImmunoCAP® assay [Phadia, Inc. Portage, MI]). Thus, the present invention includes a method comprising selecting a subject exhibiting a serum IgE level of greater than about 114 kU / L, greater than about 150 kU / L, greater than about 500 kU / L, greater than about 1000 kU / L, greater than about 1500 kU / L, greater than about 2000 kU / L, greater than about 2500 kU / L, greater than about 3000 kU / L, greater than about 3500 kU / L, greater than about 4000 kU / L, greater than about 4500 kU / L, or greater than about 5000 kU / L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0087] TARC levels in healthy subjects range from 106 ng / L to 431 ng / L, averaging about 239 ng / L. (An exemplary assay system for measuring TARC levels is the TARC quantification ELISA kit provided by R&D Systems, Minneapolis, Minn. under catalog number DDN00.) Thus, the present invention includes a method comprising selecting a subject exhibiting a serum TARC level greater than about 431 ng / L, greater than about 500 ng / L, greater than about 1000 ng / L, greater than about 1500 ng / L, greater than about 2000 ng / L, greater than about 2500 ng / L, greater than about 3000 ng / L, greater than about 3500 ng / L, greater than about 4000 ng / L, greater than about 4500 ng / L, or greater than about 5000 ng / L, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

[0088] Another AD-related biomarker is antigen-specific IgE. Phadiatop™ is a commercially available variant of a serum-specific or antigen-specific IgE assay test introduced for screening allergic sensitization (Merrett et al., 1987, Allergy 17:409-416). This test provides a simultaneous test for serum-specific IgE against a mixture of related allergens that cause common inhalant allergies. This test gives a qualitative result that is either positive or negative depending on the fluorescence response obtained. A positive test result is indicated if the patient sample gives a fluorescence response that is higher than or equal to the reference. A patient sample with a lower fluorescence response indicates a negative test result. The present invention includes a method comprising selecting a subject that shows a positive test result and administering to the subject a therapeutically effective amount of an IL-4R antagonist.

[0089] Periostin is an extracellular matrix protein involved in Th2-mediated inflammatory processes. Periostin levels have been found to be upregulated in patients with AD (Masuoka et al., 2012 J Clin Invest. 122(7):2590-2600, doi:10.1172 / JCI58978). The present invention includes methods comprising administering an IL-4R antagonist to treat patients with elevated levels of periostin.

[0090] Lactate dehydrogenase (LDH) is used as a marker of tissue damage and has been shown to be elevated in patients with AD (Kou et al., 2012; Arch. Dermatol. Res. 304:305-312). The present invention includes methods comprising administering an IL-4R antagonist to treat patients with elevated levels of LDH.

[0091] According to another aspect of the invention, a method is provided for treating AD comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist, wherein administration of the pharmaceutical composition to the subject results in a decrease in at least one AD-associated biomarker (e.g., IgE, TARC, eosinophils, eotaxin-3, antigen-specific IgE, LDH, etc.) at a time point after administration compared to the level of the biomarker in the subject prior to administration of the pharmaceutical composition.

[0092] As will be appreciated by those skilled in the art, an increase or decrease in an AD-related biomarker can be determined by comparing (i) the level of the biomarker measured in a subject at a defined time point after administration of a pharmaceutical composition comprising an IL-4R antagonist with (ii) the level of the biomarker measured in the subject before administration of a pharmaceutical composition comprising an IL-4R antagonist (i.e., a "baseline measurement"). The defined time point at which the biomarker is measured can be, for example, about 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, 35 days, 40 days, 50 days, 55 days, 60 days, 65 days, 70 days, 75 days, 80 days, or more after administration of a pharmaceutical composition comprising an IL-4R antagonist.

[0093] According to certain embodiments of the present invention, a subject may exhibit a decrease in one or more levels of TARC and / or IgE following administration of a pharmaceutical composition comprising an IL-4R antagonist (e.g., an anti-IL-4R antibody). For example, on about the 4th, 8th, 15th, 22nd, 25th, 29th, 36th, 43rd, 50th, 57th, 64th, 71st or 85th day after administration of a pharmaceutical composition comprising a first, second, third or fourth dose of about 75 mg, 150 mg or 300 mg of an anti-hIL-4R antibody (e.g., mAb1), a subject, according to the present invention, may exhibit a decrease in TARC of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more from baseline (wherein "baseline" is defined as the level of TARC in the subject immediately prior to the first administration). Similarly, on about the 4th, 8th, 15th, 22nd, 25th, 29th, 36th, 43rd, 50th, 57th, 64th, 71st or 85th day after administration of a pharmaceutical composition comprising a first, second, third or fourth dose of about 75 mg, 150 mg or 300 mg of an anti-hIL-4R antibody (e.g., mAb1), a subject, according to the present invention, may exhibit a decrease in IgE from baseline of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more (wherein "baseline" is defined as the level of IgE in the subject immediately prior to the first administration).

[0094] The present invention also includes a method for determining whether a subject is a suitable subject for which administration of a pharmaceutical composition comprising an IL-4R antagonist is beneficial. For example, if an individual shows a certain level of AD-related biomarkers indicative of a disease state before receiving a pharmaceutical composition comprising an IL-4R antagonist, the individual is identified as a suitable patient for which administration of a pharmaceutical composition of the present invention (a composition comprising an anti-IL-4R antibody) is beneficial. In a related embodiment, the present invention includes a method for treating a suitable subject who may be more susceptible to AD due to, for example, race or ethnicity. For example, the present invention includes a method comprising administering an IL-4R antagonist to an African-American subject who may be more susceptible to AD. Such a subject population may have elevated levels of AD-related biomarkers.

[0095] According to certain exemplary embodiments, the individual has (i) a blood glucose level of greater than about 114 kU / L, greater than about 150 kU / L, greater than about 500 kU / L, greater than about 1000 kU / L, greater than about 1500 kU / L, greater than about 2000 kU / L, greater than about 2500 kU / L, greater than about 3000 kU / L, greater than about 3500 kU / L, greater than about 4000 kU / L, greater than about 4500 kU / L, or or (ii) an IgE level greater than about 431 ng / L, greater than about 500 ng / L, greater than about 1000 ng / L, greater than about 1500 ng / L, greater than about 2000 ng / L, greater than about 2500 ng / L, greater than about 3000 ng / L, greater than about 3500 ng / L, greater than about 4000 ng / L, greater than about 4500 ng / L, or greater than about 5000 ng / L. If the individual exhibits one or more of the following: (iii) high TARC level; or (iii) a positive Phadiatop™ test, the individual can be identified as a good candidate for anti-IL-4R therapy. Additional criteria, such as other clinical indicators of AD (e.g., elevated IGA, BSA, EASI, SCORAD, 5-D pruritus, and / or NRS scores indicative of AD), can be used in combination with any of the AD-related biomarkers to identify the individual as a suitable candidate for anti-IL-4R therapy as described elsewhere herein.

[0096] Interleukin-4 receptor antagonist As disclosed in detail above, the present invention includes a method comprising administering a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist to a subject in need thereof. 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 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.

[0097] As used herein, the terms "IL-4R," "hIL-4R," and the like, are intended to refer to the alpha chain of the human cytokine receptor, IL-4Rα (SEQ ID NO: 274), which specifically binds interleukin-4 (IL-4). Unless specifically specified as being derived from a non-human species, the term "IL-4R," as used herein, should be understood to mean the human interleukin-4 receptor alpha chain.

[0098] The term "antibody" as used herein is intended to refer to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (HCVR or V H The heavy chain constant region is made up of three domains: H 1. C H 2 and C H Each light chain comprises a light chain variable region (LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L The regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), interspersed with regions that are more conserved, called framework regions (FRs). H and V L comprises three CDRs and four FRs arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the invention, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally occurring or artificially modified. An amino acid consensus sequence may be defined based on a comparative analysis of two or more CDRs.

[0099] The term "antibody" as used herein also includes antigen-binding fragments of complete antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, include any natural, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from complete antibody molecules using any suitable standard technique, such as, for example, proteolytic digestion or recombinant genetic engineering techniques involving 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 (e.g., phage-antibody libraries, etc.), or can be synthesized. The DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to place one or more variable and / or constant domains in a suitable configuration, or to introduce codons, create or modify cysteine ​​residues, add or delete amino acids, etc.

[0100] 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) antibodies (e.g., isolated complementarity determining regions (CDRs) such as CDR3 peptides) or minimal recognition units consisting of amino acid residues that mimic the hypervariable regions of constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed by the term "antigen-binding fragments" as used herein.

[0101] Antigen-binding fragments of antibodies typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and generally contains at least one CDR adjacent to or in frame with one or more framework sequences. L Domain associated with V H In the case of an antigen-binding fragment having a V domain, H and V L The domains may be positioned relative to each other in any suitable configuration. For example, the variable region may be a dimer, with the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a monomeric V H or V L It may contain domains.

[0102] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in an antigen-binding fragment of an antibody of the invention include: (i) a 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 -CH 3;(xi)V L -C H 1-C H 2;(xii)V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L In any configuration of variable and constant domains, such as 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. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present invention may be linked to each other and / or to one or more V H Or V L It may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above in non-covalent association (e.g., via disulfide bonds) between the domains.

[0103] As with intact antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, where each variable domain can specifically bind to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using routine techniques available in the art.

[0104] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, an antibody isotype can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0105] The term "human antibody" as used herein is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of the present invention may include, for example, in the CDRs and in particular the CDR3, amino acid residues 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" as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0106] The term "recombinant human antibody" as used herein is intended to include all human antibodies that are produced, 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 (e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies produced, expressed, created or isolated by any other means including splicing of human immunoglobulin gene sequences into 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, in the case of animals transgenic for human Ig sequences, in vivo somatic mutation), thus modifying the V and V regions of the recombinant antibody. Hand V L The amino acid sequence of the region is H and V L These are sequences that are derived from and related to sequences, but may not naturally occur within the human antibody germline repertoire in vivo.

[0107] Human antibodies may exist in two forms that are associated with hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa in which the dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not linked via interchain disulfide bonds, forming molecules of approximately 75-80 kDa that contain covalently coupled light and heavy chains (half antibodies). These forms have been extremely difficult to separate, even after affinity purification.

[0108] 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 typically significantly reduce the occurrence of the second form to the level observed with a human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). The present invention provides a method for modifying the hinge, C, C-terminal region of a human IgG4 hinge, which may be desirable in production, for example, to improve the yield of a desired antibody type. H 2 or C H Antibodies with one or more mutations in three regions are included.

[0109] As used herein, an "isolated antibody" refers to an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell, in which the antibody naturally occurs or is naturally produced, is considered a "natural antibody" for purposes of the present invention. 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.

[0110] The term "specifically binds" and the like means that an antibody or an 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, as used in the context of the present invention, an antibody that "specifically binds" to IL-4R 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 in a surface plasmon resonance assay. D However, an isolated antibody that specifically binds to human IL-4R may have cross-reactivity to other antigens, such as IL-4R molecules from other (non-human) species.

[0111] Anti-IL-4R antibodies useful for the methods of the invention may contain one or more amino acid substitutions, insertions and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains when compared to the corresponding germline sequences from which the antibodies are 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. The invention includes methods involving 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 in one or more framework and / or CDR regions are 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 and light chain variable region sequences disclosed herein, one of skill in the art can readily produce several antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, the V H and / or V LAll framework and / or CDR residues in the domain are backmutated to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are backmutated to the original germline sequence, e.g., only mutated residues found in 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 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, the antibodies of the present invention may contain any combination of two or more germline mutations in 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, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic 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 invention.

[0112] The present invention also relates to an HCV polypeptide disclosed herein having one or more conservative substitutions. The present invention also includes methods that include the use of anti-IL-4R antibodies that contain variants of any of the HCVR, LCVR and / or CDR amino acid sequences. For example, the present invention includes the use of anti-IL-4R antibodies having HCVR, LCVR and / or CDR amino acid sequences that include, e.g., 10 or less, 8 or less, 6 or less, 4 or less, etc., conservative amino acid substitutions compared to any of the HCVR, LCVR and / or CDR amino acid sequences disclosed herein.

[0113] As used herein, the term "surface plasmon resonance" refers to a method for detecting surface plasmon resonance (SPPR) using, for example, the BIAcore™ system (Biacore Life Sciences division of Protein dynamics refers to an optical phenomenon that allows analysis of real-time interactions by detection of changes in protein concentration in a biosensor matrix using a cellular biosensor (GE Healthcare, Piscataway, NJ).

[0114] As used herein, the term "K D " is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0115] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as the paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different regions on the antigen and have different biological effects. Epitopes may be conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are those produced by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes may include saccharide moieties, phosphoryl groups, or sulfonyl groups on the antigen.

[0116] Human antibody production Methods for generating human antibodies in transgenic mice are known in the art. Any such known method can be used in the context of the present invention to generate human antibodies that specifically bind to human IL-4R.

[0117] Using VELOCIMMUNE™ technology (e.g., U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for making monoclonal antibodies, a high affinity chimeric antibody against IL-4R with a human variable region and a mouse constant region is first isolated. VELOCIMMUNE® technology involves the creation of a transgenic mouse with a genome that includes human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces antibodies containing the human variable region and the mouse constant region in response to antigenic stimulation. DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing a fully human antibody.

[0118] 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. The lymphoid cells can be fused with myeloma cell lines to produce immortalized hybridoma cell lines, which are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy and light chains can be isolated and linked to the desired isotype constant regions of the heavy and light chains. Such antibody proteins can be produced in cells such as CHO cells. Alternatively, DNA encoding the antigen-specific chimeric antibodies or the variable domains of the light and heavy chains can be isolated directly from antigen-specific lymphocytes.

[0119] First, a high affinity chimeric antibody having a human variable region and a mouse constant region is isolated. The antibody is characterized and selected for desirable characteristics such as affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant region is replaced with the desired human constant region to create the fully human antibody of the present invention, for example, wild-type or modified IgG or IgG4. The constant region selected may vary according to the specific use, but the high affinity antigen binding and target specificity properties reside in the variable region.

[0120] Generally, the antibody that can be used in the method of the present invention has high affinity as described above, as measured by binding to antigen immobilized on solid phase or in liquid phase.The mouse constant region is replaced with the desired human constant region to create the fully human antibody of the present invention.The constant region selected may vary depending on the specific use, but the high affinity antigen binding and target specificity properties reside in the variable region.

[0121] Specific examples of human antibodies or antigen-binding fragments of antibodies that specifically bind to IL-4R that can be used in the context of the methods of the present invention include any antibody or antigen-binding fragment that comprises the three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 22, 26, 42, 46, 50, 66, 70, 74, 90, 94, 98, 114, 118, 122, 138, 142, 146, 162, 166, 170, 186, 190, 194, 210, 214, 218, 234, 238, 242, 258 and 262. The antibody or antigen-binding fragment may comprise three light chain CDRs (LCVR1, LCVR2, LCVR3) contained within a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 20, 24, 34, 44, 48, 58, 68, 72, 82, 92, 96, 106, 116, 120, 130, 140, 144, 154, 164, 168, 178, 188, 192, 202, 212, 216, 226, 236, 240, 250, 260 and 264. 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 specific HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National See, 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.

[0122] In certain embodiments of the invention, the antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 166 / 168, 170 / 1 The antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) derived from heavy chain and light chain variable region amino acid sequence pairs (HCVR / LCVR) selected from the group consisting of 78, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

[0123] In certain embodiments of the invention, the antibody or antigen-binding fragment thereof is selected from the group consisting of: 4 / 6 / 8 / 12 / 14 / 16; 28 / 30 / 32 / 36 / 38 / 40; 52 / 54 / 56 / 60 / 62 / 64; 76 / 78 / 80 / 84 / 86 / 88; 100 / 102 / 104 / 108 / 110 / 112; 124 / 126 / 128 / 132 / 134 / 136; 148 / 150 / 152 / 156 / 158 / 160; 172 / 174 / 176 / 180 / 182 / 184; 196 / 198 / 200 / 204 / 206 / 208; 220 / 222 / 224 / 228 / 230 / 232; and 244 / 246 / 248 / 252 / 254 / 256.

[0124] In certain embodiments of the invention, the antibody or antigen-binding fragment thereof is selected from the group consisting of 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, The HCVR / LCVR amino acid sequence pairs are selected from the group consisting of 146 / 154, 162 / 164, 166 / 168, 170 / 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

[0125] Pharmaceutical Compositions The present invention includes a method comprising administering an IL-4R antagonist to a patient, where the IL-4R antagonist is contained within a pharmaceutical composition. The pharmaceutical composition of the present invention is formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerability, etc. A number of suitable formulations can be found in a formulary known to any pharmacist: 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 absorption pastes, oil-in-water and water-in-oil emulsions, emulsions 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.

[0126] The dose of the antibody administered to the patient according to the method of the present invention may vary depending on the age and size of the patient, 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. Effective doses and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies can be determined empirically; for example, the progress of the patient can be monitored by periodic evaluation and the dose adjusted accordingly. Furthermore, interspecies scaling of doses can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Specific exemplary doses of anti-IL4R antibodies that can be used in the context of the present invention, and dosing regimens including same, are disclosed elsewhere herein.

[0127] Various delivery systems are known and can be used to administer the pharmaceutical compositions of the invention, including, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). (Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through the epithelial or mucocutaneous system (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other bioactive agents.

[0128] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously using a standard needle and syringe. Furthermore, for subcutaneous delivery, a pen delivery device can be easily applied to deliver the pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally uses a replaceable cartridge containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes pre-filled with the pharmaceutical composition held in a reservoir in the device. Once the reservoir is empty of the pharmaceutical composition, the entire device is discarded.

[0129] Some reusable pen and autoinjector delivery devices are applicable for subcutaneous delivery of the pharmaceutical composition of the present invention. Examples include, but are not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX75 / 25™ pen, HUMALOG™ pen, HUMALIN70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN ... STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen delivery devices applicable in subcutaneous delivery of pharmaceutical compositions of the present invention include, but are not limited to, SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ pen (Abbott Labs, Abbott Park IL), to name just a few.

[0130] In certain circumstances, the pharmaceutical composition 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, a polymeric material can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the 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, Medical Applications (See, for example, "Controlled Release Systems," supra, vol. 2, pp. 115-138.) Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0131] The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, drip infusions, and the like. These injectable preparations can be manufactured by known methods. For example, the injectable preparations can be manufactured by dissolving, suspending or emulsifying the above-mentioned antibody or its salt in, for example, a sterile aqueous medium or oily medium conventionally used for injections. As the aqueous medium for injection, there are isotonic solutions containing physiological saline, glucose and other auxiliary agents, which can be used together with suitable solubilizing agents such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], and the like. As the oily medium, for example, sesame oil, soybean oil, and the like can be used together with solubilizing agents such as benzyl benzoate, benzyl alcohol, and the like. The injection solution thus manufactured can be filled into a suitable ampoule.

[0132] Advantageously, the pharmaceutical compositions for oral or parenteral use are prepared in dosage forms in unit doses adapted to the dosage of the active ingredient, such as tablets, pills, capsules, injection solutions (ampoules), suppositories, etc.

[0133] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present invention are disclosed, for example, in US Patent Application Publication No. 2012 / 0097565.

[0134] dose The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) administered to a subject according to the method of the present invention 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 one or more of: (a) improvement of one or more AD-related parameters (as defined elsewhere herein); and / or (b) a detectable improvement of one or more symptoms or signs of atopic dermatitis. "Therapeutically effective amount" also includes an amount of IL-4R antagonist that inhibits, prevents, reduces, or delays the progression of AD in a subject.

[0135] In the case of an anti-IL-4R antibody, the therapeutically effective amount is about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg The amount of the anti-IL-4R antibody may be about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. In certain embodiments, 75 mg, 150 mg, or 300 mg of the anti-IL-4R antibody is administered to the subject.

[0136] The amount of IL-4R antagonist contained in an individual dose can be expressed in units of milligrams of antibody per kilogram of patient body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to a patient at a dose of about 0.0001 to about 10 mg per kg of the patient's body weight.

[0137] Combination Therapy The method of the present invention, according to certain embodiments, comprises administering to a subject one or more additional therapeutic agents together with an IL-4R antagonist. As used herein, the expression "together" means that the additional therapeutic agent is administered before, after, or simultaneously with a pharmaceutical composition comprising an IL-4R antagonist. The term "together" also includes sequential or simultaneous administration of an IL-4R antagonist and a second therapeutic agent.

[0138] For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent can be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition comprising an IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, the additional therapeutic agent can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition comprising an IL-4R antagonist. Administration "concurrently with" or in conjunction 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 containing both the additional therapeutic agent and the IL-4R antagonist.

[0139] The additional therapeutic agent may be, for example, another IL-4R antagonist, an IL-1 antagonist (including, for example, the IL-1 antagonists described in U.S. Pat. No. 6,927,044), an IL-6 antagonist, an IL-6R antagonist (including, for example, the anti-IL-6R antibodies described in U.S. Pat. No. 7,582,298), an IL-13 antagonist, a TNF antagonist, an IL-8 antagonist, an IL-9 antagonist, an IL-17 antagonist, an IL-5 antagonist, an IgE antagonist, a C The antagonist may be a D48 antagonist, an IL-31 antagonist (including, for example, those described in U.S. Patent No. 7,531,637), a thymic stromal lymphopoietin (TSLP) antagonist (including, for example, those described in U.S. Patent Application No. 2011 / 027468), an interferon-gamma (IFNγ) antibiotic, a topical corticosteroid, tacrolimus, pimecrolimus, cyclosporine, azathioprine, methotrexate, cromolyn sodium, a proteinase inhibitor, or a combination thereof. In certain embodiments, a pharmaceutical composition comprising an anti-IL4R antagonist is administered to a subject in conjunction with a non-pharmaceutical therapy, such as ultraviolet (UV) therapy.

[0140] The method of the present invention includes administering an IL-4R antagonist with a second therapeutic agent for additive or synergistic activity to treat AD. In one embodiment, the present invention includes a method for treating moderate to severe AD. Certain embodiments of the present invention include a method for treating moderate to severe AD by administering an IL-4R antagonist simultaneously with a TCS. The TCS may be a strong TCS, such as a group III TCS. Examples of group II TCS include methylprednisolone aceponate, mometasone furoate, fluticasone propionate, and betamethasone valerate. In some embodiments, the TCS may be a moderate TCS, such as a group II TCS, or a weak TCS, such as a group I TCS.

[0141] Dosing regimen The present invention provides a method for administering the drug about 4 times a week, twice a week, once a week, or every two weeks, as long as a therapeutic response is achieved. The present invention also includes methods comprising administering to a subject a pharmaceutical composition comprising an IL-4R antagonist at a dosing frequency of once a week, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or less frequently. In certain embodiments involving administration of a pharmaceutical composition comprising an anti-IL-4R antibody, a once a week dose in an amount of about 75 mg, 150 mg, or 300 mg can be used.

[0142] According to certain embodiments of the present invention, multiple doses of IL-4R antagonist can be administered to a subject over a defined time course. The method according to this aspect of the present invention includes sequentially administering multiple doses of IL-4R antagonist to a subject. As used herein, "sequentially administering" means administering each dose of IL-4R antagonist to a subject at different time points, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes a method comprising sequentially administering a single initial dose of IL-4R antagonist, followed by one or more second doses of IL-4R antagonist, optionally followed by one or more third doses of IL-4R antagonist to a patient.

[0143] The terms "first dose", "second dose" and "third dose" refer to the temporal order of administration of the IL-4R antagonist. Thus, the "first dose" is the dose administered at the beginning of the treatment regimen (also called the "baseline dose"); the "second dose" is the dose administered after the first dose; and the "third dose" is the dose administered after the second dose. The first, second and third doses may all contain the same amount of IL-4R antagonist, but generally may differ from each other in terms of frequency of administration. However, in certain embodiments, the amount of IL-4R antagonist contained in the first, second and / or third dose differs from each other during the course of treatment (e.g., adjusted upwards or downwards as necessary). In certain embodiments, one or more doses (e.g., 1, 2, 3, 4 or 5) are administered at the beginning of the treatment regimen as a "loading dose", followed by subsequent doses on a less frequent basis (e.g., "maintenance doses"). For example, the IL-4R antagonist can be administered to a patient with AD at a loading dose of about 300 mg or about 600 mg, followed by one or more maintenance doses of about 75 mg to about 300 mg. In one embodiment, the initial dose and one or more second doses each contain 50 mg to 600 mg of the IL-4R antagonist, e.g., 100 mg to 400 mg of the IL-4R antagonist, e.g., 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg of the IL-4R antagonist. In some embodiments, the initial dose and one or more second doses each contain the same amount of the IL-4R antagonist. In other embodiments, the initial dose contains a first amount of the IL-4R antagonist, and one or more second doses each contain a second amount of the IL-4R antagonist. For example, the first amount of the IL-4R antagonist may be 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times or more the second amount of the IL-4R antagonist.

[0144] In one exemplary embodiment of the invention, each second and / or third dose is administered 1 to 14 weeks (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 The phrase "immediately preceding dose" as used herein means, in a multiple administration sequence, a dose of an IL-4R antagonist that is administered to a patient prior to administration of the immediately succeeding dose in a sequence with no intervening doses.

[0145] The method according to this aspect of the invention may include administering any number of second and / or third doses of an IL-4R antagonist to the patient. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) second doses are administered to the patient. Similarly, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) third doses are administered to the patient.

[0146] In embodiments that include multiple second doses, each second dose can be administered with the same frequency as the other second doses. For example, each second dose can be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments that include multiple third doses, each third dose can be administered with the same frequency as the other third doses. For example, each third dose can be administered to the patient 2-4 weeks after the immediately preceding dose. Alternatively, the frequency with which the second and / or third doses are administered to the patient can vary over the course of the treatment regimen. The frequency of administration can also be adjusted during the course of treatment by the physician according to the needs of the individual patient after clinical testing.

[0147] The present invention includes methods for treating AD, comprising sequential administration of an IL-4R antagonist and a second therapeutic agent to a patient. In some embodiments, the methods of the invention include administering one or more doses of an IL-4R antagonist, followed by one or more doses of a second therapeutic agent. For example, one or more doses of about 75 mg to about 300 mg of an IL-4R antagonist can be administered after one or more doses of a second therapeutic agent (e.g., a topical corticosteroid or a calcineurin inhibitor or any other therapeutic agent described elsewhere herein) have been administered to treat, alleviate, reduce, or ameliorate one or more symptoms of AD. In some embodiments, the IL-4R antagonist is administered at one or more doses that result in an improvement in one or more AD-related parameters, followed by administration of a second therapeutic agent to prevent recurrence of at least one symptom of AD. An alternative embodiment of the invention relates to the simultaneous administration of an IL-4R antagonist and a second therapeutic agent. For example, one or more doses of an IL-4R antagonist are administered and the second therapeutic agent is administered in a separate dose at a similar or different frequency compared to the IL-4R antagonist, hi some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-4R antagonist.

[0148] IL-4R antagonists as vaccine adjuvants The present invention also includes compositions and methods that are useful in vaccine applications. For example, an IL-4R antagonist (e.g., an anti-IL-4R antibody disclosed herein) can be administered to a subject together with a vaccine to improve or enhance the immune response (including humoral and cellular immune responses) elicited by the vaccine, i.e., as a vaccine adjuvant. In certain embodiments, the IL-4R antagonist is administered immediately before, simultaneously with, and / or after administration of a vaccine composition to a subject. For example, the present invention includes a method of eliciting or enhancing an immune response to an antigen in a subject by first administering to the subject a pharmaceutical composition comprising an IL-4R antagonist, followed by administering to the subject a vaccine composition comprising an antigen (either alone or together with an IL-4R antagonist), and optionally administering to the subject additional doses of an IL-4R antagonist for a period of time after administration of the vaccine antigen.

[0149] The IL-4R antagonists of the present invention can be administered as an adjuvant with any type of vaccine, such as, for example, live vaccines, live / attenuated vaccines, killed vaccines, subunit vaccines, DNA vaccines, and cancer immunotherapy vaccines. Vaccines that can be used with L-4R antagonists include vaccines against bacterial pathogens, viruses, parasites, and other infectious agents.Non-limiting examples of infectious agents and diseases that can be targeted by the vaccine compositions and methods of the present invention include, for example, HIV, HCV, RSV, Neisseria meningitides, streptococcus, tuberculosis, malaria, smallpox, diphtheria, whooping cough, tetanus, polio, measles, rubella, mumps, influenza, anthrax, SARS, Ebola virus, Hantavirus, Dengue virus, etc.

[0150] The present invention also includes pharmaceutical compositions comprising an IL-4R antagonist and one or more vaccine antigens. The pharmaceutical compositions according to this aspect of the invention may include one or more additional immune enhancing agents, such as MPL, MDP, CpG oligonucleotides, lipopeptides, saponins, dsRNA, small molecule immune enhancing agents, etc.

[0151] In addition to IL-4R antagonists, other inhibitors of the IL-4 / IL-13 signaling pathway (e.g., anti-IL-4 antibodies, anti-IL-13 antibodies, bispecific anti-IL-4 / anti-IL-13 antibodies, etc.) can be used in the context of the vaccine methods and compositions disclosed herein. EXAMPLES

[0152] The following examples are provided 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 of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be expected. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0153] Example 1 Generation of human antibodies against human IL-4R Human anti-hIL-4R antibodies were generated as described in U.S. Patent No. 7,608,693. Table 1 lists the heavy and light chain variable region amino acid sequence pairs, as well as sequence identifiers for the CDR amino acid sequences, of selected anti-IL-4R antibodies and their corresponding antibody names.

[0154] [Table 1]

[0155] [Table 2]

[0156] An exemplary IL-4R antagonist used in the following examples is the human anti-IL-4R antibody designated H1H098-b in Table 1 (also referred to herein as "mAb1").

[0157] Example 2 Single Ascending Dose Clinical Trial of Intravenously and Subcutaneously Administered Anti-IL-4R Antibody (mAb1) in Healthy Subjects A. Study Design This was a randomized, double-blind, placebo-controlled, sequential, single ascending dose study of mAb1 administered intravenously (IV) and subcutaneously (SC) in healthy subjects. The primary objective of this study was to evaluate the safety and tolerability of mAb1 administered intravenously and subcutaneously in healthy subjects.

[0158] Screening occurred from day -21 to day -3. On day 1 (baseline), subjects were randomized to receive IV or SC study drug (mAb1 or placebo) infused over 2 hours. Subjects returned for clinical examination on days 4, 8, 11, 15, 22, 29, 43, 57, and 85 (last day of study) for safety assessments and blood draws.

[0159] A total of 48 subjects were enrolled in the study. Four sequential ascending dose cohorts (1.0, 3.0, 8.0, and 12.0 mg / kg) were designed for IV administration and two sequential ascending dose cohorts (150 and 300 mg) were designed for SC administration. Each dose cohort consisted of eight subjects (in the absence of cohort expansion): six randomized to receive mAb1 and two randomized to receive placebo. To optimize safety, the first three subjects in IV cohort 1 (1.0 mg / kg) were dosed at least 24 hours apart, and the remaining five subjects were dosed 5–7 days later. In subsequent IV cohorts, three of the eight subjects were dosed on day 1, and the remaining five subjects were dosed 5–7 days later. All eight subjects in SC dose cohort 1 (150 mg) were dosed on the same day, and all eight subjects in the subsequent SC cohort (300 mg) were dosed on the same day. The SC cohort was administered after the IV cohort was completed.

[0160] Inclusion criteria for the study were: (1) males or females aged 18–65 years; (2) weight greater than 50 kg but not greater than 120 kg; (3) for females of childbearing potential, a negative serum pregnancy test at the screening visit (Visit 1) and a negative urine pregnancy test on day -1; (4) willingness to abstain from consumption of more than two standard alcoholic drinks in any 24-hour period during the study. A standard alcoholic drink was considered equivalent to 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of hard liquor; (5) willingness to abstain from alcohol consumption in the 24-hour period prior to each study visit; (6) for males and females of childbearing potential, willingness to use adequate contraception to avoid becoming pregnant (or to prevent their partner from becoming pregnant) for the entire duration of the study. Adequate means of contraception included intrauterine devices (IUDs); tubal ligation; and fertility treatment. tubal resection; condoms or diaphragms, and contraceptive sponges, foams, or gels; and (7) willingness, commitment, and ability to return for all clinic visits and complete all study-related procedures.

[0161] Exclusion criteria for the study were as follows: (1) initiation of a new regular exercise regime or major changes to a previous regular exercise regime within 4 weeks prior to screening (Visit 1). Subjects must be willing to maintain a similar level of exercise over the study period and to refrain from unusually strenuous exercise over the study period; (2) pregnant or lactating women; (3) history of significant comorbidities or significant diseases such as cardiac, renal, neurological, endocrine, metabolic or lymphatic disease, or any other disease or condition that adversely affected the subject's participation in this study; (4) any clinically significant abnormality observed during the screening visit; (5) hospitalization for any reason within 60 days prior to screening (Visit 1); (6) known history of human immunodeficiency virus (HIV), hepatitis B or hepatitis C, and / or positive hepatitis B surface antigen, positive hepatitis C antibody or positive HIV serotype at the time of the screening visit; (7) history of drug or alcohol abuse or positive drug screen within 1 year prior to the screening visit; (8) doxycycline. (9) participation in any clinical research trial evaluating another investigational drug or therapy within 30 days or at least 5 half-lives of the investigational drug (whichever is longer) prior to the Screening Visit; (10) exposure to any therapeutic agent or investigational biological agent; (11) any medical or psychiatric condition that, in the opinion of the Investigator, places the subject at risk; prevents participation in the study or interferes with interpretation of the study results; (12) subject with a positive QuantiFERON tuberculosis (TB) test; (13) history of parasitic infection or recent (within the previous 6 months) travel to a parasite-endemic area; (14) history of alcohol or substance abuse within the previous 5 years; (15) positive urine drug screen result at Screening (Visit 1) or Baseline (Visit 2); and / or (16) receipt of live / attenuated vaccination within 12 weeks of Screening or during the study.

[0162] B. Study Treatment mAb1 drug product was supplied as a lyophilized powder in 20 ml glass vials for IV or SC administration. When delivered IV, mAb1 drug product was reconstituted in a single-use vial with 7.8 ml of sterile water for injection to yield a solution containing 50 mg / mL of mAb1. A pharmacist or designee withdrew the required amount of reconstituted mAb1 (dependent on subject dose and weight) or placebo and injected it into an infusion bag containing 0.9% saline for IV delivery. The infusion was given over 2 hours.

[0163] When delivered SC, the mAb1 drug product was reconstituted with 2.3 ml of sterile water for injection to yield a solution containing 150 mg / mL of mAb1. The pharmacist or designee administered the injections into the abdomen; administration into the extremities was not permitted due to the potential for different absorption and bioavailability. If administration of multiple injections on the same day was required, each injection was delivered at a different injection site.

[0164] Dose levels of mAb1 tested were 1.0, 3.0, 8.0, and 12.0 mg / kg for IV administration and 150 and 300 mg for SC administration.

[0165] Placebo-matched mAb1 was made in the same formulation as mAb1, but no antibody was added.

[0166] C. Results and Conclusions mAb1 was generally well tolerated with a favorable safety profile. The overall adverse event (AE) profile was characteristic of a healthy population. Fewer than 5% of subjects (19 / 36) experienced one or more treatment-emergent adverse events (TEAEs) compared with fewer than 59% of subjects (7 / 12) treated with placebo. The most frequently reported TEAEs were elevated blood creatine phosphokinase (CPK), elevated blood pressure, nasopharyngitis, and toothache. Most subjects experienced TEAEs of mild or moderate intensity; only three subjects reported a TEAE that was considered serious. Only one serious TEAE (elevated blood CPK) was considered by the investigator to be related to treatment. One serious adverse event (SAE) was reported during the study, which was considered by the investigator to be unrelated to study drug. No subjects discontinued the study due to an AE, and no deaths were reported. No other clinically significant laboratory findings (blood chemistry, hematology, or urinalysis) were reported during the study. No mean / median baseline trends were noted in any laboratory parameters. There were no significant trends in the mean or median changes from baseline in temperature or pulse throughout the study. No clinically significant abnormalities were noted on physical examination, ECG, or vital signs.

[0167] This study was significant in that the study population consisted of a high proportion of Black / African American subjects (Table 2).

[0168] [Table 3]

[0169] Although subjects were healthy volunteers, African Americans as a group may be more susceptible to atopic diseases (Caggana et al., 1999; Genet. Med. 1:267-271), and therefore this population may be appropriate for evaluation of mechanistic evidence based on exploratory biomarker analysis.

[0170] Regarding pharmacokinetic (PK) analysis, non-linear kinetics were observed. The target-mediated pathway of elimination appeared to be saturated at 8 and 12 mg / kg IV doses when the concentration of functional mAb1 was above about 30 mg / L. Low titers of anti-drug antibodies were observed in nine subjects. No sudden and sustained decline in the concentration of functional mAb1 was observed, indicating that ADA did not have a significant effect on PK.

[0171] Example 3 Clinical trial of two different drugs of anti-IL-4R antibody (mAb1) following subcutaneous administration of anti-IL-4R antibody (mAb1) in healthy patients A. Study Design This study was a single-center, single-dose, double-blind, randomized, non-placebo-controlled study to evaluate the safety and pharmacokinetic profile of subcutaneous administration of two different anti-IL-4R mAb (mAb1) drug products created from different cell lines and manufacturing methods. The drug products were provided in 2 mL doses of 150 mg / mL, and 300 mg (2 mL) was administered subcutaneously to 30 healthy adults (15 subjects per group) in two parallel groups. The subjects were 30 subjects, 22 males (73.3%) and 8 females (26.7%), aged 19-45 years, with body weights ranging from 54.8 to 94.3 kg.

[0172] The serum concentrations of mAb1 were used to determine the following PK parameters: maximum serum concentration (C max ), and the real time from time 0 to the final concentration above the lower limit of quantification (t last ) area under the serum concentration versus time curve (AUC last ), and the extrapolated area under the serum concentration versus time curve (AUC) from time zero to infinity. Also, the time to reach maximum concentration (t max ) and terminal half-life (t 1 / 2z ) was also measured.

[0173] B. Criteria for Evaluation and Methodology Safety was assessed by measuring adverse events, including treatment-emergent adverse events (TEAEs), clinical laboratory assessments (biochemistry, hematology, and urinalysis), vital signs, automated reading electrocardiogram (ECG), anti-mAb1 antibodies (negative or titer), and local tolerability assessments (including injection site pain using a visual analog scale [VAS; 100-mm unscaled line], erythema [diameter at injection site in mm], and edema [diameter at injection site in mm]) for up to 2 months after dosing.

[0174] Adverse events of note (AESI) were AEs (serious or nonserious) of scientific and medical interest requiring specific monitoring, documentation, and management as described in the protocol. The following AEs were defined as AESIs: Hypersensitivity / anaphylaxis: anaphylactic or acute allergic reaction requiring immediate treatment, severe injection site reaction lasting longer than 24 hours, severe infection, any parasitic infection, increase in alanine aminotransferase (ALT) ≥ 2 ULN, QTc ≥ 500 ms, pregnancy, or overdose.

[0175] Blood samples were taken for hematological and biochemical assessments on days -1 and 2 (i.e., 24 hours after dosing) pre-dose and on day 57, and on days 8, 15, 22, 29, 36, 43 and 50 for biochemical assessment limited to liver function.

[0176] Blood samples for determination of anti-mAb1 antibodies in serum were taken on day 1 and days 15, 29 and 57.

[0177] Local tolerability assessments were performed on day 1 prior to dosing, and at 2 minutes, 2 hours, 6 hours, and 12 hours after dosing, as well as on days 2 (i.e., 24 hours after dosing), 3, 4, and 8 after mAb1 administration.

[0178] For pharmacokinetic and pharmacogenetic sampling, blood samples were collected pre-dose on day 1 and 12 hours post-dose, and on days 2, 3, 4, 8, 11, 15, 22, 29, 36, 43, 50, and 57 after mAb1 administration. Serum concentrations of functional mAb1 were determined using a validated enzyme-linked immunosorbent assay (ELISA) with a lower limit of quantification (LLOQ) of 78 ng / mL.

[0179] Samples were taken at baseline (pre-dose day 1) for optional pharmacogenetic analysis.

[0180] Serum functional mAb1 pharmacokinetic parameters were summarized by treatment group using descriptive statistics (mean, geometric mean, median, standard deviation (SD), coefficient of variation [CV], minimum, and maximum). Log-transformed C max , AUC last For AUC, the test / reference treatment ratio was assessed using a linear fixed-effects model with sex and treatment as fixed effects and weight as a covariate. Estimates and 90% confidence intervals (CI) for the treatment ratio were calculated using the max , AUC last and AUC were provided.

[0181] Safety assessment was based on review of individual values ​​and descriptive statistics. All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 15.0, and the frequency of treatment-emergent adverse events (TEAEs) was categorized and tabulated (counts and percentages) by primary system organ class, preferred term, and treatment group. Clinically significant abnormalities (PCSA; definitions as of September 14, 2009, version 2.0) for laboratory data, vital signs, and ECG values, as well as values ​​outside normal ranges for laboratory data, were flagged and summarized by treatment group.

[0182] Anti-mAb1 antibody results were listed with titer values ​​as negative or positive in the confirmatory assay by treatment group, subject, and visit. Data were summarized as number (count and percent) of subjects showing negative or positive anti-drug antibody (ADA) responses by treatment group.

[0183] Descriptive statistics (mean, SD, minimum, median, and maximum) for pain VAS, erythema diameter, and edema diameter were provided by treatment group for each scheduled time point. Each of these measurements was further summarized by treatment group as time averages (including study drug administration through the day 8 assessment) and peak values ​​(using the post-dose assessment).

[0184] C. Pharmacokinetic Results [Table 4]

[0185] [Table 5]

[0186] Estimates are based on a linear fixed-effects model with fixed terms for sex, weight, and treatment.

[0187] D. Safety Results Twelve (80.0%) of 15 subjects on drug A (test drug) and eight of 15 subjects on drug B (reference drug) had TEAEs. Apparent treatment imbalances emerged in only some organ system classes and were often attributed to events unrelated to IMPs, as alternative causes were identified. Four SAEs were reported in two subjects during the study.

[0188] A 23-year-old male subject in the Drug 1 treatment group experienced a "type II herpes simplex virus infection" with symptoms of blurred vision, sweating, fever, and headache beginning 4 days after dosing, followed by a swollen tongue (6 days after dosing) and coughing, chest congestion, and muscle spasms in both calves (7 days after dosing). During the course of this event, the subject went to the emergency room several times and received multiple treatments including Solumedrol® (3 IV doses), prednisone (9 days), Rocephin® (1 IV dose), and Zithromax® (5 days). The subject had received tongue barbell piercings 3 months prior to dosing. It is notable that the patient had a puncture wound that had been placed on the nasal cavity. All symptoms resolved 19 days after treatment. Initial herpes simplex virus (HSV) II IgG titers performed 10 days after treatment were negative but converted to positive when reevaluated 7 weeks after treatment. This SAE was determined by the investigator and company to be related to IMP. More than 4 weeks after treatment, the subject was diagnosed with left-sided "Bell's palsy" and diagnosed by the investigator as having HSV II IgG. The SAE was thought to be the result of HSV II infection. The event was treated with prednisone (6 days) and acyclovir (10 days). This SAE was deemed not related to IMP by the investigator due to the multiple and repeated steroid administrations in the acute state of HSV II infection, and alternative explanations were considered. The company considered that a causal relationship to IMP could not be excluded. Both events had resolved by the end of the study. The subject did not develop ADAs at any time during the study.

[0189] A 22-year-old male subject in the Drug A treatment group experienced "ALT Elevation" (ALT up to 11.4 ULN) along with "Rhabdomyolysis" (creatine phosphokinase up to 392 ULN), both of which were discovered by routine laboratory testing 7 weeks after dosing. These events were followed by a physical challenge (consisting of swimming, push-ups, pull-ups, sit-ups and other endurance-type exercises; the subject is a lifeguard) and injury to his triceps (NSAE). The subject was admitted to the hospital for rehydration. Hepatic causes of the increased liver function tests were ruled out, and the elevation of ALT (as well as elevation of aspartate aminotransferase [AST] up to 50.5 ULN) was determined to be associated with rhabdomyolysis. Creatinine and and glomerular function were within normal limits during the course of the events. Both events resolved within 3 weeks. These two SAEs were considered by the investigator to be unrelated to IMP. This subject also developed ADA with a positive titer detected on Day 29 (titer value = 120) and on EOSV on Day 58 (titer value = 30).

[0190] Apart from the ALT increase, no other AESIs were observed during the study.

[0191] Four subjects experienced infections during the study. Apart from the herpes simplex infections mentioned above, cases of mild upper respiratory tract infection, pharyngitis, and sinusitis (one case each) were observed 54, 7, and 1 days after administration, respectively. These three latter events were observed in subjects treated with C1P2.

[0192] Fifteen cases of injection site reactions occurred in 12 subjects: erythema (8 cases in 8 patients, 4 cases in each group), pain (3 cases, 2 in C2P1 and 1 in C1P2), nodules (2 cases, 1 in each group), hematoma (1 in C1P2), and pruritus (1 in C2P1). All were mild and resolved within 24 hours of injection.

[0193] No other TEAEs were observed in more than one subject in each treatment group, except for two cases of pruritus (not at the injection site) in two subjects treated with C2P1 and three cases of headache (one subject treated with C2P1 and two subjects treated with C1P2).

[0194] Apart from the laboratory abnormalities already described, there were increases in other laboratory values ​​above the prescribed thresholds for PCSA.

[0195] Anti-mAb1 antibodies were positive in 6 of 27 subjects (22.22%) who completed the study (no ADA was detected in subjects who did not complete the study). Of the 6 subjects with positive ADA titers, 4 were treated with C2P1 and 2 with C1P2. No relationship was observed between the occurrence of ADA and TEAEs.

[0196] E. Specific local tolerance assessment For the pain VAS, the mean peak values ​​were 4.4 and 4.2 mm (on a 100 mm scale) in the C2P1 and C1P2 treatment groups, respectively, with a median of 2.0 mm in both groups. Five of the 15 subjects in each group had "no pain" (peak value 0 mm). The highest measurements were 17 and 18 mm in the C2P1 and C1P2 treatment groups, respectively, and were generally observed 2 minutes after administration (range 2 minutes to 12 hours after administration).

[0197] The mean peak erythema diameters measured were 12.5 and 10.9 mm in the C2P1 and C1P2 treatment groups, respectively. Nine of the 15 subjects in each group had no erythema at any time point. The maximum observed was 40 mm in both groups, all observed 2 minutes after administration, except for one subject whose maximum (3 mm) was observed 48 hours after administration.

[0198] The mean peak edema diameters measured were 1.1 and 0 mm in the C2P1 and C1P2 treatment groups, respectively. Thirteen of 15 subjects and 15 of 15 subjects in the C2P1 and C1P2 treatment groups, respectively, had no edema at any time point. The maximum values ​​were 15 and 1 mm in two subjects in the C2P1 treatment group, observed 2 hours after administration.

[0199] F. Conclusion Following a single subcutaneous dose of 300 mg mAb1 to healthy subjects, serum functional mAb1 exposure was similar for the two test drugs. The geometric mean treatment ratios (DP1 / DP2) with 90% CI were C max For, the AUC was 1.10 (0.89–1.35). last for RR, it was 0.90 (0.71-1.16), and for AUC, it was 1.05 (0.86-1.29).

[0200] mAb1 was generally well tolerated. One subject receiving DP1 experienced a serious adverse event of "Herpes simplex virus type II infection" followed by "Bell's palsy."

[0201] There were no clinically significant local tolerability issues and no apparent differences in local tolerability parameters (ie, pain, erythema, and edema) between treatment groups.

[0202] The most common TEAE was erythema at the injection site (8 of 30 subjects), which was observed with equal incidence in both treatment groups (4 of 15 subjects [26.7%] in each group).

[0203] In conclusion, following a single 300 mg SC dose of mAb1 to healthy subjects, there were no clinically important differences identified in the PK profiles, safety, and local tolerability of the two different pharmaceutical agents.

[0204] Example 4 A clinical trial on the safety, tolerability, and pharmacokinetics of ascending single subcutaneous doses of an anti-IL-4R antibody in healthy adult Japanese male subjects A. Study Design This study was a randomized, double-blind, placebo-controlled study of ascending single subcutaneous doses of an anti-IL-4R antibody (mAb1) in healthy adult Japanese male subjects. The primary objective was to evaluate the safety and tolerability of mAb1 after ascending single subcutaneous doses in healthy Japanese male subjects. The secondary objective was to evaluate the pharmacokinetics, immunogenicity, and exploratory pharmacodynamics of ascending single subcutaneous doses of mAb1 in healthy Japanese male subjects.

[0205] mAb1 was derived from cell line 2 and supplied in a liquid formulation at 75 mg / mL or 150 mg / mL concentration in vials. Single ascending doses of 75, 150, 300, and 600 mg of mAb1 were administered subcutaneously on day 1 (one injection for 75 mg and 150 mg; two injections for 300 mg; and four injections for 600 mg). The observation period was approximately 11 weeks for each subject (including a 2-21 day screening period prior to dosing, 5 days in the clinic [including one treatment day - days 1-4], and outpatient follow-up visits up to 57 days after dosing).

[0206] B. Evaluation Criteria Safety: Adverse events (AEs), physical examination, clinical laboratory evaluations (hematology, biochemistry, urinalysis), vital signs (supine and orthostatic blood pressure and heart rate, temperature), 12-lead electrocardiogram (ECG), and anti-mAb1 antibody.

[0207] Pharmacokinetics: The following mAb1 serum functional pharmacokinetic parameters were calculated using non-compartmental analysis - maximum observed serum concentration (C max ), time to reach maximum serum concentration (t max ), dose normalized C max (C max / dose), real-time t corresponding to the final concentration above the lower limit of quantification from time zero last Area under the serum concentration versus time curve (AUC last ), dose-normalized AUC last (AUC last / dose), the extrapolated area under the serum concentration versus time curve from time zero to infinity (AUC), the apparent volume of distribution at steady state (V ss / F), apparent total body clearance (CL / F), mean residence time (MRT), and terminal half-life Decrease period (t 1 / 2z ).

[0208] Pharmacodynamics (PD): Pharmacodynamic effects of mAb1 on total IgE and TARC.

[0209] Blood samples for PK assessment were collected pre-dose (day 1) and on days 1, 2, 4, 8, 11, 15, 18, 22, 25, 29, 36, 43, 50, and 57 after mAb1 administration (± 1 day for days 15-25; ± 2 days for days 29-57). Serum concentrations of mAb1 were determined using a validated ELISA with a lower limit of quantification (LLOQ) of 78 ng / mL (0.078 mg / mL). Blood samples for PD assessment were collected pre-dose on days -1 and 1, then on days 8, 15, 22, 29, 43, and 57 after mAb1 administration (± 1 day for days 15-25; ± 2 days for days 29-57). Serum screening for total IgE and TARC was determined using validated methods.

[0210] C. Statistical methods Safety assessment was based on review of individual values ​​and descriptive statistics. All adverse events were coded using MedDRA version 15.1, and the frequency of treatment-emergent adverse events (TEAEs) was categorized and tabulated (counts and percentages) by system organ class, preferred term, and treatment group. Clinically significant abnormalities for laboratory data, vital signs, and ECG data, as well as values ​​outside normal ranges for laboratory data, were flagged and summarized by treatment group. Additionally, raw data and changes from baseline for vital signs, ECG, and selected laboratory parameters were summarized in descriptive statistics.

[0211] Pharmacokinetic parameters of serum functional mAb1 were summarized for each dose group using descriptive statistics (mean, geometric mean, standard error of the mean [SEM], median, standard deviation [SD], and coefficient of variation [CV], minimum and maximum). Dose proportionality was calculated using the C max , AUC last , and AUC power models were used to evaluate the mean mean. 1 / 2z Dose effects on t were assessed using a linear fixed-effects model. max The distribution of values ​​was represented by a histogram plot. mAb1 PD biomarkers (total IgE and TARC:CCL17) were summarized for each dose group using descriptive statistics.

[0212] D. Safety Results Administration of a single subcutaneous dose of mAb1 up to 600 mg was well tolerated in healthy Japanese adult male subjects with a median body weight of 65.1 kg. No serious TEAEs or premature discontinuations were reported during the study. During the 57-day observation period following dosing, a total of three TEAEs were reported among the 32 study subjects, as follows: one of eight subjects in the placebo group (influenza), one of six subjects in the 150 mg group (influenza), and one of six subjects in the 600 mg group (orthostatic hypotension).

[0213] There were no local skin reactions or discomfort at the injection site with a maximum volume of 2.0 mL x 4 sites (600 mg).

[0214] Anti-mAb1 antibodies (ADA) were positive in 5 of 32 subjects with low titer levels (1 in the 75 mg group, 2 in the 150 mg group, 1 in the 300 mg group, and 1 in the 600 mg group). ADA was undetectable at baseline and in the placebo group in all subjects. No ADA-positive subjects experienced any TEAEs.

[0215] Very little PCSA in blood and biochemistry parameters was identified in the mAb1 treatment group, without any dose-incidence relationship. Notably, no changes in liver enzymes were observed. There was little PCSA on vital signs or ECG, but no dose-related relationship. Subjects had QT No prolongation of cB (>450 ms) was experienced, and no change from baseline of >60 ms was observed during the study.

[0216] E. Pharmacokinetic Results The mean (SD) serum functional mAb1 concentration-time profiles after a single subcutaneous dose are shown in Figure 1. Pharmacokinetic parameters for serum functional mAb1 are summarized for all subjects treated with mAb1 in Table 5.

[0217] [Table 6]

[0218] Central t of mAb1 max The mean terminal half-life (t 1 / 2z ) was dose-dependent (p<0.01), ranging from 2.77 days at 75 mg to 8.77 days at 600 mg. An eight-fold increase in dose from 75 mg to 600 mg resulted in a geometric mean C max , AUC last and AUC, resulting in a 13.1-, 30.4-, and 24.2-fold increase, respectively.

[0219] F. Pharmacodynamic Results Serum IgE and TARC values ​​were highly variable within treatment groups. No drug-related effects were observed over time with respect to serum IgE (percent change from baseline) at single subcutaneous doses of 75 mg and 150 mg. At 300 mg and 600 mg, there was a trend to decrease serum IgE after treatment. A treatment effect was observed with respect to TARC. Single subcutaneous doses of 75 mg to 600 mg were associated with decreases in serum TARC levels compared with placebo. More sustained decreases were associated with increasing doses.

[0220] G. Conclusion Single subcutaneous doses of mAb1 up to 600 mg were well tolerated in healthy Japanese male subjects. No serious TEAEs or premature discontinuations were reported during the study. A total of 3 TEAEs were reported among the 32 study subjects. There were no local skin reactions or discomfort at the injection site with a maximum volume of 2.0 mL x 4 sites (600 mg). Overall, the reported TEAEs and laboratory, vital sign, and ECG assessments did not suggest a dose-related effect.

[0221] Following a single dose to healthy Japanese adult males, mAb1 was absorbed with a median tmax of 7 days and had a dose-dependent mean terminal half-life (t 1 / 2z ) Mean serum functional mAb1 exposure increased in a more than dose-proportional manner, with an 8-fold increase in dose from 75 mg to 600 mg resulting in a geometric mean C max , AUC last and AUC, resulting in a 13.1-, 30.4-, and 24.2-fold increase, respectively.

[0222] A pharmacodynamic effect was observed. Serum levels of TARC decreased after treatment with mAb1. A more sustained decrease was associated with increased dose. Low titer ADA was detected in 5 of 32 subjects. ADA was undetectable at baseline and in the placebo group in all subjects. No ADA-positive subjects experienced any TEAEs.

[0223] Example 5 A Clinical Trial to Evaluate the Effect of Infusion Rate on the Safety and Tolerability of mAb1 Administered Subcutaneously in Healthy Volunteers A. Overview and Study Design This study was conducted to aid in the development of a large volume injection device for administering mAb1. The study was a comparative evaluation of two different injection rates that approximated the corresponding attributes of two different subcutaneous (SC) delivery devices: the fast injection is an autoinjector and the slow injection is a microinfuser. The primary objective of the study was to evaluate the relative safety and tolerability of a single 300 mg / 2 mL dose of mAb1 administered SC at two different rates in normal healthy volunteers. Secondary objectives of the study were to compare the pharmacokinetic (PK) parameters of a single 300 mg / 2 mL dose of mAb1 administered SC at two different rates in two separate cohorts of NHVs; and to evaluate the relative immunogenicity of a single 300 mg / 2 mL dose of mAb1 administered SC at two different rates in NHVs.

[0224] This was an open-label, randomized, parallel-group, single-dose study of the safety, tolerability, PK, and immunogenicity of mAb1 administered SC at two different infusion rates. The study was randomized to avoid any potential bias in assigning subjects to study treatments and to minimize systematic differences between treatment groups with respect to baseline variables that may affect outcome. Because the study was open-label, it was not possible to effectively blind the infusion method and duration. Thirty-six subjects (18 subjects per treatment group) were recruited in the United States and randomized at one center. The sample size for this study was selected empirically. No formal sample size or power calculations based on the primary endpoint were used. However, it was estimated that enrollment of 18 subjects per group would provide 80% power to detect a difference of 20 in the pain VAS of two-group values, assuming a typical standard deviation of 20.8 in the pain VAS in a two-sided test at a significance level of 0.05.

[0225] Subjects were screened on days -14 to -2. On day -1, subjects were admitted to the clinic for training and familiarization with the injection procedure and randomized to either Group 1 (fast infusion) or Group 2 (slow infusion): Group 1 (fast injection): Subjects were tested by manual SC injection administered over 30 seconds. Received an investigational drug. · Group 2 (slow injection): Subjects received the study drug via an SC infusion set connected to a syringe pump programmed to deliver 2 mL in 10 minutes.

[0226] On day -1, all subjects underwent a mock injection in which an SC infusion set was briefly attached to the skin. This process involved the insertion of a 27G, 6mm needle, which was left in place for approximately 10-15 seconds, followed by removal. Subjects rated their pain / discomfort associated with each corresponding step of the mock injection procedure as follows: Immediately after needle insertion and needle removal (within 10 seconds), subjects rated their pain / discomfort associated with each corresponding step of the procedure. Global Assessment (GA): One minute after needle removal, subjects were asked to provide a GA by recalling and rating the pain / discomfort experienced during the entire procedure. · Comparative assessment (CA): Approximately 1 minute after removal of the needle (immediately after GA), in addition to a visual analogue scale (VAS), subjects provided a CA by relating their global pain / discomfort to common experiences, such as a bee sting or a flu shot.

[0227] On day 1, all subjects received 300 mg of mAb1 in a 2 mL volume and completed the VAS assessment as outlined in the diagram in FIG.

[0228] Information on the incidence, extent and severity of injection site reactions (ISR), such as erythema, edema, induration, tenderness and itching, was monitored for all subjects (Group 1 and Group 2). The extent of erythema, edema and induration (maximum diameter mm) and the severity of erythema and edema were evaluated at 1, 2, 4 and 8 hours after the completion of injection and at follow-up visits until the end of the study or until the injection site was considered normalized in two consecutive evaluations based on all parameters evaluated.Subjects were also asked to evaluate any pruritus (itch) and tenderness (pain on palpation) present using a VAS.

[0229] Subjects were discharged from the clinic on Day 2. Subjects returned to the clinic for outpatient follow-up visits on Days 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, and 64 (last day of study). Clinic visits on Days 8, 11, and 15 occurred within a + / - 1 day window. Visits on Days 22 through 64 occurred within a + / - 2 day window. The total observation period for each subject was 9 weeks after Day 1 dosing.

[0230] B. Analytical variables and statistical methods The following demographic and baseline characteristic variables were collected: age (years), sex, ethnicity, race, baseline weight (kg), height (m), and BMI (kg / m2) at screening, pain / discomfort VAS. Primary variables included the following measures of safety and tolerability: (i) incidence and severity of treatment-emergent adverse events (TEAEs) through Day 64 (last day of study); incidence, extent, severity, and duration of ISRs through Day 64; (ii) overall pain / discomfort (GA) associated with the injection procedure; (iii) individual pain / discomfort components upon needle insertion, while injecting study drug, and upon needle removal; and (iv) residual pain / discomfort over time: pain / discomfort present at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1, 2, 4, and 8 hours after study administration, and at subsequent study visits.

[0231] Information on the incidence, extent, and severity of ISR such as erythema, edema, induration, tenderness, and itching was monitored for all subjects (Groups 1 and 2). The extent of erythema, edema, and induration (maximum diameter in mm) was assessed. In addition, the severity of erythema and edema was assessed using a standard 0-4 skin tolerability scale (Draize) at 1, 2, 4, and 8 hours after completion of the injection, and at follow-up visits until the end of the study or until the injection site was considered normalized in two consecutive evaluations based on all parameters evaluated. was used for qualitative evaluation.

[0232] The following scale was used to grade the severity of erythema and edema: Erythema: 0 = no erythema 1 = Very slight erythema (barely noticeable) 2 = Well-defined erythema 3 = moderate to severe erythema 4 = Severe erythema (beet-like redness) to slight crusting (deep injury) edema: 0 = no edema 1 = Very slight swelling (barely noticeable) 2 = slight edema (well-defined edges) 3 = Moderate edema (>1 mm elevation) 4 = severe edema (>1 mm elevation beyond the exposed area).

[0233] The VAS is a continuous rating scale (0-100 mm) used by patients to rate their pain / discomfort associated with the study drug injection. The VAS was anchored with "no pain / discomfort" on the left and "worst pain / discomfort imaginable" on the right. The same scale was used to quantify itching and tenderness at the injection site and was assessed as part of the ISR.

[0234] Safety and tolerability of mAb1 was assessed by physical examination, vital signs, electrocardiogram (ECG), and clinical laboratory evaluations. Subjects were asked to monitor and report all adverse events (AEs) experienced from the time they signed the informed consent through the last study visit on day 64. Adverse events, serious adverse events, and treatment-emergent adverse events are defined elsewhere herein.

[0235] Blood samples were collected for PK analysis beginning at baseline and throughout the study (Day 1, pre-dose, and post-dose [end of injection, and 1, 2, 4, 8, and 12 hours post-dose]). Blood samples were collected for analysis of anti-mAb1 antibody levels on Day 1 (pre-dose), and Days 29 and 64 (last day of study).

[0236] For continuous variables, descriptive statistics included: number of patients (n), mean, median, standard deviation, minimum, and maximum values ​​reflected in the calculation. For categorical or ordinal data, frequencies and percentages were presented for each category.

[0237] C. Results Injection pain and residual pain: Both injection modalities - fast and slow - were well tolerated and associated with relatively low levels of injection pain. For both modalities, pain peaked approximately 15-30 seconds after the start of the injection. The mean peak pain level was below 15 mm on a 0-100 mm VAS. Mean pain scores, including global assessment (overall pain recalled 1 minute after injection), as well as residual pain over time, were comparable between fast and slow injections; the differences observed were not clinically relevant (i.e., Δ<10 on a 0-100 VAS scale). More subjects receiving slow injections reported little to no pain (VAS<5 mm) compared with those receiving fast injections. Overall, the injection pain profile was considered slightly more favorable for slow injections, but did not clearly distinguish the two injection modalities.

[0238] Injection site reactions: The overall incidence of ISR was similar between the two study groups (89% for fast injection and 94% for slow injection). However, no objective ISR findings (erythema and / or The incidence of induration was higher in the slow injection group (83%) compared with the fast injection group (44%), especially with respect to erythema at the injection site (61% and 11%, respectively). Subjective ISR included tenderness and pruritus at the injection site, the incidence of which was somewhat higher for the fast injection (72%) compared with the slow injection (56%), especially with respect to tenderness at the injection site (72% and 39%, respectively). Onset of ISR ranged from 1 hour to several days after injection. Time to ISR resolution was also reported from 1 hour to several days after onset. Overall, the ISR profile appeared somewhat more favorable in the fast injection group, but did not provide a clear distinction between the two injection modalities.

[0239] Adverse Events: The number and incidence of treatment-emergent adverse events was higher in the slow injection group (35 TEAEs reported in 15 subjects) compared with the fast injection group (19 TEAEs reported in 11 subjects). Many TEAEs were ISRs reported as adverse events based on the investigator's assessment of clinical relevance. No TEAEs led to discontinuation. There were three severe TEAEs related to study drug and one case unrelated to injection mode. Overall, the adverse event profile appeared slightly more favorable in the fast injection group, mostly due to ISRs reported as adverse events.

[0240] D. Conclusion The study achieved the primary and secondary objectives described in the protocol. mAb1 was safe and well tolerated when administered by either fast or slow injection. The results of the study did not provide a clear distinction between the two injection modalities.

[0241] Example 6 A sequential ascending multiple dose clinical trial of subcutaneously administered anti-IL-4R antibody (mAb1) in patients with moderate to severe atopic dermatitis A. Study Design This study was a phase 1b, randomized, double-blind, placebo-controlled, sequential ascending, multiple-dose study of mAb1 administered subcutaneously in patients with moderate to severe exogenous atopic dermatitis (AD). Thirty patients were randomized in the study (6 to placebo, 8 each to the 75 mg, 150 mg, and 300 mg groups). Twenty-eight patients received all treatments. The treatment period was 4 weeks in duration; patients were followed for 8 weeks after the treatment period ended. Patients were randomized in a 4:1 ratio to receive mAb1 or placebo in each of the three ascending dose cohorts (75, 150, or 300 mg of mAb1). The primary objective of the study was to evaluate safety and tolerability, with PK as a secondary objective. Exploratory objectives included efficacy and biomarker endpoints. Exploratory efficacy variables included (i) the proportion of patients achieving an IGA score of 0 or 1 by week 4 and at each study visit; (ii) change and rate of change from baseline to each visit in BSA, EASI, and 5-D pruritus scales; and (iii) week-to-week change from baseline in NRS scales.

[0242] B. Efficacy Variables The efficacy variables IGA, BSA, EASI, SCORAD, 5-D Pruritus Scale, and Pruritus NRS assessments are described elsewhere herein (see, e.g., Example 7).

[0243] IGA, BSA, EASI and SCORAD scores were assessed at every clinic visit. Patients underwent 5-D pruritus assessments at the following visits: Screening, Day 1 / Baseline (pre-dose), and Days 15, 29, 43, 57, 71 and 85 (last day of study) or early termination. Patients used the IVRS to record their pruritus NRS score twice daily until the last study visit.

[0244] The baseline for efficacy variables is defined as the last nonmissing value on or before the date of randomization. For patients who do not have a value on or before his / her randomization date, the last nonmissing value on or before the date of first dose injection is used as the baseline.

[0245] C. Statistical methods Summary safety and exploratory efficacy variables were generated by dose group and overall. Safety and tolerability summaries were based on the Safety Analysis Set (SAF). Safety analyses were based on reported adverse events (AEs), clinical laboratory assessments, vital signs, and 12-lead electrocardiograms.

[0246] All categorical variables were analyzed using Fisher's exact test with nominal p-values ​​and reported confidence intervals.

[0247] All continuous variables were analyzed by analysis of covariance (ANCOVA). Unless otherwise specified, assessment of change from baseline and construction of confidence intervals for continuous measures were based on an ANCOVA model with treatment as the main factor and baseline value as the covariate. Point estimates and 95% CIs of the difference in adjusted mean change from baseline between the two treatment groups were provided. Due to the small sample size of this study, p values ​​from testing of exploratory efficacy variables were provided for descriptive purposes. Missing values ​​were imputed by last observation carried forward (LOCF).

[0248] D. Patient predisposing factors Patients in the placebo group were the youngest, and 33% of patients in the placebo group were Hispanic or Latino, compared with the treatment group, in which all patients were non-Hispanic. Table 6 summarizes the demographic characteristics of the patient population.

[0249] [Table 7]

[0250] Table 7 summarizes the baseline disease characteristics of the patient population.

[0251] [Table 8]

[0252] The mean baseline IGA, EASI, BSA, and pruritus NRS for study participants were approximately 3.8, 28.2, 48.5, and 6.4, respectively.

[0253] E. Results Subcutaneous administration of mAb1 to patients with moderate to severe AD was safe and well tolerated in this study. A single serious adverse event was recorded for a patient in the 150 mg group diagnosed with exercise-associated CPK increase. No deaths were reported. Twenty-five treated patients or 83% reported at least one treatment-emergent adverse event (TEAE). The most frequent TEAEs from the treatment groups were infections and infestations (n=7 [29%] vs. 1 [17%] for placebo), followed by headache in patients receiving mAb1 (n=3 [13%] vs. 1 [17%] for placebo).

[0254] Baseline and exploratory efficacy results from the study are summarized in Figures 3-14. Administration of mAb1 did not induce statistically significant improvements in any of the AD exploratory endpoints. This may be due to the small sample size and the fact that placebo patients were less severely ill and younger than the active treatment group.

[0255] Example 7 Clinical trial of subcutaneously administered anti-IL-4R antibody (mAb1) in patients with moderate to severe atopic dermatitis A. Study Design This study was a 12-week, double-blind, randomized, placebo-controlled, serial ascending, multiple-dose study to evaluate the safety and pharmacokinetic profile of subcutaneous administration of an anti-IL-4R mAb, herein referred to as "mAb1," in adult patients with moderate to severe atopic dermatitis. Patients with moderate to severe AD had an Eczema Area and Severity Index (EASI) of 12 or greater and a minimum of 10% body surface area involvement. The treatment period was 4 weeks in duration and patients were followed for 8 weeks after the treatment period ended. Patients were weaned from topical medications (e.g., pimecrolimus, tacrolimus, and topical corticosteroids) for at least 1 week prior to baseline. Oral corticosteroids and immunosuppressants (e.g., cyclosporine, mycophenolate-mofetil, IFNγ) were also prohibited for ≥4 weeks prior to baseline.

[0256] Patients were randomized in a 3:1 ratio to receive mAb1 or placebo in each of two ascending dose cohorts (150 mg or 300 mg). The study consisted of a screening period (days -14 to -3), a treatment period (days 1 to 29) (local The study consisted of a treatment period (days 29 to 85) (topical steroids were not allowed), and a follow-up period (days 29 to 85) (topical steroids were allowed). During the treatment period, patients were seen in the clinic at least once a week for safety, laboratory evaluations, and on days 1, 4, 8, 15, 22, 25, and 29 (week 4) for clinical efficacy evaluations. Patients received doses of study medication on days 1, 8, 15, and 22. Patients were monitored at the study site for 2 hours after each dose of study medication. The end of the study visit for the treatment period was day 29 (week 4). During the follow-up period, patients were seen in the clinic for follow-up evaluations on days 36, 43, 50, 57, 64, 71, and 85 (last study visit).

[0257] B. Efficacy Variables Exploratory efficacy variables measured in this study included: (1) proportion of patients achieving an Investigator Global Assessment (IGA) score of 0 or 1 by week 4 and each study visit; (2) change and percent change from baseline to each visit in atopic dermatitis body surface area lesions (BSA), eczema area and severity index (EASI), SCORAD, and 5-D pruritis scale; (3) week change from baseline in pruritis numeric rating scale (NRS); (4) change from baseline in circulating eosinophils, TARC, eotaxin-3, and total IgE by week 4; (5) change from baseline in circulating eosinophils, TARC, eotaxin-3, and total IgE by week 12; and (6) change from baseline in eosinophils, TARC, eotaxin-3, Phadiatop™ results, and total IgE associated with response by week 4.

[0258] The baseline of an efficacy variable is defined as the last nonmissing value at or before the date of randomization. For patients who do not have a value at or before his / her randomization date, the last nonmissing value at or before the date of first dose injection is used as the baseline.

[0259] Investigator Global Assessment (IGA): The IGA is a rating scale used in clinical trials to determine the severity of AD and the clinical response to treatment on a 6-point scale ranging from 0 (clear) to 5 (very severe). IGA scores were assessed at every clinic visit.

[0260] Atopic Dermatitis Body Surface Area Lesions (BSA): BSA affected by AD was assessed for each major part of the body (head, trunk, upper extremities, and lower extremities) and reported as the sum of the percentages originating from each body part. Patients were assessed for BSA at the following visits: Screening, Day 1 / Baseline (pre-dose), and Days 15, 29, 36, 43, 57, 71, and 85 (last day of study) or early termination.

[0261] Eczema Area and Severity Index (EASI): The EASI is a validated scale used in clinical practice and clinical trials to assess the severity and extent of AD (Hanifin et al., 2001, Exp. Dermetol. 10:11-18). EASI score calculation is based on a physician's assessment of individual signs [erythema (E), induration / papulation (I), excoriation (X), and lichenification (L)], where each sign is scored as 0=absent, 1=mild, 2=moderate, or 3=severe, and on an area score [based on % affected (BSA)], where 0=0% BSA, 1=1-9% BSA, 2=10-29% BSA, 3=30-49% BSA, 4=50-69% BSA, 5=70-89% BSA, and 6=90-100% BSA.

[0262] For each major body part (head, upper limbs, trunk and lower limbs), the EASI score = (E+I+X+L) x area score. The total EASI score is calculated by dividing the weight 10% = head, 2 It is a weighted sum of partial EASI with 0%=upper extremities, 30%=trunk, 40%=lower extremities. The minimum possible EASI score is 0 and the maximum possible EASI score is 72, where higher scores indicate greater severity of atopic dermatitis. Achieving EASI50 (≥50% improvement in EASI score) is considered by dermatology investigators to be a clinically meaningful level of improvement for use as an endpoint.

[0263] Patients underwent EASI score assessments at the following visits: Screening, Day 1 / Baseline (pre-dose), and Days 15, 29, 36, 43, 57, 71 and 85 (last day of study) or early termination.

[0264] SCORAD: SCORAD is a validated tool used in clinical research and practice developed to standardize the assessment of the extent and severity of AD (Dermatology 1993, 186:23-31). The extent of AD is assessed as a percentage of each defined body area and reported as the sum of the total area, with a maximum score of 100% (assigned an "A" in the overall SCORAD calculation). The severity of six specific symptoms of AD (erythema, edema / papulation, excoriation, lichenification, oozing / scabbing, and dryness) is assessed using the following scale: none (0), mild (1), moderate (2), or severe (3) (assigned a "B" in the overall SCORAD calculation, for a maximum total score of 18). Subjective assessments of itch and sleep deprivation are recorded by the patient for each symptom or compared on a visual analog scale (VAS), where 0 is no itch (or sleep deprivation) and 10 is the worst itch (or sleep deprivation) imaginable, with the maximum possible score being 20. This parameter is assigned a "C" in the overall SCORAD calculation. The SCORAD score is calculated as A / 5+7B / 2+C. The maximum SCORAD score is 103.

[0265] Patients underwent SCORAD assessments at the following visits: Screening, Day 1 / Baseline (pre-dose), and Days 15, 29, 36, 43, 57, 71 and 85 (last day of study) or early termination.

[0266] 5-D Pruritus Scale: The 5-D Pruritus Scale is a five-question tool used in clinical trials to assess five dimensions of background itch: severity, duration, direction, disability, and distribution (Elman et al., 2010, Brit. J. Dermatol. 162:587-593). Patients rate their symptoms over the preceding two weeks as "present" or on a scale of 1 to 5, with 5 being most affected for each question in severity, duration, direction, and disability. Single item domain scores (duration, severity, and direction) are equal to the values ​​shown below the response choices (range 1 to 5).

[0267] The disability domain includes four items that assess the impact of itch on daily activities: sleep, recreational / social activities, housework / errands, and work / school. A score on the disability domain is achieved by taking the highest score on any of the four items.

[0268] For the distribution domain, tally the number of body parts affected (potential total 0-16) and sort the sum into five scoring bins: sum of 0-2 = score of 1, sum of 3-5 = score of 2, sum of 6-10 = score of 3, sum of 11-13 = score of 4, and sum of 14-16 = score of 5.

[0269] Scores for each of the five domains are achieved separately and then summed together to obtain a total 5-D score, which can potentially range from 5 (no pruritus) to 25 (most severe pruritus).

[0270] Patients underwent a 5-D pruritus assessment at the following visits: Screening, Day 1 / Baseline (pre-dose), and Days 15, 29, 36, 43, 57, 71, and 85 (last day of study) or early termination.

[0271] Pruritus Numeric Rating Scale (NRS): The Pruritus NRS is a single-question assessment tool used to rate a patient's worst itch as a result of AD in the previous 12 hours. Patients call the IVRS twice daily, beginning the evening of their screening visit, and are asked the following question: "On a scale of 0 to 10, with 0 being 'no itch' and 10 being 'the worst itch imaginable,' how would you rate the worst degree of itch you have experienced in the previous 12 hours?" Patients are instructed to record their Pruritus NRS score at the screening visit when using the IVRS, and are queried for compliance at each subsequent clinic visit. Patients complete the scale twice daily until the final study visit.

[0272] Baseline NRS is defined as the average of the reported NRS between immediately after the screening visit and immediately before the baseline visit. For post-baseline NRS, the weekly average NRS is calculated as the average of the reported daily NRS within that week (daily average).

[0273] C. Safety Assessment Safety was assessed throughout the study by monitoring adverse events and serious adverse events.

[0274] An adverse event (AE) is any undesirable medical occurrence in a subject administered a medicinal product or in a clinical investigational subject. An AE may therefore be any undesirable, unintended sign (e.g., laboratory abnormality), symptom, or disease that is temporally related to the use of a medicinal product, whether or not it is causally related to the medicinal product. AEs also include any worsening (i.e., any clinically meaningful change in frequency and / or intensity) of an existing condition that is temporally related to the use of the study drug; laboratory abnormalities that are considered clinically significant by the investigator; and any undesirable medical occurrence.

[0275] A serious adverse event (SAE) is any untoward medical occurrence at any dose that results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability / incapacity; is a congenital anomaly / birth defect; or is a major medical event.

[0276] In addition, laboratory safety variables, vital sign variables, 12-lead electrocardiogram (ECG) variables, and physical examination variables were measured throughout the study.

[0277] Clinical laboratory data consisted of hematology, blood chemistry and urinalysis. Blood samples for hematology were collected at each study visit; blood samples for serum chemistry and urine samples for urinalysis were collected at screening, day 1 / baseline (pre-dose), day 8, day 15, day 29, day 36, day 57, day 85 (last day of study) or at early termination if the subject discontinued the study to measure overall patient health.

[0278] Vital signs parameters included respiratory rate (bpm), pulse rate (bpm), systolic and diastolic blood pressure (mmHg) and temperature (°C). Vital signs were collected at screening and Day 1 / baseline (pre-dose, dosing day), and Days 4, 8, 15, 22, 25, 29, 36 and 85 (last day of study) or early termination. Vital signs were taken after study drug administration on Days 1, 8, 15, and 22, and at 1 and 2 hours post-injection.

[0279] 12-lead ECG parameters included ventricular HR, PR interval, QRS interval, and corrected QT interval (QTcF = QT / [RR 0.33 ] and QTcB=QT / [RR 0.5 ])ECG status: normal, clinically insignificant abnormalities, or clinically significant abnormalities. Standard 12-lead ECGs were performed at screening, day 29, and day 85 (last day of study) or at early termination.

[0280] A complete, thorough physical examination was performed at screening, day 29, and day 85 (last day of the study) or at early termination.

[0281] D. Data Analysis 1. Analysis of exploratory efficacy variables All categorical variables were analyzed using Fisher's exact test with nominal p-values ​​and reported confidence intervals. All continuous variables were analyzed by analysis of covariance (ANCOVA). Unless otherwise specified, evaluation of change from baseline for continuous measures and construction of confidence intervals were based on an ANCOVA model with treatment as main factor and baseline value as covariate. Point estimates and 95% CIs of the difference in adjusted mean change from baseline between the two treatment groups were provided. Missing values ​​were imputed by the last observation carried forward (LOCF) method. In the event that model assumptions were not guaranteed, analyses based on the ranks of the covariates were used. Correlation analyses were performed using Spearman's correlation coefficient.

[0282] 2. Safety Data Analysis Safety analyses are based on reported AEs, clinical laboratory assessments, vital signs, and 12-lead ECGs. Thresholds for potentially clinically significant values ​​(PCSV) in laboratory variables, vital signs, and ECGs are defined in the SAP. The time interval for detecting any events or abnormalities is between the infusion of study medication and the end of the study. Data collected outside this interval are excluded from the calculation of descriptive statistics and the identification of abnormalities for laboratory evaluation, vital signs, and ECG.

[0283] E. Results As above, patients were treated with 150 mg or 300 mg subcutaneous mAb1 or placebo once weekly for 4 weeks. Demographic and clinical characteristics were generally similar between treatments, except for a higher age at diagnosis in the 300 mg treatment group (Table 8). The study population was primarily male (62.2%), Caucasian (94.6%), with a mean age of 43.6 (15.4) years. Of the 37 patients, 31 (83.8%) completed treatment and 25 (67.6%) completed the entire study. The most common reason for withdrawal was lack of efficacy (four placebo patients and one in each treatment group). There were no withdrawals due to adverse events related to the administered mAb1.

[0284] Baseline and exploratory efficacy results from the study are summarized in Tables 9-14.

[0285] [Table 9]

[0286] [Table 10]

[0287] [Table 11]

[0288] [Table 12]

[0289] [Table 13]

[0290] [Table 14]

[0291] [Table 15]

[0292] [Table 16]

[0293] [Table 17]

[0294] [Table 18]

[0295] [Table 19]

[0296] [Table 20]

[0297] F. Conclusion Subcutaneous administration of anti-IL-4R antibody (mAb1) to adult patients with moderate to severe atopic dermatitis was generally safe and well tolerated after 4-week doses of 150 or 300 mg, with adverse event (AE) rates similar to placebo and no dose-limiting toxicities or serious AEs. The most common AEs with mAb1 were nasopharyngitis and headache. mAb1 rapidly reduced pruritus (by day 8) and improved skin disease in a dose-dependent manner. Administration of mAb1 at 150 and 300 mg resulted in significant improvements in IGA, EASI, BSA, SCORAD and NRS pruritus as early as days 8 to 85, both in mean and absolute change and percent change, compared to baseline (see Tables 9-14). In the 300 mg group on day 29, the proportion of patients who achieved an EASI50 response was 71.4% compared to 18.8% for placebo (p=0.0025), and NRS pruritus scores decreased by 45.4% compared to 18.6% for placebo (p=0.0016). The effect was sustained through day 85 for EASI50 and through day 75 for NRS pruritus. , differences from placebo remained significant for an additional 6 weeks after the end of the treatment period. The mAb significantly improved the mean percent change in other clinical outcomes at day 29: IGA (p=0.0002), EASI (p<0.0001), BSA (p=0.0037) and 5D pruritus (p<0.0001). These improvements were generally observed by day 8 and persisted after the end of treatment. No rebound phenomenon was observed after the end of treatment.

[0298] Thus, the results presented in this example demonstrate that mAb1 is safe and effective for the treatment of atopic dermatitis.

[0299] Example 8 Treatment of patients with moderate to severe atopic dermatitis with anti-IL-4R antibodies: Analysis of pooled phase 1b trials AD efficacy parameters were measured in patients with moderate to severe AD and pooled for analysis from two separate clinical trials. "Study A" was a 12-week double-blind, randomized, placebo-controlled, sequential ascending dose study to evaluate the safety and tolerability of administered anti-IL-4R antibody (mAb1) in patients with atopic dermatitis. The treatment period was 4 weeks and patients were followed for 8 weeks after completion of the treatment period. Patients were randomized in a 4:1 ratio to receive mAb1 or placebo in each of three ascending dose cohorts (75 mg, 150 mg or 300 mg). The study consisted of a screening period (days -14 to -3), a treatment period (days 1 to 29), and a follow-up period (days 29 to 85). During the treatment period, patients were seen in the clinic once a week for evaluation of safety, laboratory values, and clinical efficacy on days 1, 4, 8, 15, 22, 25, and 29 (week 4). Patients received doses of mAb1 or placebo on days 1, 8, 15, and 22. The end date of the treatment period was day 29 (week 4). Patients were monitored at the study site for 6 hours after injection (mAb1 or placebo) on day 1, and 3 hours after injection on days 8, 15, and 22. During the follow-up period, patients were seen in the clinic for follow-up evaluations on days 36, 43, 50, 57, 64, 71, and 85 (end of study visit).

[0300] "Study B" was a 12-week, double-blind, randomized, placebo-controlled, sequentially ascending, multiple-dose study in patients with moderate to severe AD. AD subjects were administered 150 mg or 300 mg of mAb1, or placebo on days 1, 8, 15, and 22 (four weekly doses) of the study (see Example 3 herein). All administrations in both studies were subcutaneous.

[0301] Inclusion criteria were: (1) male or female aged 18 years or older; (2) having chronic atopic dermatitis for 3 years; (3) having an EASI of 12 or greater; (4) an IGA of 3 or greater; (5) 15% or greater BSA of AD lesions (in the United States) or 10% or greater BSA of AD lesions (outside the United States); and (6) a history of inadequate response to a stable regimen of topical corticosteroids (TCS) or calcineurin inhibitors.

[0302] The exclusion criteria were: (1) 3.5x10 3 (2) WBC less than 125x10 / μl; 3 / μl platelets; (3) 1.75x10 3 (4) AST / ALT >1.5x ULN; (5) Hepatitis B or C positivity; and (6) treatment with TCS or calcineurin inhibitors within 1 week of baseline.

[0303] The primary endpoint of the study was to monitor the occurrence of treatment-emergent adverse events (TEAEs) from baseline to week 12. Exploratory endpoints for efficacy variables were (i) percent achievement of an IGA of 0 or 1 by week 4; (ii) percent improvement from baseline in BSA and EASI; and (iii) baseline NRS scale scores. This was a change from the previous system.

[0304] The efficacy variables IGA, BSA, EASI, SCORAD, 5-D Pruritus Scale, and Pruritus NRS assessment are described elsewhere herein (see, e.g., Example 4).

[0305] IGA, BSA, EASI and SCORAD scores were assessed at every clinic visit. Patients underwent 5-D pruritus assessments at the following visits: Screening, Day 1 / Baseline (pre-dose), and Days 15, 29, 36, 43, 57, 71 and 85 (last day of study) or early termination. Patients recorded their pruritus NRS scores using the IVRS twice daily until the last study visit.

[0306] The baseline for efficacy variables is defined as the last nonmissing value on or before the date of randomization. For patients who do not have a value on or before his / her randomization date, the last nonmissing value on or before the date of first dose injection is used as the baseline.

[0307] The baseline demographics of the patient population are provided in Table 15 below. [Table 21]

[0308] Mean baseline disease characteristics are given in Table 16. [Table 22]

[0309] Exploratory efficacy results from the pooled studies are summarized in Table 17 and Figures 15-22. do.

[0310] [Table 23]

[0311] [Table 24]

[0312] [Table 25]

[0313]

Table 26

[0314]

Table 27

[0315]

Table 28

[0316]

Table 29

[0317]

Table 30

[0318]

Table 31

[0319]

Table 32

[0320]

Table 33

[0321]

Table 34

[0322]

Table 35

[0323] [Table 36]

[0324] mAb1 was well tolerated and effective in adults with moderate to severe AD. Administration of mAb1 significantly improved AD disease activity and severity. At 4 weeks, 150 mg and 300 mg of mAb1 achieved significant improvements versus placebo for change from baseline in BSA% (p<0.05) (Figure 15), IGA (p<0.001) (Figure 16), EASI (p<0.001) (Figure 17), and Pruritus NRS (p<0.01, 300 mg) (Figure 18). Many patients experienced a 50% or greater reduction in EASI scores with 150 mg (54.5%) and 300 mg (71.4%) of mAb1 versus placebo (18.8%; p<0.05 for both) (Figures 19 and 20). Many Patients achieved EASI-25, EASI-50 and EASI-75 with mAb1 compared to placebo at week 4 (Figure 21).

[0325] For 300mg mAb1, significant improvements in BSA% (p<0.02), IGA (p<0.05) and EASI (p<0.0001) were observed within 2 weeks. Improvements in BSA, IGA and EASI (p<0.05 vs placebo) were maintained for 8 weeks. The proportion of patients with IGA 0 or 1 at week 4 was higher than placebo, but not statistically significant (Figure 22).

[0326] The most common treatment-emergent adverse events (AEs) associated with mAb1 administration were nasopharyngitis (19.6% vs. 12.5% ​​with placebo) and headache (11.8% vs. 6.3% with placebo).

[0327] Example 9 A parallel-group, dose-ranging clinical trial of a subcutaneously administered anti-IL-4R antibody (mAb1) in adult patients with moderate to severe atopic dermatitis. A. Study Design This study was a 32-week randomized, double-blind, placebo-controlled, parallel-group study to evaluate the dose-response profile of weekly doses of mAb1 in adults with moderate to severe AD. The primary objective of the study was to evaluate the efficacy of multiple mAb1 dose regimens compared to placebo in adult patients with moderate to severe AD. Secondary objectives were (1) to evaluate the safety of multiple mAb1 dose regimens compared to placebo in adult patients with moderate to severe AD; (2) to evaluate the pharmacokinetics (PK) of multiple mAb1 dose regimens in adult patients with moderate to severe AD; and (3) to evaluate potential immune responses across multiple mAb1 dose regimens compared to placebo in adult patients with moderate to severe AD.

[0328] The target population included adults with moderate to severe AD that could not be adequately controlled with topical medications or for whom topical treatment was otherwise inadvisable (e.g., side effects or safety risks). Approximately 240-288 patients were enrolled. Eligible patients were randomized in a 1:1:1:1:1:1:1 ratio to receive one of six weekly treatment regimens (five active agents, one placebo). Randomization was stratified by disease severity (moderate vs. severe AD) and region (Japan vs. rest of the world). The dosing schedule followed is given in Table 26.

[0329] [Table 37]

[0330] All patients received two injections (loading dose) on day 1, followed by weekly injections. For the every 2 weeks (q2w) and every 4 weeks (q4w) dosing regimens, the following doses of study drug were administered at weeks 2 and 4, respectively. Patients assigned to the q2w and q4w dosing regimens received volume-matched placebo every week if mAb1 was not administered. After providing informed consent, patients were assessed for study eligibility at the screening visit. Patients who met the eligibility criteria underwent a day 1 / baseline assessment, randomization, and then received weekly injections of study drug from days 1 through week 15. At this time, patients returned for weekly clinic visits, with a few weeks requiring only telephone contact. Patients (and / or health care providers) were trained to inject study drug at visits 2, 3, 4, 5, and 6, and self-injected study drug at later study visits requiring only telephone contact. Patients were closely monitored at the study site for a minimum of 1 hour after each of the first 5 weekly injections. Safety, laboratory, and clinical efficacy assessments were performed at selected clinic visits. The end of the treatment period visit, when the primary endpoint was assessed, was at week 16, 1 week after the last dose of study drug. Follow-up visits occurred every 2 weeks from week 18 to week 32. The end of the study visit was at week 32. Study patients were offered rescue treatments for AD (medication and / or phototherapy) at the discretion of the investigator, if necessary. Patients who required rescue treatments were asked to immediately discontinue study drug but continue to follow the schedule of study assessments. Efficacy measurements were obtained (Investigator Global Assessment [IGA], Eczema Area and Severity Index [EASI], etc.) immediately prior to administration of any rescue treatment. One sample for DNA analysis and multiple samples for RNA analysis were taken from patients who consented to participate in the optional genomic substudy.

[0331] Study treatment: mAb1 subcutaneously: 300 mg, 300 mg q2w, 300 mg q4w, 200 mg q2w, or 100 mg q4w weekly (qw) from days 1 to week 15, or placebo subcutaneously once weekly from days 1 to week 15. Basic branded topical emollient was applied twice daily from days -7 to 8.

[0332] Study endpoints: The primary endpoint of the study was the percent change in EASI score from baseline to week 16. Secondary endpoints were: (1) the proportion of patients achieving an IGA score of 0 (clear) or 1 (almost clear) at week 16; (2) the proportion of patients achieving a reduction in IGA score of ≥2 at week 16; (3) the absolute change in EASI score from baseline to week 16; (4) proportion of patients achieving EASI-50, EASI-75 and EASI-90 (50, 75 and 90% reduction from baseline in EASI score) at week 16; (6) proportion of patients achieving SCORAD-50, SCORAD-75 and SCORAD-90 (50, 75 and 90% reduction from baseline in SCORAD score) at week 16; (7) absolute and percent change from baseline in pruritus scores (NRS and 4-point classification scale); (8) absolute and percent change from baseline in POEM score; (9) change from baseline in GISS components (erythema, infiltration / clusters, excoriation, and lichenification); (10) change from baseline in GISS cumulative score; (11) occurrence of treatment-emergent adverse events (TEAEs) from baseline to week 32; and (12) pharmacokinetic profiles of multiple mAb1 dose regimens.

[0333] Other exploratory endpoints include: (1) distribution of disease severity scores (e.g., IGA, EASI, SCORAD) and their change at various time points from baseline to week 16; (2) change in Pruritus NRS, Pruritus Classification Scale, SCORAD (Pruritus VAS and Sleep Disturbance VAS), Patient Global Assessment of Disease Status, Patient Global Assessment of Treatment Effect, DLQI, POEM, EQ-5D, Itch QOL, and HADS at various time points from baseline to week 16; (3) absolute and percent change in BSA%, SCORAD score, EASI, and Pruritus NRS at various time points from baseline to week 16; (4) proportion of patients achieving a reduction in IGA score of ≥2 at various time points from baseline to week 16; (5) proportion of patients achieving a reduction in IGA score of ≥3 at various time points from baseline to week 16; (6) change in efficacy parameters from week 16 to week 32; (7) mAb1 These included the occurrence and profile of ADA (titer over time); (8) effect of mAb1 plasma concentration on ADA formation and persistence; (9) effect of ADA on mAb1 plasma concentration; (14) effect of ADA on clinical outcomes (safety and efficacy); (10) effect of PK parameters (Cmax and AUC) on clinical outcomes; and (11) effect of body weight on drug exposure and clinical outcomes.

[0334] Rationale for Study Design: The objective of this study was to find an optimal dose regimen to be further investigated in a confirmatory Phase 3 study. The design of this Phase 2b study was informed by results from a previous mAb1 study that investigated the safety and efficacy of a 300 mg dose of mAb1 administered weekly (qw) for 12 consecutive weeks in patients with moderate to severe AD. The selection of the Phase 2b dose regimen was also supported by observed and simulated correlations with pharmacokinetic (PK) and pharmacodynamic (PD) parameters (PK / PD model) from previous clinical trials. Using 300 mg qw (i.e., the dose regimen tested in Phase 2a) as the high anchor of the dose range, the goal was to identify the lowest dose regimen that showed maximal or near-maximal efficacy and / or to find the dose regimen that showed the best benefit / risk ratio depending on the safety profile produced by mAb1. Thus, the five mAb1 dose regimens were selected to reasonably encompass the spectrum between potentially supratherapeutic dose regimens (i.e., high anchors) and clearly suboptimal efficacy (i.e., low anchors). The protocol also included a placebo group to allow comparison of each active dose regimen with a control.

[0335] Use of a loading dose: Many patients received a loading dose on day 1, consisting of twice the nominal dose administered at subsequent visits. This allows systemic concentrations of mAb1 to reach steady state and targeted systemic concentrations, potentially reducing the time to clinical benefit more quickly. Study treatments were administered for 16 weeks to allow functional mAb1 systemic concentrations to stabilize for all dose regimens investigated. Pharmacokinetic modeling suggested that a "every 4 weeks" (q4w) dose regimen may result in reduced trough concentrations after the initial loading dose. As a result, the immunocompetence of these regimens may be improved over a shorter course of treatment. After the last dose of study drug, all patients were followed for an additional 16 weeks to ensure that clearance of mAb1 was essentially complete (plasma concentrations below the lower limit of quantification) before the end of the study visit.

[0336] Rationale for dose selection: The highest mAb1 dose regimen administered in this study was 300 mg qw. When given as a short (4 week) treatment course, this dose regimen was safe and appeared to be the most effective in an early Phase 1b clinical trial where it was investigated alongside lower dose regimens (150 mg qw and 75 mg qw). Pharmacokinetic modeling suggested that 300 mg qw may be supratherapeutic in longer runs: mAb1 plasma concentrations did not reach steady state by week 4 and were designed to stabilize at levels well above those required to saturate the target, i.e., the membrane-bound alpha subunit of the IL-4 receptor. However, this needed to be confirmed by comparing 300 mg qw with the lower dose regimens in the context of longer study treatments (12 weeks or more) so that plasma concentrations could reach steady state for all dose regimens investigated. 300 mg qw was administered for 12 weeks in earlier studies (e.g., Phase 2a proof of concept), and this dose regimen was repeated in Phase 2b to confirm the Phase 2a results and allow direct comparison with lower dose regimens within the same study. Thus, 300 mg qw was the high anchor of the dose range in this study.

[0337] The low anchor of the dose regimen range was 100 mg administered q4w. Based on PK / PD modeling, the resulting mAb1 plasma concentrations at steady state were expected to be consistently below target-mediated clearance (i.e., at a low enough level that mAb1 elimination was primarily achieved by its binding to the IL-4 receptor), suggesting that the clinical responses associated with this dose regimen were incomplete. Three other dose regimens were selected between the high and low anchors. An overview of these dose regimens and the main rationale for their selection is provided below: 300 mg qw: High anchor. Same dose regimen as studied in Phase 2a. 300 mg every 2 weeks (q2w): High probability of success based on PK / PD data and models. May be sufficient to maintain therapeutic drug levels over multiple dosing intervals. 300 mg q4w: PK modeling showed that mAb1 plasma levels rose rapidly above 60 mg / L after administration of the loading dose, associated with a fast onset of action. q4w dosing may be sufficient to maintain therapeutic effect over an extended period of time. Because the 300 mg dose was the highest available, this regimen had the best opportunity to demonstrate efficacy of q4w dosing. 200mg q2w: Some efficacy was expected without reaching maximum therapeutic effect. Useful for dose-response assessment and further PK / PD modeling. Helpful to evaluate the full spectrum of the q2w regimen. 100mg q4w: Low anchor. Probably not the optimal effective dose. · Placebo: Provided a reliable reference for any apparent drug effect.

[0338] Inclusion and Exclusion Criteria: Patients had to meet the following criteria to be eligible for inclusion in the study: (1) male or female aged 18 years or older; (2) chronic AD (according to AAD consensus criteria [Eichenfeld 2004]) present for at least 3 years prior to the screening visit; (3) EASI score of 16 or greater at the screening and baseline visits; (4) IGA score of 3 or greater (on an IGA scale of 0 to 4) at the screening and baseline visits; (5) body surface area (BSA) of 10% or greater AD lesions at the screening and baseline visits; (6) patients with a documented recent history (within 3 months prior to the screening visit) of an inadequate response to outpatient treatment with topical medications or patients for whom topical treatment would not otherwise be advisable (e.g., significant side effects or (often due to safety risks) *(7) patients must have been applying a stable dose of a basic branded emollient without additives twice daily for at least 7 days prior to the baseline visit; (8) willing and able to complete all clinic visits and study-related procedures; (9) able to understand and complete study-related questionnaires; and (10) sign informed consent. * Note: For the purposes of this protocol, an inadequate response represented the failure to achieve and maintain remission or low disease activity (e.g., IGA 0=clear to 2=mild) despite treatment with a medium- to high-potency topical corticosteroid (± topical calcineurin inhibitor, if needed) applied daily for at least 28 days or the maximum duration recommended by the formulation prescribing information (e.g., 14 days for extra-potent topical corticosteroids), whichever is shorter. Important side effects or safety risks outweigh the potential treatment benefits (e.g., hypersensitivity reactions, significant skin atrophy, systemic effects, etc., or imminent risk) as assessed by the investigator or the patient's physician.

[0339] Patients who met any of the following criteria were ineligible to participate in this study: (1) previous treatment with mAb1; (2) treatment with the study drug within 8 weeks or within 5 half-lives (if known), whichever is longer, prior to the baseline visit; (3) any of the following treatments within 4 weeks prior to the baseline visit, or any condition that may require such treatment during the first 4 weeks of study treatment: systemic corticosteroids, immunosuppressants / immunomodulatory agents (e.g., cyclosporine, mycophenolate mofetil, IFN-γ, azathioprine, or methotrexate). (4) treatment with topical corticosteroids, tacrolimus, and / or pimecrolimus within 1 week prior to the Baseline visit; (5) treatment with biopharmaceuticals, including but not limited to, any cell depleting agent, such as rituximab, within 6 months prior to the Baseline visit or until lymphocyte and CD19+ lymphocyte counts return to normal, whichever is longer; infliximab, within 16 weeks prior to the Baseline visit for any indication or within 5 years for a dermatological indication; , adalimumab, golimumab, certolizumab pegol, abatacept, etanercept, anakinra, or other biologics within 5 half-lives (if known) or 16 weeks, whichever is longer; (6) treatment of AD with a prescription moisturizer classified as a medical device (e.g., Atopiclair®, MimyX®, Epicerum®, Cerave®, etc.) within 1 week prior to the baseline visit; (7) regular use of a tanning room / sun bed (≥2 times per week) within 4 weeks prior to the baseline visit more than one visit); (8) planned or anticipated use of any prohibited medications and procedures during study treatment (including but not limited to topical tacrolimus and pimecrolimus; corticosteroids; prescription moisturizers classified as medical devices, such as Atopiclair®, MimyX®, Epicerum®, Cerave®; allergen immunotherapy; systemic treatment for AD with immunosuppressants / immunomodulators; treatment with live (attenuated) vaccines or investigational drugs (other than mAb1); major elective surgery);(9) treatment with a live (attenuated) vaccine within 12 weeks prior to the baseline visit; (10) chronic or acute infection requiring treatment with an antibiotic, antiviral, antiparasitic, antiprotozoal, or antifungal agent within 4 weeks prior to the screening visit, or a superficial skin infection within 1 week prior to the screening visit; (11) history of invasive opportunistic infection (e.g., histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis) despite resolution of the infection, as determined by the investigator. Any known or suspected immunosuppression, or otherwise any unusual frequency of recurrent infections, or any prolonged infection suggestive of an immunocompromised state; (12) known history of human immunodeficiency virus (HIV) infection or HIV seropositivity at the time of the screening visit; (13) positive or indeterminate hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C antibody at the time of the screening visit; (14) transaminases (ALT and / or ALT) ≥3 times the upper limit of normal (>3xULN) at the time of the screening visit; (15) history of clinical endoparasitosis within 12 months prior to the baseline visit, other than treated vaginal trichomoniasis; (16) presence of skin complications that could interfere with study evaluation; (17) complete cervical infarction. (18) History of malignancy within 5 years prior to the baseline visit, except for carcinoma in situ, completely excised nonmetastatic squamous cell carcinoma or basal cell carcinoma of the skin; (19) History of nonmalignant lymphoproliferative disorder; (20) High risk of parasitic infection, such as residence in or recent travel (within 12 months prior to the baseline visit) to an area endemic for endoparasitosis where the environment is consistent with parasitic exposure (e.g., extended stay, rural or slum area, lack of running water, consumption of uncooked, undercooked, or otherwise potentially contaminated foods, close contact with a carrier or vector, etc.), unless subsequent medical evaluation (e.g., stool tests, blood tests, etc.) rules out the possibility of parasitic infection / infestation; (21) History of alcohol or drug abuse within 2 years prior to the screening visit; (22) Any severe intercurrent illness that, in the judgment of the investigator, would adversely affect the patient's participation in the study. Examples include, but are not limited to, patients with short life expectancy, uncontrolled diabetes (HbA1c ≧9%), cardiovascular conditions (e.g., stage III or IV heart failure according to the New York Heart Association classification), severe renal conditions (e.g., dialysis patients), hepato-biliary conditions (e.g., Child-Puig class B or C), neurological conditions (e.g., demyelinating diseases), active primary autoimmune diseases (e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), and other severe endocrine, gastrointestinal, metabolic, pulmonary, or lymphatic diseases. The specific reasons for a patient being excluded under this criterion will be noted in the study documentation (chart notes, case report form [CRF], etc.); (22) Any other medical or psychological condition, such as relevant laboratory abnormalities at screening, that, in the opinion of the investigator, suggests a new and / or poorly understood disease that may pose an unreasonable risk to the study patient as a result of his / her participation in this clinical trial, may make the patient's participation unreliable, or may interfere with study evaluation.Specific reasons for patients being excluded under this criterion will be noted in the study documentation (chart notes, CRF, etc.);(23) planned major surgery while the patient is participating in this study;(24) the patient is a member of the investigational team or his / her immediate family;(25) pregnant or lactating women; and (26) unwillingness to use adequate contraception if of reproductive potential and sexually active. Adequate contraception is defined as agreement to consistently practice an effective and acceptable method of contraception throughout the study and for 16 weeks after the last dose of study drug.

[0340] B. Safety Safety was assessed throughout the study by monitoring adverse events and serious adverse events.

[0341] An adverse event (AE) is any undesirable medical occurrence in a subject administered a medicinal product or in a clinical investigational subject. An AE may therefore be any undesirable, unintended sign (e.g., laboratory abnormality), symptom, or disease that is temporally related to the use of a medicinal product, whether or not it is causally related to the medicinal (investigational) product. AEs also include any worsening (i.e., any clinically meaningful change in frequency and / or intensity) of an existing condition that is temporally related to the use of the study drug; laboratory abnormalities that are considered clinically significant by the investigator; and any undesirable medical occurrence.

[0342] A serious adverse event (SAE) is any untoward medical occurrence at any dose that results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability / incapacity; is a congenital anomaly / birth defect; or is a major medical event.

[0343] In addition, laboratory safety variables, vital sign variables, 12-lead electrocardiogram (ECG) variables, and and physical examination variables were measured throughout the study.

[0344] Clinical laboratory data consisted of hematology, blood chemistry and urinalysis. Blood samples for hematology were collected at each study visit; blood samples for serum chemistry and urine samples for urinalysis were collected at screening, day 1 / baseline (pre-dose), day 15, day 29, day 43, day 57, day 71, day 85, day 99, day 113, day 141, day 169, and day 197 (last day of study) or at early termination if the subject discontinued the study to measure overall patient health.

[0345] Vital signs parameters included respiratory rate (bpm), pulse rate (bpm), systolic and diastolic blood pressure (mmHg) and temperature (°C). Vital signs were collected at screening and Day 1 / baseline (pre-dose, dosing day), and Days 4, 8, 15, 22, 25, 29, 43, 64, 71, 85, 99, 113, 127, 141, 155, 169, 183, 197 and 211 (last day of study) or at early termination. Vital signs were taken after study drug administration on Days 1, 8, 15, and 22, 1 and 2 hours after injection.

[0346] 12-lead ECG parameters included ventricular HR, PR interval, QRS interval, and corrected QT interval (QTcF = QT / [RR 0.33 ] and QTcB=QT / [RR 0.5 ]) ECG status: normal, clinically insignificant abnormalities, or clinically significant abnormalities. Standard 12-lead ECGs were performed at screening, day 29, and day 113 (last day of treatment) or at early termination.

[0347] A complete, thorough physical examination was performed at screening, day 29, and day 113 (last day of treatment) or upon early termination.

[0348] C. Efficacy variables The efficacy variables IGA, BSA, EASI, SCORAD, 5-D Pruritus Scale, and Pruritus NRS assessments are described elsewhere herein (see, e.g., Example 7).

[0349] IGA, BSA, EASI and SCORAD scores were assessed at every clinic visit. Patients underwent 5-D pruritus assessments at the following visits: Screening, Day 1 / Baseline (pre-dose), Day 113 (last day of treatment), and Day 211 (last day of study) or early termination. Patients recorded their pruritus NRS scores using the IVRS twice daily until the final study visit.

[0350] In addition, other variables such as Global Individual Symptom Score (GISS), Pruritus Classification Scale, Patient Oriented Eczema Scale (POEM), Dermatological Quality of Life Index (DLQI), Itch QOL, EQ-50, HADS, and Patient Global Assessment of Disease Status and Treatment Effect were also evaluated.

[0351] Baseline for efficacy variables was defined as the last nonmissing value on or before the date of randomization. For patients without a value on or before his / her randomization date, the last nonmissing value on or before the date of first dose injection was used as the baseline.

[0352] Example 10 A multiple-dose clinical trial of subcutaneously administered anti-IL-4R antibody (mAb1) in adult patients with moderate to severe atopic dermatitis A. Study Design This study was a 28-week randomized, double-blind, placebo-controlled trial of an anti-IL-4R mAb, referred to herein as "mAb1," administered subcutaneously in patients with moderate to severe atopic dermatitis. The treatment period was for a 12-week period for patients followed by an additional 16 weeks after treatment ceased.

[0353] 109 patients were included and randomized in a 1:1 ratio for the study (54 to placebo and 55 to 300 mg antibody). 43 patients (30 to placebo and 13 to 300 mg group) withdrew from the study. Randomization was stratified by IgE levels (IgE < 150 kU / L vs. ≥ 150 kU / L at screening visit) to test the efficacy of mAb1 in patients with extrinsic or intrinsic AD. Patients who met the eligibility criteria underwent day 1 / baseline assessment, randomization, and then received 300 mg of mAb1 or placebo SC. Each weekly dose of study drug was given as a single 2 mL injection or split into two 1 mL injections. Patients returned for weekly clinic visits and received injections of study drug on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Patients were closely monitored at the study site for a minimum of 2 hours after each dose of study drug. The end of the treatment period was day 85. Follow-up visits occurred on days 92, 99, 106, 113, 120, 127, 134, 141, 148, 155, 162, 169, 176, 183, 190, and the end of study visit on day 197.

[0354] Inclusion criteria were as follows: (1) male or female aged 18 years or older; (2) chronic AD, diagnosed by the revised Eichenfield criteria of Hannifin and Rajka, present for at least 3 years prior to the screening visit; (3) EASI score ≥ 16 at the screening and baseline visits; (4) IGA score ≥ 3 at the screening and baseline visits; (5) BSA of AD lesions ≥ 10% at the screening and baseline visits; (6) history of an inadequate response to a stable (≥ 1 month) regimen with topical corticosteroids or calcineurin inhibitors as treatment for AD within the last 3 months prior to the screening visit; (7) patients must have applied a stable dose of a basic brand emollient without additives twice daily for at least 7 days prior to the baseline visit; (8) willingness, commitment, and ability to return for all clinic visits and complete all study-related procedures and willingness and ability to sign an informed consent form (ICF).

[0355] Exclusion criteria were: (1) previous treatment with mAb1; (2) presence of any of the following laboratory abnormalities at the screening visit: 3.5x10 3 White blood cell count less than 125x10 / μL 3 Platelet count less than 1.75x10 / μL 3Neutrophil count less than 1 / μL; aspartate aminotransferase (AST) / alanine aminotransferase (ALT) greater than 1.5 times the ULN; and CPK greater than 2 times the ULN; (3) positive or indeterminate results for hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody at the screening visit; (4) initiation of a new regular exercise routine or a major change to a previous regular exercise routine within 4 weeks prior to screening (Visit 1). Subjects had to be willing to maintain similar levels of exercise over the study period and to refrain from unusually strenuous exercise over the study period;(5) treatment with the study drug within 8 weeks or within 5 half-lives, if known, whichever is longer, prior to the baseline visit;(6) treatment with a live (attenuated) vaccine within 12 weeks prior to the baseline visit;(7) treatment with allergen immunotherapy within 6 months prior to the baseline visit;(8) treatment with a leukotriene inhibitor within 4 weeks prior to the baseline visit;(9) treatment with systemic corticosteroids within 4 weeks prior to the baseline visit;(10) treatment with topical corticosteroids, tacrolimus, and / or pimecrolimus within 1 week prior to the baseline visit;(11) treatment with immunosuppressants / immunomodulators, e.g., cyclosporine, mycophenolate mofetil, IFN-γ, phototherapy (narrowband uvB, uvB, uvA1, psoralen+, uvA1 ... (12) 3 or more bleaching baths in any week within 4 weeks prior to the baseline visit; (13) treatment for AD with a medical device (e.g., Atopiclair®, MimyX®, Epicerum®, Cerave®, etc.) within 1 week prior to the baseline visit; (14) chronic or acute infection requiring treatment with oral or IV antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to the screening visit, or a superficial skin infection within 1 week prior to the screening visit; (15) known history of HIV infection; (16) history of hypersensitivity reaction to doxycycline or related compounds; (17) history of clinical parasitic infection other than vaginal trichomoniasis; (18) history of fully treated cervical in situ hybridization. History of malignancy within 5 years prior to the baseline visit, except for patients with a history of carcinoma in situ and nonmetastatic squamous cell carcinoma or basal cell carcinoma of the skin; (19) planned surgery during the length of the patient's participation in the study; (20) use of tanning rooms / sun beds within 4 weeks prior to the screening visit; (21) significant intercurrent illness or history of significant illness, such as psychiatric, cardiac, renal, neurological, endocrine, metabolic or lymphatic disease, or any other disease or condition that adversely affected the subject's participation in this study; (22) pregnant or breastfeeding women; and / or (23) willingness to use adequate contraception. Adequate contraception is defined as agreement to consistently practice an effective and acceptable method of contraception throughout the study period and for 16 weeks after the last dose of study drug. For women, adequate contraception is defined as hormonal contraception, intrauterine device (IUD), or dual barrier contraception (i.e., condom + diaphragm, condom or diaphragm + spermicide gel or air bubble). For men, an adequate method of contraception is defined as double barrier contraception (i.e., condom + diaphragm, condom or diaphragm + spermicide gel or foam). For women, menopause is defined as 24 months without menstruation; if problematic, a follicle-stimulating hormone of 25 U / mL or greater must be recorded.Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation, as appropriate, must be recorded.

[0356] B. Efficacy Variables The primary endpoint was the percent change in EASI score from baseline to week 12. Secondary endpoints measured in the study included (1) the proportion of patients achieving an Investigator Global Assessment (IGA) score of 0 or 1 at week 12; (2) the proportion of patients achieving at least a 50% global improvement in EASI score (also known as EASI50) from baseline to week 12; (3) the change in EASI score from baseline to week 12; and (4) the percent change from baseline to week 12 in IGA score, Atopic Dermatitis Body Surface Area Lesion (BSA), Eczema Area and Severity Index (EASI), SCORAD, Pruritus NRS, and 5-D Pruritus Scale. (5) occurrence of TEAEs from baseline to week 28; (6) change from baseline in eosinophils, TARC, Phadiatop™ result, and total IgE associated with response; (7) change in QoLIAD from baseline to week 12; (8) proportion of patients achieving a reduction in IGA score of ≥2 from baseline to week 12; (9) proportion of patients achieving a reduction in IGA score of ≥3 from baseline to week 12; and (10) PD responses in circulating eosinophils, TARC, and total IgE.

[0357] The baseline for efficacy variables is defined as the last nonmissing value on or before the date of randomization. For patients who do not have a value on or before his / her randomization date, the last nonmissing value on or before the date of first dose injection is used as the baseline.

[0358] Investigation Procedure Efficacy variables IGA, BSA, EASI, SCORAD, 5-D pruritus scale, and pruritus Itch NRS assessment is described elsewhere herein (see, e.g., Example 7).

[0359] IGA, BSA, EASI and SCORAD scores were assessed at every clinic visit. Patients underwent 5-D pruritus assessments at the following visits: Screening, Day 1 / Baseline (pre-dose), and Days 15, 29, 43, 57, 71, 85, 99, 113, 127, 141, 155, 169, 183 and 197 (last day of study) or early termination. Patients recorded their pruritus NRS scores using the IVRS twice daily until the last study visit.

[0360] Quality of Life Index for Atopic Dermatitis (QoLIAD): The QoLIAD is a 25-item validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatments on QoL. The format is a simple yes / no response of 25 items with a scoring system of 0-25; higher scores indicate poorer QoL. The questionnaire was administered at screening and day 1 / baseline (pre-dose), and at days 29, 57, 85, 99, 113, 127, 141, 155, 169, 183 and 197 (last day of study) or at early termination.

[0361] C. Subject Treatment mAb1 drug product was supplied as a lyophilized powder in 5 ml glass vials for SC administration. When delivered SC, mAb1 drug product was reconstituted with 2.5 ml of sterile water for injection to give a solution containing 150 mg / mL of mAb1. The dose level of mAb1 tested was 300 mg for SC administration. mAb1 or placebo was administered as one (2 mL) or two (1 mL) SC injections at the clinic on Day 1 / Baseline and Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. It was preferred that each weekly dose of study drug be given as a single 2 mL injection, although each weekly dose could be split into two 1 mL injections. Subcutaneous injection sites were rotated between the following sites: back of the arm, abdomen (excluding umbilicus or lower back), and upper thigh. Administration to the extremities was not permitted due to the possibility of different absorption and bioavailability. If administration of multiple injections on the same day was required, each injection was delivered at a different injection site (e.g., one injection was administered in the right lower quadrant of the abdomen and the other injection was administered in the left lower quadrant of the abdomen). Subcutaneous injection sites were rotated to avoid injecting at the same site on two consecutive weeks.

[0362] Placebo-matched mAb1 was made in the same formulation as mAb1, but no antibody was added.

[0363] Patients were monitored at the study site for a minimum of 2 hours after each dose of study drug.

[0364] In addition, patients were required to apply a stable dose of a basic, brand-name emollient without additives twice daily for at least 7 days prior to the baseline visit and throughout study participation. Patients reported compliance with background treatments during the study using the IVRS or IWRS. This system prompted patients to answer the following question regarding emollient use: "Did you use a moisturizer approved by the study physician on affected areas of skin?"

[0365] D. Safety Assessment Safety was assessed throughout the study by monitoring adverse events and serious adverse events.

[0366] An adverse event (AE) is any undesirable event in a subject administered a medicinal product or in a clinical investigation. An AE is an unexpected medical occurrence. An AE may therefore be any untoward, unintended sign (e.g., laboratory abnormality), symptom, or disease that is temporally related to the use of a medicinal product, whether or not it is causally related to the medicinal (test) product. AEs also include any worsening (i.e., any clinically meaningful change in frequency and / or intensity) of an existing condition that is temporally related to the use of the study drug; a laboratory abnormality that is considered clinically significant by the investigator; and any untoward medical occurrence.

[0367] A serious adverse event (SAE) is any untoward medical occurrence at any dose that results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability / incapacity; is a congenital anomaly / birth defect; or is a major medical event.

[0368] In addition, laboratory safety variables, vital sign variables, 12-lead electrocardiogram (ECG) variables, and physical examination variables were measured throughout the study.

[0369] Clinical laboratory data consisted of hematology, blood chemistry and urinalysis. Blood samples for hematology were collected at each study visit; blood samples for serum chemistry and urine samples for urinalysis were collected at screening, day 1 / baseline (pre-dose), day 15, day 29, day 43, day 57, day 71, day 85, day 99, day 113, day 141, day 169, and day 197 (last day of study) or at early termination if the subject discontinued the study to measure overall patient health.

[0370] Vital signs parameters included respiratory rate (bpm), pulse rate (bpm), systolic and diastolic blood pressure (mmHg) and temperature (°C). Vital signs were collected at screening and Day 1 / baseline (pre-dose, day of dosing), and Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 99, 113, 141, 169, and 197 (last day of study) or at early termination. Vital signs were taken after study drug administration on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78, and 1 and 2 hours after injection.

[0371] 12-lead ECG parameters included ventricular HR, PR interval, QRS interval, and corrected QT interval (QTcF = QT / [RR 0.33 ] and QTcB=QT / [RR 0.5 ])ECG status: normal, clinically insignificant abnormalities, or clinically significant abnormalities. Standard 12-lead ECGs were performed at screening, day 141, and day 197 (last day of study) or at early termination.

[0372] Study samples (serum / RNA / plasma) were collected at screening and Day 1 / baseline (pre-dose), as well as Days 8, 15, 22, 29, 57, 85, and 197 (last day of study) or early termination, and at unscheduled visits.

[0373] A complete, thorough physical examination was performed at screening, day 85, and day 197 (last day of the study) or at early termination.

[0374] E. Data Analysis 1. Analysis of exploratory efficacy variables All categorical variables were analyzed using Fisher's exact test with nominal p-values ​​and reported confidence intervals. All continuous variables were analyzed by analysis of covariance (ANCOVA) with baseline IgE strata (<150 kU / L vs. ≥150 kU / L at screening visit). Unless otherwise specified, assessment of change from baseline for continuous measures and construction of confidence intervals were based on ANCOVA with treatment as main factor and baseline value as covariate. The analysis was based on the OVA model. Point estimates and 95% CIs of the difference in adjusted mean change from baseline between the two treatment groups were provided. Missing values ​​were imputed by the last observation carried forward (LOCF) method. In the event that model assumptions were not warranted, analyses based on the rank order of covariates were used.

[0375] 2. Safety Data Analysis Safety analyses are based on reported AEs, clinical laboratory assessments, vital signs, and 12-lead ECGs. Thresholds for potentially clinically significant values ​​(PCSV) in laboratory variables, vital signs, and ECGs are defined in the SAP. The time interval for detecting any events or abnormalities is between the infusion of study medication and the end of the study. Data collected outside this interval are excluded from the calculation of descriptive statistics and the identification of abnormalities for the evaluation of laboratory values, vital signs, and ECGs.

[0376] F. Safety: Results mAb1 was generally well tolerated with a favorable safety profile. The overall adverse event (AE) profile was characteristic of a healthy population. No deaths were reported. Eight patients had SAEs, one in the mAb1 group (facial bone fracture) and seven in the placebo group (angina, cellulitis, herpetic eczema, bacterial skin infection, renal failure, asthma crisis, pulmonary disorders, and atopic dermatitis). Eight patients had TEAEs leading to discontinuation of study drug, one in the mAb1 group and seven in the placebo group. Eighty-seven patients had at least one TEAE (n = 43 [78.2%] in the mAb1 group and 44 [81.5%] in the placebo group). The most frequent TEAE was nasopharyngeal infection in subjects receiving mAb1 (n = 22 [40%] and 10 [18.5%] in the placebo group). Other TEAEs in the treatment groups included eye infections, nervous system disorders, and general disorders and administration site conditions. No other clinically significant laboratory findings (blood chemistry, hematology, or urinalysis) were reported during the study. No trends were noted in the mean / median baseline of any laboratory parameter. There were no significant trends in the mean or median change from baseline in temperature or pulse throughout the study. There were no clinically significant abnormalities in physical examination, ECG, or vital signs.

[0377] Subcutaneous administration of mAb1 to adult patients with moderate to severe AD was generally safe and well tolerated.

[0378] G. Efficacy: Results Baseline and exploratory efficacy results from the study are summarized in Figures 23-33 and Tables 27-35. Patients were treated with 300 mg subcutaneous mAb1, or placebo, once weekly for 12 weeks, as described above.

[0379] [Table 38]

[0380]

Table 39

[0381]

Table 40

[0382]

Table 41

[0383]

Table 42

[0384]

Table 43

[0385]

Table 44

[0386]

Table 45

[0387]

Table 46

[0388]

Table 47

[0389] H. Conclusion Subcutaneous administration of anti-IL-4R antibody (mAb1) to adult patients with moderate to severe atopic dermatitis was generally safe and well tolerated after 12 weeks of administration at 300 mg. Administration of mAb1 at 300 mg resulted in significant improvements in IGA, EASI, BSA, SCORAD and NRS pruritus by Day 85, both in mean and absolute change and percent change, when compared to baseline (see Tables 27-33). The percentage of patients achieving an IGA score of 0 or 1 at Day 85 for the 300 mg group was 40.0%, while the same number for placebo was 7.4% (Table 34). The percentage of patients achieving a 50% reduction in EASI score ("EASI-50") at Day 85 was 85.5% for the 300 mg group, while the EASI-50 for placebo-treated patients at Day 85 was 35.2% (Table 35). The percent change in EASI score from baseline to week 12 for mAb1 was statistically significantly different from the placebo group (-74.0% vs. -23.0%, p-value <0.0001). Treatment groups were statistically significantly different from the placebo group in all secondary efficacy endpoints. The following are p values ​​for IGA responders (0 or 1) (<0.0001), EASI responders (<0.0001), EASI absolute change from baseline (<0.0001), IGA absolute change from baseline (<0.0001), IGA percent change from baseline (<0.0001), BSA absolute change (<0.0001), SCORAD absolute change (<0.0001), Pruritus NRS absolute change (<0.0001), and 5-D Pruritus Scale absolute change from baseline to week 12 (<0.0001), respectively.

[0390] Example 11 A Clinical Trial to Evaluate the Safety of mAb1 Administered Concomitantly With Topical Corticosteroids in Patients With Moderate to Severe AD A. Study Design This study was a randomized, double-blind, parallel-group, placebo-controlled study to evaluate the safety and investigate the efficacy of repeated subcutaneous doses of mAb1 administered concomitantly with topical corticosteroids (TCS) to treat AD in patients with moderate to severe AD. Patients were randomized 2:1 to receive 300 mg of mAb1 or placebo by subcutaneous injection once weekly (days 1, 8, 15, and 22) for 4 consecutive weeks. All patients received a potent TCS product such as methylprednisolone acetonate 0.1%, mometasone furoate 0.1%, or betamethasone valerate 0.1% (50-100 times more potent than hydrocortisone). Patients underwent concurrent open-label daily treatment with TCS for up to 28 days. Lower potency TCS or other topical medications such as topical calcineurin inhibitors (TCIs) were used to treat AD lesions located on the face, flexors, and genital areas.

[0391] Beginning at the screening visit, patients began applying a basic brand emollient without additives twice daily for at least 7 days prior to the baseline visit and continued its use throughout the study (once daily on treatment days in the area of ​​TCS application).Environmental control measures and non-pharmaceutical treatment modalities, such as allergen avoidance and bleaching baths, were allowed at the discretion of the investigator.

[0392] Screening occurred on days -21 to -1. Patients received their first drug injection (300 mg mAb1, or placebo) on day 1, for a total of four weekly doses, and returned to the clinic for further drug injections on days 8, 15, and 22 (+ / - 1 day). Beginning on day 1, patients applied the topical medications listed above once daily in the evening, and continued application to all AD-affected areas (i.e., areas with active AD lesions) until control was achieved for up to 28 days. After control was achieved, TCS application to AD-prone areas without active lesions (i.e., areas where lesions had cleared) was limited to 2 days per week until the test day on day 28. After 28 days, topical treatment of all residual AD lesions was continued as needed. Throughout the study, patients continued to apply basic brand emollient without additives twice daily (once daily on topical treatment days to areas treated with topical medication). Patients returned for clinic visits on days 29, 36, 50, 64 and 78 (the last day of the study).

[0393] Inclusion criteria were: (1) male or female aged 18 years or older; (2) chronic AD, diagnosed by the revised Eichenfield criteria of Hannifin and Rajka, present for at least 2 years prior to screening; (3) AD activity, assessed by an IGA score of 3 or more and a SCORAD score of 20 or more at screening and baseline visits, for one or more active AD for which treatment with potent TCS is indicated; (4) at least 10% BSA affected by AD at screening and baseline visits; (5) patients must apply a basic brand emollient without additives twice daily for at least 7 days prior to the baseline visit; (6) willingness and ability to comply with clinic visits and study-related procedures; and (7) ability to read, understand, and willing to sign an informed consent.

[0394] Exclusion criteria were: (1) previous treatment with mAb1; (2) hypersensitivity to corticosteroids or to any other ingredient contained in the TCS product used during the study; (3) AD lesions (>50% cumulative lesion area) located primarily on the face, flexors, and genitals; (4) presence of skin comorbidities that may interfere with study evaluation; (5) the following treatments within 4 weeks prior to the baseline visit or any condition that may require such treatment during the study: systemic corticosteroids, immunosuppressants or immunomodulators, e.g., cyclosporine, mycophenolate mofetil, IFN-gamma, azathioprine, or methotrexate; (6) treatment with biopharmaceuticals, such as: (a) previous treatment with mAb1 within 6 months prior to the baseline visit or previous treatment with ≥ 100% CI, ≥ 100%; (b) any cytodepleting agents, such as, but not limited to, rituximab, within 8 weeks prior to the Baseline visit, (c) any other biologic within 5 half-lives (if known) or 8 weeks, whichever is longer; (7) any phototherapy for skin conditions (narrowband UVB, UVB, UVA1, psoralen + UVA) within 4 weeks prior to the Baseline visit; (8) regular use of tanning rooms / sun beds (more than 2 visits per week) within 4 weeks prior to the Baseline visit; (9) treatment with a live attenuated vaccine within 12 weeks prior to the Baseline visit; (10) within 8 weeks or 5 half-lives prior to the Baseline visit (11) chronic or acute infection requiring treatment with oral or IV antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to the screening visit, or superficial skin infection within 1 week prior to the screening visit; (12) histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, pneumocystis jirovecii, despite resolution jiroveci, invasive opportunistic infections such as aspergillosis, or JC virus (progressive multifocal leukoencephalopathy); (13) known history of HIV infection; (14) positive or indeterminate hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody at the screening visit; (15) presence of any of the following laboratory abnormalities at the screening visit: creatine phosphokinase greater than 2 times the upper limit of normal (ULN); aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) greater than 2 times the ULN; 1.75x10 3 Neutrophil count less than 100x10 / μL 3Platelet count less than 1 / μl; (16) initiation of a new or major change to a previous regular exercise regimen within 2 weeks prior to randomization, or non-agreement to maintain (not increase) current level of physical activity throughout the length of participation in the study; (17) history of hypersensitivity reaction to doxycycline or other tetracyclines; (18) history of clinical internal parasitic infection within 12 months of the baseline visit, other than treated vaginal trichomoniasis; (19) completely treated cervical in (22) males or females of childbearing potential who were not willing to practice contraception; (23) history of alcohol or drug abuse within 2 years prior to the screening visit; (24) recent travel (within 12 months of randomization) to areas endemic for parasitic infections, such as developing countries in Africa or tropical / subtropical regions of Asia; (25) previous or current history of significant comorbidities that would adversely affect the patient's participation in the study, e.g., stage III or IV heart failure, severe renal disease, neurological disease, endocrine disease, GI disease, hepato-biliary disease, metabolic disease, pulmonary disease, or lymphatic disease; and (26) any other condition that may pose an unreasonable risk to the study patient or that may make the patient's participation unreliable or interfere with the study evaluations.

[0395] The primary endpoint of the study was the occurrence and severity of adverse events.Secondary endpoints were exploratory in nature and included: (1) EASI50 index - a binary response variable of whether a 50% or greater reduction in EASI was achieved from baseline to day 29 and other post-baseline observation time points; (2) achievement of an IGA score of 1 or less (clear or almost clear) at day 29 and other post-baseline observation time points; (3) time to IGA≦1 and EASI50; (4) change in IGA, EASI, and SCORAD scores from baseline to day 29 and other baseline observation time points; and (5) proportion of patients with an IGA of 1 or less at week 4 who remained relapse-free until the end of the observation period.

[0396] B. Efficacy Variables The efficacy variables IGA, BSA, EASI, SCORAD, and Pruritus NRS assessments are described elsewhere herein (see, e.g., Example 7). IGA, BSA, EASI, Pruritus NRS, and SCORAD scores were assessed at each clinic visit.

[0397] C. Procedures and Evaluation Safety was assessed by assessing the occurrence of adverse events (described elsewhere herein) (AEs) from Days 1 through 78, as well as by detailed medical history, complete physical examination, vital signs, electrocardiogram (ECG), and clinical laboratory tests. Blinded safety data were reviewed on an ongoing basis. Concomitant medications and procedures were collected, if applicable, from screening until Day 78 (last day of study) or early termination. Safety, laboratory values ​​were collected at each clinic visit. Evaluations of efficacy and efficacy were performed. Blood samples were collected for determination of functional mAb1 systemic trough concentrations at every study visit prior to treatment starting at baseline (day 1). Blood samples were collected for analysis of anti-mAb1 antibody levels at pre-defined time points. Samples were also collected for research and exploratory biomarker analysis. Efficacy of mAb1 was assessed by EASI, IGA, SCORAD, Pruritus Numeric Rating Scale (NRS), and % Body Surface Area (BSA) of AD lesions. Blood samples were collected for pharmacokinetic (PK) analysis and analysis of anti-mAb1 antibody levels at pre-defined time points. Samples were also collected for research and exploratory biomarker analysis.

[0398] D. Statistical methods All statistical analyses described in this section were exploratory in nature, and therefore there was no multiplicity adjustment for type I error. Each test was at the 5% significance level. Categorical variables (EASI-50 and IGA responders at each post-baseline visit, IGA responders at day 29 without subsequent relapse) were analyzed using Fisher's exact test with nominal p-values ​​calculated from the comparison between the mAb1 and placebo groups. Point estimates and confidence intervals of proportions were presented. Graphs of proportions over time were provided. All continuous variables (change or percentage change in IGA, EASI and SCORAD, NRS from baseline to each post-baseline visit) were analyzed by analysis of covariance (ANOCOVA). Unless otherwise specified, assessment of change from baseline and construction of confidence intervals for continuous measures were based on ANCOVA models with treatment as main factor and baseline value as covariate. Point estimates and 95% CIs of the difference in adjusted mean change from baseline between the two treatment groups were provided. Nominal p-values ​​derived from the comparison of the mAb1 group with the placebo group are provided. In the event that the model assumptions were not warranted, an analysis based on the rank order of the covariates was used. Graphs of the mean change from baseline over time were provided. Time-to-event variables (time to EASI50 and time to IGA response) were analyzed using the log-rank test to compare the mAb1 group with the placebo group. Kaplan-Meier survival curves across the two treatment groups were provided. The following analytical approaches were performed for this study: (a) Censored LOCF: Efficacy data were set to missing after use of prohibited medication or after the patient discontinued the study. All missing values ​​were then imputed by simple LOCF. (b) Simple observed case (OC) approach: Only observed cases were analyzed.

[0399] E. Safety Overall, mAb1 was safe and well tolerated in this study. No deaths were reported. A single serious adverse event (SAE) was recorded for a patient in the placebo group, who experienced loss of consciousness and was subsequently withdrawn from the study. No other patients experienced adverse events leading to treatment discontinuation. A total of 19 of the 31 patients enrolled in the study reported at least one treatment-emergent adverse event (TEAE), including 7 patients (70%) in the placebo group and 12 patients (57%) in the mAb1 group. By system organ class (SOC), the most frequent TEAEs reported for the mAb1-treated group were infections and infestations, including 12 patients (57%) and 3 patients (30%) in the placebo group. The most frequent infection was nasopharyngitis, including 5 patients (24%) in the mAb1 group and 2 patients (20%) in the placebo group. There were no serious or opportunistic infections. Other TEAEs reported in more than one patient included nonspecific symptoms such as headache (three patients (14%) in the mAb1 group and one patient (10%) in the placebo group), somnolence (two patients (9.5%) in the mAb1 group and 0% in the placebo group), oropharyngeal pain (three patients (14%) in the mAb1 group and one patient (10%) in the placebo group), and cough (two patients (9.5%) in the mAb1 group and 0% in the placebo group). Most AEs were mild to moderate and generally resolved within 2 weeks. A single serious AE was reported in the mAb1 group: bacterial bronchitis, which began on day 63 (last dose of study drug on day 22) and was considered unrelated to study treatment. There were no adverse events in group 1. Analysis of potentially clinically significant values ​​(PCSV) during treatment for safety laboratory tests, vital signs, and ECGs showed that the ratios of PCSV were generally balanced between the two study groups, with no systematic distribution or different trends, suggesting that the occurrence of PCSV was incidental and not related to study treatment.

[0400] F. Results In this study, mAb1 was administered simultaneously with TCS to patients with moderate to severe AD. Consistent with the current standard of care in AD, a controlled TCS regimen was required for the first 4 weeks (i.e., concurrently with the study treatment), as described elsewhere herein. Table 36 lists the TCS medications used by patients participating in the study. Patients applied TCS once daily to all active lesions until lesion clearance, followed by once daily for 2 days per week to lesion-prone areas (where lesions had cleared). Potent TCS (Class III) was required to be applied to at least 50% of lesions. For lesions located on the face, skin folds, or genital areas (where potent TCS is not usually indicated), lower potency TCS (Class I or II) was permitted. The amount of TCS used each week was measured by weighing the TCS containers at the time they were dispensed to the patients and when they returned to the clinic for their next study visit. Tables 37 and 38 summarize TCS use from days 1 to 29.

[0401] [Table 48]

[0402] [Table 49]

[0403] [Table 50]

[0404] Demographic and disease characteristics were for the most part homogeneous between the two treatment groups (Tables 39 and 40). Mean baseline AD disease severity scores (IGA, EASI, SCORAD, BSA, and Pruritus NRS) were similarly reasonably balanced.

[0405] [Table 51]

[0406] [Table 52]

[0407] Exploratory efficacy results from the study are summarized in Figures 34-47 and Tables 41-44. Despite the relatively small sample size and limited treatment duration, analyses demonstrated statistically significant and clinically relevant effects of mAb1 versus placebo on key exploratory efficacy endpoints, including EASI-50 responder rate, and change and percent change from baseline in EASI, SCORAD, IGA, and Pruritus NRS, with some improvements sustained for weeks after cessation of study treatment. For EASI-50, patients in the mAb1+TCS group 100% of patients met responder criteria at day 29 compared with 50% in the placebo + TCS group (P value 0.0015). Other endpoints such as IGA 0-1 responder rate were superior to placebo but did not reach statistical significance (47.6% vs. 30.0% for placebo). Of note, patients treated with mAb1 used approximately 50% less TCS on average, which may have underestimated the effect of mAb1 treatment compared with the placebo (TCS only) comparison group.

[0408] [Table 53]

[0409] [Table 54]

[0410] [Table 55]

[0411] [Table 56]

[0412] Subcutaneous administration of mAb1 to adult patients with moderate to severe AD treated concomitantly with TCS was generally safe and well tolerated. Treatment with mAb1 administered concomitantly with TCS was associated with significantly better outcomes compared with TCS treatment alone. The proportion of patients achieving EASI-50 was numerically greater than that seen in recent trials using mAb1 as monotherapy (best EASI-50 so far was 75%), suggesting that mAb1 and TCS act additively or synergistically. However, it may also be partly due to the small sample size and slight differences in patient populations between the trials.

[0413] This study demonstrated the additional efficacy provided by mAb1 in patients with moderate to severe AD undergoing TCS treatment. These results suggested that combination therapy could provide additional clinical benefit to patients with moderate to severe AD compared to either treatment used as monotherapy. The results also suggested the possible TCS-sparing effect of mAb1, which could result in safer long-term management of patients with AD.

[0414] Example 12 Biomarker analysis Biomarker analysis was performed on samples obtained from subjects who participated in clinical trials of mAb1. In particular, IgE and thymus and activation chemokine (TARC) levels were measured in patient-derived samples at baseline and at various times after the start of study treatment. Phadiatop™ test was performed to detect antigen-specific IgE. In addition, molecular profiling was performed on skin lesions of patients who participated in clinical trials of mAb1.

[0415] A. Administration of mAb1 to Healthy Subjects In the first clinical trial, subjects were administered a single intravenous (IV) (1.0, 3.0, 8.0 and 12.0 mg / kg) or subcutaneous (SC) (150 and 300 mg) dose of mAb, or placebo (see Example 2 herein). Samples for biomarker analysis were taken from antibody and placebo treated subjects on days 1 (baseline), 8, 29 and 85 (or at early termination). IgE and TARC levels were measured in each sample. A p-value of less than 0.10 was considered statistically significant to allow for small sample sizes. A mixed-effect repeated measures model was used for mean analysis and non-parametric tests were used for median analysis. The median percent change in IgE and TARC levels from patient samples are summarized in Table 45 and Table 46, respectively.

[0416] [Table 57]

[0417] [Table 58]

[0418] Baseline levels of IgE were highly variable as shown in the comparison of mean and median baseline IgE per treatment group (Figure 48A). The laboratory reference range for the IgE assay used was 0-114 kU / L, with 15 of 40 subjects having total IgE levels above 114 kU / L at baseline. As shown in Table 43 and Figure 48B, IgE levels generally decreased in proportion to mAb1 dose and exposure time. By day 85 post-dose, subjects receiving mAb1 administered SC showed a median decrease in IgE levels of 16.5% (150 mg) and 17.2% (300 mg). Significant IgE decreases were also observed in patients receiving mAb1 administered IV, with a 10.7% and 25.6% decrease in IgE observed in the 8 mg / kg and 12 mg / kg groups, respectively. In contrast, IgE levels increased over time in placebo-treated subjects.

[0419] Median serum TARC levels at baseline were generally comparable between treatment groups (Figure 49A) and higher than those reported in the literature. Mean baseline TARC was 616 pg / mL with a range of 134-1327 pg / L. TARC levels in healthy subjects have been reported to range from 106 to 431 ng / L (Hijnen et al., 2004, J. Allergy Clin. Immunol. 113:334-340). A significant reduction in TARC was observed in samples taken from mAb1-treated subjects compared to placebo using both subcutaneous doses (p=0.044 for 150 mg and p=0.047 for 300 mg) (Figure 49B and Table 44). For example, a single SC dose of 300 mg mAb1 caused a median decrease in TARC levels of nearly 35% at day 8 (p=0.052), whereas TARC levels increased by 7.7% in placebo-treated patients. Significant decreases in TARC levels persisted in mAb1-treated patients from day 29 through the last day of the study (day 85) in both the SC and IV administration groups. When data were pooled for all subjects treated with mAb1, the overall difference between mAb1 and placebo in percent change from baseline in TARC was significant (p=0.004) (Figure 50). Significant differences were observed at day 8 ( p = 0.012) and at 29 days (p = 0.022).

[0420] B. Administration of mAb1 to Subjects with Atopic Dermatitis Biomarker levels were also measured in samples from two separate clinical trials involving subjects with atopic dermatitis (AD). In "Study A", AD subjects were administered either mAb1 (75, 150 or 300 mg) or placebo on days 1, 8, 15 and 22 (i.e., 4 weekly doses) of the study. In "Study B", AD subjects were administered 150 mg or 300 mg of mAb1, or placebo on days 1, 8, 15 and 22 (i.e., 4 weekly doses) of the study (see Example 7 herein). All administrations for both studies were subcutaneous (SC). Samples for biomarker analysis were taken from antibody and placebo-treated subjects from both studies on days 1 (baseline), 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71 and 85 (or at early termination). Levels of IgE, TARC, lactate dehydrogenase (LDH), and antigen-specific IgE (Phadiatop) were measured in each sample.

[0421] Serum TARC was measured using a validated assay (Human CCL17 / TARC Quantikine ELISA kit, R&D Systems; validation and assay performed by Quest Diagnostics). Total serum IgE levels were determined using the ImmunoCAP® Total IgE test (Thermo Scientific FDA approved test; performed by Quest Diagnostics). Lactate dehydrogenase (LDH) was measured using the Roche Modular test (FDA approved; performed by Covance Central Laboratories). The Phadiatop® (Thermo Scientific FDA approved test) assay was performed by Viracor-IBT. Biomarker changes from baseline for mAb1 were compared to placebo using two-sample central testing.

[0422] The mean baseline levels of serum TARC, total IgE and LDH for all AD patients enrolled in Study "B" were higher than the reported upper limit of normal (ULN) (Table 47 and Figure 51).

[0423] [Table 59]

[0424] The mean baseline eosinophil levels were at the upper limit of the reference range (Table 47). All but two patients with available data had a positive Phadiatop test. Both of these patients had normal total serum IgE levels. Phadiatop results were unavailable for one patient.

[0425] A wide spectrum of baseline TARC and IgE was observed in the enrolled moderate-to-severe AD population. 27 / 36 patients had serum TARC levels above 1000 pg / mL (approximately twice the average level reported for healthy volunteers) (Figure 51A). 32 / 36 patients had IgE levels above 150 kU / L (the cutoff cited to distinguish between extrinsic and intrinsic AD) (Figure 51B). 17 / 37 had LDH levels above 234 U / L (Figure 51C). No patients had LDH levels below 100 U / L.

[0426] Using local linear regression, an overall mAb1 treatment effect (percent change from baseline) on total serum IgE compared to placebo in both dose groups was observed (p<0.0001) (Figure 52). Total serum IgE levels decreased with mAb1 treatment, whereas an overall increase was observed in the placebo treatment group on the final day of the study.

[0427] The median percent change in IgE levels from baseline for each group from both Studies A and B (combined data) are summarized in Table 48.

[0428] [Table 60]

[0429] As shown in Table 48 and Figure 52, a statistically significant decrease in IgE was observed in samples from mAb1-treated subjects compared to placebo. The median percent change in IgE at day 85 was -23.9% in patients treated with 300 mg mAb1 compared to an increase of 41.7% in the placebo group (p<0.0001). The median percent change from baseline in the 150 mg group compared to placebo was significant at all time points from days 29 to 85 (p<0.03). The median percent change from baseline in the 300 mg group compared to placebo was significant at all time points from days 15 to 85 (p<0.04).

[0430] Local linear regression was used to observe the overall treatment effect on LDH. There was a statistically significant decrease in LDH in the 300 mg treatment group (p=0.0051) (Figure 53). The median percent change was not statistically significant at any single time point, but a time trend was observed (p=0.008).

[0431] mAb1 treatment rapidly suppressed serum TARC levels in AD patients (Figure 54). The median percent change in TARC levels from baseline for each group from both studies (combined data) is summarized in Table 49.

[0432] [Table 61]

[0433] A statistically significant reduction in serum TARC was observed in patients treated with 300 mg mAb1 compared to placebo (p<0.0001; local linear regression analysis). Approximately one month after the last dose (administered on day 21 of the study), statistically significant suppression was maintained in patients treated with 300 mg mAb1 until day 50. The 150 mg group achieved a similar magnitude of suppression, but levels were observed to increase more quickly in the 300 mg group. Statistically significant suppression (median percent change in TARC from baseline compared to placebo) was observed at days 36 and 43 in the 150 mg group (p<0.03) and at days 22, 25, 29, 36, and 50 for the 300 mg group (p<0.04).

[0434] Intrapatient variability in TARC levels was observed in placebo-treated patients over the course of the study. Due to high dropout rates in the placebo-treated group, data from only four patients in that group were available at the end of the study.

[0435] In conclusion, TARC, IgE and LDH biomarkers associated with Th2 infiltration and / or AD disease activity were all suppressed by mAb1 treatment in AD patients. mAb1 rapidly reduced serum TARC levels in AD patients compared with placebo. The duration of suppression appeared to be dose-related, and the data suggested that the effect may persist after discontinuation of the drug. Total serum IgE levels were significantly reduced in mAb1-treated patients. IgE continued to decrease after the treatment phase in the 300 mg group (median percent change), suggesting that maximum IgE suppression had not yet been achieved. A consistent decrease in LDH levels from baseline was observed in patients treated with mAb1. Although the direct relationship of LDH to IL-4 and IL-13 is unclear, its association with disease severity suggested that LDH may be a measure of the degree of skin damage in AD patients. Suppression of TARC and IgE indicated that mAb1 is a potent inhibitor of Th2 inflammation.

[0436] Correlations between biomarkers and AD-related parameters In Study "B" (see Example 7), patients with severe AD received 150 or 300 mg of mAb1 or placebo (PBO) for 4 weeks. Pruritus was measured using a twice-daily Pruritus Numeric Rating Scale (NRS; range 0-10) to generate mean weekly NRS scores and biweekly 5-D Pruritus Scale ratings. The 5-D scale is a five-question tool used to assess multiple dimensions of itch: severity, duration, direction, disability, and distribution. Mean baseline NRS and 5-D scores were 5.5 and 19, respectively. Mean weekly NRS scores rapidly declined (mean percent change from baseline) in the 300 mg group to 31.9% (p<0.02) at week 2 and 55.2% (p=0.01) at week 7, versus +1.3% and -17.3%, respectively, in the PBO group. A rapid decline in 5-D scores was also observed in patients treated with 300 mg mAb1 (mean percent change -28.2% at day 15, p=0.0009; -37.1% at day 29, p=0.0007; -42.5% at day 43, p=0.012; +3.6%, +8.1% and -9.4% in the PBP group, respectively). Serum levels of CCL17, a marker of IL4 / IL13 activity, also declined rapidly upon treatment. Both CCL17 and pruritus were suppressed for several weeks after treatment ceased. Table 50 shows the correlation of pruritus (5D and NRS) with outcomes of dermatitis (EASI) and CCL17.

[0437] [Table 62]

[0438] Overall, for all treatment groups, 5D scores correlated significantly with CCL17 (r=0.46 at baseline, p=0.004; r=0.55 at day 29, p=0.002) and EASI scores (r=0.41 at baseline, p=0.011; 0.62 at day 29, p<0.0001) in this study. Percentage change in 5D was significantly correlated with EASI (r=0.65 at day 15, p<0.0001; and r=0.61 at day 29, p<0.0001) as well as CCL17 (r=0.05 at day 15, p=0.002; and r=0.06 at day 29, p<0.0001) for all treatment groups at days 15 and 29. At day 15, only the 150 mg group showed a strong and significant correlation between the percent change in EASI and the percent change in 5D (r=0.81, p=0.0005). Similarly, at day 29, the significant correlation was only for the 150 mg group (r=0.57, p=0.0036). At both days 15 and 29, there was a significant overall correlation between the percent change in CCL17 and the percent change in 5D scores, but none of the individual treatment groups showed such a correlation at each day.

[0439] Pruritus severity assessed using the NRS showed a moderate to strong correlation with the EASI, which was significant. However, NRS values ​​correlated with CCL17 levels only at baseline, and there was no significant correlation for the percentage change from baseline. The rapid and sustained improvement of pruritus observed in adult AD patients treated with mAb1 suggests that IL-4 / IL-13 signaling is an important mechanism for AD pruritus. The correlation between pruritus and CCL17 levels highlights the relationship between IL-4 / IL-13-mediated inflammation, AD disease activity, and pruritus in severe AD.

[0440] C. Repeated administration of mAB1 to subjects with moderate to severe atopic dermatitis IgE and TARC levels were measured in samples from clinical trials involving subjects with moderate to severe atopic dermatitis (AD). AD subjects were administered 300 mg of mAb1 or placebo on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 of the study (i.e., 12 weekly doses) (see Example 10 herein). All administrations for both studies were subcutaneous (SC). Serum samples for biomarker analysis were collected from antibody and placebo-treated subjects from both studies on days 1 (baseline), 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, 85, 99, 113, 127, 141, 155, 169, 183 and 197 (last day of study) or at early termination. Levels of IgE, TARC and antigen-specific IgE (Phadiatop™ test) were measured in each sample.

[0441] TARC is an IL-4 / IL-13 induced chemokine that has been shown to be strongly associated with AD disease severity and may be involved in disease development. Baseline TARC levels were evaluated for their potential predictive value for treatment response. Post-treatment samples were evaluated for the pharmacodynamic effect of mAb1 on TARC.

[0442] Patients with AD often have elevated IgE. It has been shown that total IgE levels correlate with AD severity and may be involved in the development of the disease. Baseline IgE levels were evaluated for their potential predictive value for treatment response. Post-treatment samples were evaluated for the pharmacodynamic effect of mAb1 on total IgE.

[0443] The Phadiatop™ test is an in vitro diagnostic screening tool used to detect antigen-specific IgE against common inhaled antigens. Baseline results of the Phadiatop™ test were evaluated for their potential predictive value for treatment response. Post-treatment samples were evaluated for the pharmacodynamic effect of mAb1 against the Phadiatop™ antigen panel.

[0444] Consistent with results from earlier clinical trials (see Sections A and B above), TARC and IgE levels declined and remained suppressed below baseline up to the 16-week post-treatment follow-up period (Figures 55-56).

[0445] 300mg for 12 weeks compared with mAb1 for 4 weeks during the 16 week follow-up Greater IgE suppression was observed with mAb1 treatment (median -57%). The magnitude of TARC suppression was similar at the end of treatment after 12 weeks (median -83%) and weeks (median -76%) of mAb1 treatment.

[0446] D. Coadministration of mAb1 and topical corticosteroids in patients with moderate to severe atopic dermatitis In a study evaluating the safety and efficacy of mAb1 in combination with topical corticosteroids (TCS) in adult patients with moderate to severe AD, modulation of TARC and IgE was examined. Two treatment groups were compared (administered weekly for 4 weeks): (300 mg mAb1 + TCS) vs. (placebo + TCS). TCS was administered from day 1 to day 28 (patients stopped TCS treatment when lesions disappeared) (see Example 11 herein). Patients were assessed at screening, baseline (day 1), weekly until week 5, and then biweekly until week 11. TARC levels were reduced in both treatment groups and tended to be more strongly suppressed in the mAb1 + TCS group compared to placebo (PBO) + TCS. The differences were statistically significant at days 22, 29, and 50. IgE levels were also reduced in both treatment groups. There was no statistically significant difference in IgE suppression between the groups.

[0447] [Table 63]

[0448] TARC was measured using the Human TARC Quantikine ELISA kit from R&D Systems. Table 51 summarizes baseline TARC levels by treatment group. Mean and median baseline TARC levels for both treatment groups were above the normal range of 106-431 pg / mL (Weihrauch et al., 2005; Cancer Res. 65:13), as well as the observed baseline levels described in Section A above.

[0449] [Table 64]

[0450] TARC levels decreased from baseline in both treatment groups, thus TCS alone can reduce serum TARC levels in AD patients. The magnitude of the median percent change in TARC from baseline was consistently greater in the mAb1 + TCS group compared to the placebo + TCS group, but the differences were only statistically significant at days 22, 29, and 50 (least squares mean difference estimated from analysis of covariance) (Table 52).

[0451] The mean and median baseline IgE levels are summarized in Table 53.

[0452] [Table 65]

[0453] IgE levels decreased in both treatment groups. After day 29, the magnitude of the median percent change in IgE tended to be greater in the mAb1+TCS group and was not statistically significantly different at any time point during the study (LS mean difference estimated from analysis of covariance; Table 54).

[0454] [Table 66]

[0455] Approximately 50% of patients achieved at least EASI50 by day 29 on placebo+TCS, and the suppression of TARC and IgE in this group was consistent with the observed clinical improvement. All patients on mAb1+TCS achieved at least EASI50 by day 29 (see Example 11). A trend toward stronger suppression of TARC and IgE was observed in mAb1+TCS compared to placebo+TCS. However, statistically significant differences were only observed in TARC suppression at days 22, 29, and 50.

[0456] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to be within the scope of the appended claims.

Claims

1. A method of treating moderate to severe atopic dermatitis (AD) in a patient who is resistant, non-responsive, or does not respond adequately to treatment with either topical corticosteroids (TCS) or calcineurin inhibitors, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL-4R) antagonist.

2. administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL-4R) antagonist, wherein administering the IL-4R antagonist to the patient results in an improvement in an AD-related parameter, and the improvement in the AD-related parameter is (a) at least 40% reduction from baseline in Investigator Global Assessment (IGA) score; (b) at least 40% reduction from baseline in atopic dermatitis body surface area lesion (BSA) score; (c) at least 55% reduction from baseline in Eczema Area and Severity Index (EASI) score; (d) at least 40% reduction from baseline in SCORAD score; (e) at least a 25% reduction from baseline in the 5-D itch scale; and (f) at least 45% reduction from baseline in pruritus numeric rating scale (NRS) score 1. A method of treating moderate to severe atopic dermatitis (AD) in a patient selected from the group consisting of:

3. administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL-4R) antagonist, wherein administering the IL-4R antagonist to the patient results in an improvement in an AD-related parameter, and the improvement in the AD-related parameter is (a) at least 40% reduction from baseline in Investigator Global Assessment (IGA) score; (b) at least 40% reduction from baseline in atopic dermatitis body surface area lesion (BSA) score; (c) at least 55% reduction from baseline in Eczema Area and Severity Index (EASI) score; (d) at least 40% reduction from baseline in SCORAD score; (e) at least a 25% reduction from baseline in the 5-D itch scale; and (f) at least 45% reduction from baseline in pruritus numeric rating scale (NRS) score 1. A method of treating moderate to severe atopic dermatitis (AD) in patients who are resistant, non-responsive, or do not respond adequately to treatment with either topical corticosteroids (TCS) or calcineurin inhibitors, comprising administering to said patients a therapeutically effective amount of a compound selected from the group consisting of:

4. 4. The method of claim 2 or 3, wherein the improvement in the AD-related parameter is at least a 45% decrease from baseline in IGA from day 85 to at least day 197 after administration of the pharmaceutical composition.

5. 4. The method of claim 2 or 3, wherein the improvement in the AD-related parameter is at least a 50% decrease from baseline in BSA score from day 85 to at least day 197 after administration of the pharmaceutical composition.

6. 2. The improvement in the AD-related parameter is at least a 60% decrease from baseline in the EASI score from day 85 to at least day 197 after administration of the pharmaceutical composition. Or the method according to claim 3.

7. 4. The method of claim 2 or 3, wherein the improvement in the AD-related parameter is at least a 45% decrease from baseline in the SCORAD score from day 85 to at least day 197 after administration of the pharmaceutical composition.

8. 4. The method of claim 2 or 3, wherein the improvement in the AD-related parameter is at least a 30% decrease from baseline in the 5-D itch scale from day 85 to at least day 197 after administration of the pharmaceutical composition.

9. 4. The method of claim 2 or 3, wherein the improvement in the AD-related parameter is at least a 50% decrease from baseline in the NRS score by the end of at least 16 weeks after administration of the pharmaceutical composition.

10. The method of any one of claims 1 to 9, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

11. The method of claim 10, wherein the pharmaceutical composition comprises about 75 mg to about 300 mg of an antibody or antigen-binding fragment that specifically binds to IL-4R.

12. The antibodies or antigen-binding fragments that specifically bind to IL-4R are selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 1 12. The method of claim 10 or 11, comprising heavy and light chain CDR sequences derived from a HCVR / LCVR sequence pair selected from the group consisting of 66 / 168, 170 / 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

13. The method of claim 12, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

14. The method of claim 13, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

15. The method of claim 14, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises a HCVR having the amino acid sequence of SEQ ID NO:162 and a LCVR having the amino acid sequence of SEQ ID NO:

164.

16. The method of any one of claims 1 to 15, wherein the pharmaceutical composition is administered subcutaneously to the subject.

17. The method of any one of claims 1 to 16, wherein a second therapeutic agent is administered to the subject before, after, or simultaneously with the pharmaceutical composition.

18. 18. The method of claim 17, wherein the second therapeutic agent is selected from the group consisting of a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, an NSAID, and an IFNγ. Method of posting.

19. A method for treating, reducing, alleviating, ameliorating, or preventing pruritus in a patient comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an interleukin-4 receptor (IL-4R) antagonist.

20. 20. The method of claim 19, wherein the patient has moderate to severe atopic dermatitis (AD).

21. 21. The method of claim 20, wherein the patient is resistant, non-responsive, or does not respond adequately to treatment with either topical corticosteroids (TCS) or calcineurin inhibitors.

22. 22. The method of any one of claims 19-21, wherein administration of the pharmaceutical composition to a patient results in a reduction in pruritus as measured by either at least a 25% reduction from baseline in the 5D pruritus scale or at least a 45% reduction from baseline in pruritus numerical rating scale (NRS) score.

23. Administering a pharmaceutical composition to a patient (a) at least 40% reduction from baseline in Investigator Global Assessment (IGA) score; (b) at least 40% reduction from baseline in atopic dermatitis body surface area lesion (BSA) score; (c) at least 55% reduction from baseline in Eczema Area and Severity Index (EASI) score; and (d) at least 40% reduction from baseline in SCORAD score The method of any one of claims 20 to 22, which results in an improvement in an AD-related parameter selected from the group consisting of:

24. The method of any one of claims 19 to 23, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

25. 25. The method of claim 24, wherein the pharmaceutical composition comprises about 75 mg to about 300 mg of an antibody or antigen-binding fragment that specifically binds to IL-4R.

26. The antibodies or antigen-binding fragments that specifically bind to IL-4R are selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 16 26. The method of claim 25, comprising heavy and light chain CDR sequences derived from a HCVR / LCVR sequence pair selected from the group consisting of: 4, 166 / 168, 170 / 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

27. 27. The method of claim 26, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

28. The antibody or antigen-binding fragment that specifically binds to IL-4R is represented by SEQ ID NO: 148, respectively.

28. The method of claim 27, comprising three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 150, 152, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

29. The method of claim 28, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises a HCVR having the amino acid sequence of SEQ ID NO: 162 and a LCVR having the amino acid sequence of SEQ ID NO:

164.

30. The method of any one of claims 19 to 29, wherein the pharmaceutical composition is administered to the patient subcutaneously or intravenously.

31. A method for treating or preventing moderate to severe AD in a patient, comprising: (a) selecting a patient that exhibits an elevated level of at least one AD-related biomarker prior to or at the time of treatment; and (b) administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

32. A method for treating or preventing moderate to severe AD in patients who are resistant, non-responsive, or do not adequately respond to either TCS or a calcineurin inhibitor, comprising: (a) selecting a patient who exhibits an elevated level of at least one AD-related biomarker prior to or at the time of treatment; and (b) administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist.

33. The method of claim 31 or 32, wherein the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R.

34. The method of claim 33, wherein the pharmaceutical composition comprises about 75 mg to about 300 mg of an antibody or antigen-binding fragment that specifically binds to IL-4R.

35. The antibody or antigen-binding fragment thereof that specifically binds to IL-4R is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 1 35. The method of claim 34, comprising heavy and light chain CDR sequences derived from a HCVR / LCVR sequence pair selected from the group consisting of: 64, 166 / 168, 170 / 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

36. The method of claim 35, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

37. 37. The method of claim 36, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

38. The method of claim 37, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises a HCVR having the amino acid sequence of SEQ ID NO: 162 and a LCVR having the amino acid sequence of SEQ ID NO:

164.

39. The method of any one of claims 31 to 38, wherein the pharmaceutical composition is administered to the patient subcutaneously or intravenously.

40. The method of any one of claims 31 to 39, wherein the AD-related biomarker is IgE.

41. The method of any one of claims 31 to 39, wherein the AD-related biomarker is thymus and activation-regulated chemokine (TARC).

42. 41. The method of claim 40, wherein the subject is selected based on exhibiting an IgE level greater than 2000 kU / L prior to or at the time of treatment ("baseline").

43. 42. The method of claim 41, wherein the subject is selected based on exhibiting a TARC level greater than 1000 pg / mL prior to or at the time of treatment ("baseline").

44. 43. The method of claim 42, wherein the subject exhibits at least a 5% decrease in IgE levels from baseline after day 50 or more following administration.

45. 45. The method of claim 44, wherein the subject exhibits at least a 10% decrease in IgE levels from baseline after day 50 or more following administration.

46. 44. The method of claim 43, wherein the subject exhibits at least a 25% decrease in TARC levels from baseline after day 4 or more following administration.

47. 47. The method of claim 46, wherein the subject exhibits at least a 70% decrease in TARC levels from baseline at or after day 29 post-administration.

48. 1. A method for treating atopic dermatitis (AD) in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein administration of the pharmaceutical composition to the subject results in a decrease in at least one AD-associated biomarker in the subject by 4, 8, 15, 22, 25, 29, or 36 days after administration of the pharmaceutical composition, compared to the level of the biomarker in the subject prior to administration.

49. 1. A method for treating atopic dermatitis (AD) in a subject that is resistant, non-responsive, or poorly responsive to either TCS or a calcineurin inhibitor, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), wherein administering the pharmaceutical composition to the subject results in a decrease in at least one AD-associated biomarker in the subject by 4, 8, 15, 22, 25, 29, or 36 days after administration of the pharmaceutical composition, compared to the level of the biomarker in the subject prior to administration.

50. 50. The method of claim 48 or 49, wherein the AD-related biomarker is IgE or thymus and activation-regulated chemokine (TARC).

51. The method of any one of claims 48 to 50, wherein the pharmaceutical composition comprises about 75 mg to about 300 mg of an antibody or antigen-binding fragment that specifically binds to IL-4R.

52. Administration of the pharmaceutical composition to a subject reduces the IgE level in the subject compared to the IgE level before administration of the pharmaceutical composition.

51. The method of claim 50, wherein the method results in at least a 5% decrease in IgE in the subject 36 days after administration.

53. 51. The method of claim 50, wherein administration of the pharmaceutical composition to a subject results in at least a 25% decrease in TARC in the subject by day 4 after administration of the pharmaceutical composition, compared to the TARC level in the subject prior to administration.

54. 54. The method of claim 53, wherein administration of the pharmaceutical composition to a subject results in at least a 70% decrease in TARC in the subject by day 29 after administration of the pharmaceutical composition, compared to the TARC level in the subject prior to administration.

55. The antibodies or antigen-binding fragments that specifically bind to IL-4R are selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 166 55. The method of any one of claims 48-54, comprising heavy and light chain CDR sequences derived from a HCVR / LCVR sequence pair selected from the group consisting of: 168 / 168, 170 / 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

56. 56. The method of claim 55, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

57. 57. The method of claim 56, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

58. 58. The method of claim 57, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises a HCVR having the amino acid sequence of SEQ ID NO:162 and a LCVR having the amino acid sequence of SEQ ID NO:

164.

59. The method of any one of claims 48 to 58, wherein the pharmaceutical composition is administered to the subject subcutaneously or intravenously.

60. 60. The method of any one of claims 48 to 59, wherein the second therapeutic agent is administered to the subject before, after, or simultaneously with the pharmaceutical composition.

61. 61. The method of claim 60, wherein the second therapeutic agent is selected from the group consisting of a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, an NSAID, and IFNγ.

62. A method for improving one or more atopic dermatitis (AD)-associated parameters in a subject in need thereof, or for decreasing the level of at least one AD-associated biomarker in the subject, comprising sequentially administering to the subject a single initial dose of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, followed by one or more second doses of a pharmaceutical composition comprising an IL-4R antagonist.

63. The method of claim 62, wherein the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R.

64. 64. The method of claim 63, wherein the pharmaceutical composition comprises about 75 mg to about 300 mg of an antibody or antigen-binding fragment that specifically binds to IL-4R.

65. The antibodies or antigen-binding fragments that specifically bind to IL-4R are selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 1 65. The method of claim 63 or 64, comprising heavy and light chain CDR sequences derived from a HCVR / LCVR sequence pair selected from the group consisting of 66 / 168, 170 / 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

66. 66. The method of claim 65, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

67. 67. The method of claim 66, wherein the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

68. The method of claim 67, wherein the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises a HCVR having the amino acid sequence of SEQ ID NO: 162 and a LCVR having the amino acid sequence of SEQ ID NO:

164.

69. The method of any one of claims 62 to 68, wherein the pharmaceutical composition is administered to the patient subcutaneously or intravenously.

70. 69. The method of any one of claims 62-68, wherein the one or more second doses of the pharmaceutical composition are administered weekly.

71. The method of any one of claims 62-70, wherein a second therapeutic agent is administered to the subject before, after, or simultaneously with the pharmaceutical composition.

72. 72. The method of claim 71, wherein the second therapeutic agent is selected from the group consisting of a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, an NSAID, and IFNγ.

73. 1. A method for improving one or more atopic dermatitis (AD)-related parameters in a subject in need thereof or reducing the level of at least one AD-related biomarker in a subject, comprising administering to the subject about 75 mg to about 300 mg of a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, wherein the pharmaceutical composition is administered to the subject at a dosing frequency of once a week.

74. The antibody or antigen-binding fragment that specifically binds to IL-4R is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 166 / 168, 170 / 178, 18 74. The method of claim 73, comprising heavy and light chain CDR sequences derived from a HCVR / LCVR sequence pair selected from the group consisting of: 6 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

75. 75. The method of claim 74, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

76. 76. The method of claim 75, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

77. The method of claim 76, wherein the antibody or antigen-binding fragment thereof that specifically binds to IL-4R comprises a HCVR having the amino acid sequence of SEQ ID NO: 162 and a LCVR having the amino acid sequence of SEQ ID NO:

164.

78. The method of any one of claims 73 to 77, wherein the pharmaceutical composition is administered to the subject subcutaneously or intravenously.

79. 79. The method of any one of claims 73-78, wherein a second therapeutic agent is administered to the subject before, after, or simultaneously with the pharmaceutical composition.

80. 80. The method of claim 79, wherein the second therapeutic agent is selected from the group consisting of a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, an NSAID, and IFNγ.

81. A method for enhancing or potentiating an immune response to an antigen in a subject, comprising administering a pharmaceutical composition comprising the antigen and an IL-4R antagonist.

82. 1. A method for enhancing or potentiating an immune response to an antigen in a subject, comprising: (a) administering to the subject a vaccine composition comprising the antigen; and (b) administering an IL-4R antagonist prior to, concomitantly with, and / or after administration of the vaccine composition to the subject.

83. The method of claim 81 or 82, wherein the IL-4R antagonist is an anti-IL-4R antibody.

84. A pharmaceutical composition for enhancing or potentiating an immune response to an antigen in a subject, comprising: (a) an antigen; and (b) an IL-4R antagonist.

85. The pharmaceutical composition of claim 84, wherein the IL-4R antagonist is an anti-IL-4R antibody.

86. Topical corticosteroids (TCS) and concurrent therapeutically effective amounts of interleukin-4 receptor antagonists The method includes administering to the patient an interleukin-4 receptor (IL-4R) antagonist, wherein the administration results in an improvement in an AD-related parameter, and the improvement in the AD-related parameter includes: (a) at least a 50% reduction from baseline in Investigator Global Assessment (IGA) score; (b) at least 65% reduction from baseline in pruritus Numeric Rating Scale (NRS) score; (c) at least 70% reduction from baseline in Eczema Area and Severity Index (EASI) score; and (d) at least 60% reduction from baseline in SCORAD score 1. A method of treating moderate to severe atopic dermatitis (AD) in a patient selected from the group consisting of:

87. 87. The method of claim 86, wherein the TCS is selected from the group consisting of a Group I TCS, a Group II TCS, and a Group III TCS.

88. 87. The method of claim 86, wherein the TCS is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate and hydrocortisone butyrate.

89. The method of any one of claims 86 to 88, wherein the patient uses 50% less TCS compared to a patient not treated with an IL-4R antagonist.

90. The method of any one of claims 86 to 89, wherein the IL-4R antagonist is an anti-IL-4R antibody.

91. The anti-IL-4R antibody is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 166 / 168 91. The method of claim 90, comprising heavy and light chain CDR sequences derived from a HCVR / LCVR sequence pair selected from the group consisting of: 170 / 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

92. 91. The method of claim 90, wherein the antibody is administered at a dose of about 300 mg.

93. 1. A method for monitoring whether a therapeutic dose of an interleukin-4 receptor (IL-4R) antagonist administered to a human subject is safe, comprising: obtaining information regarding the safety of the antagonist following administration to humans, including the occurrence of one or more events selected from the group consisting of anaphylactic or acute allergic reactions requiring immediate treatment, severe injection site reactions lasting longer than 24 hours, severe infection, any parasitic infection, an increase in alanine aminotransferase (ALT) greater than or equal to 2-fold the upper limit of normal (ULN), QTc > 500 ms, pregnancy, overdose, and herpes simplex virus type II infection; determining that one or more of said events have occurred; determining that the therapeutic dose is unsafe, and optionally, and advising the patient to discontinue or reduce the therapeutic dose.

94. 94. The method of claim 93, wherein the infection is an upper respiratory tract infection, pharyngitis, or sinusitis.

95. 94. The method of claim 93, wherein the injection site reaction is erythema, pain, nodule, hematoma, or pruritus.

96. 96. The method of claim 95, wherein the pain is greater than 2mm VAS, for example, between 3mm and 30mm VAS.

97. 96. The method of claim 95, wherein the erythema has a diameter of 9 mm or more.

98. 1. A method for monitoring whether a therapeutic dose of an interleukin-4 receptor (IL-4R) antagonist administered to a human subject is safe, comprising: obtaining information regarding the safety of the antagonist following administration to humans, including the occurrence of one or more events selected from the group consisting of anaphylactic or acute allergic reactions requiring immediate treatment, severe injection site reactions lasting longer than 24 hours, severe infection, any parasitic infection, an increase in alanine aminotransferase (ALT) greater than or equal to 2-fold the upper limit of normal (ULN), QTc > 500 ms, pregnancy, overdose, and herpes simplex virus type II infection; determining that one or more of said events did not occur; and determining that said therapeutic dose is safe; The method comprising:

99. 99. The method of claim 98, wherein the infection is an upper respiratory tract infection, pharyngitis, or sinusitis.

100. 99. The method of claim 98, wherein the injection site reaction is erythema, pain, nodule, hematoma, or pruritus.

101. 101. The method of claim 100, wherein the pain is greater than 2mm VAS, for example, between 3mm and 30mm VAS.

102. 101. The method of claim 100, wherein the erythema has a diameter of 9 mm or more.

103. 1. A method for quantifying or monitoring the amount of anti-drug antibodies in the serum of a human subject following administration of a drug that is an interleukin-4 receptor (IL-4R) antagonist, comprising: (a) obtaining said sample of serum from a human subject administered a dose of said IL-4R antagonist; and (b) determining the amount of anti-drug antibodies in the serum sample. The method comprising:

104. The IL-4R antagonist specifically binds to IL-4R and is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 166 / 168, 170 104. The method of any one of claims 93 to 103, which is an antibody or antigen-binding fragment comprising heavy and light chain CDR sequences derived from a HCVR / LCVR sequence pair selected from the group consisting of: 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

105. The method of claim 104, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

106. The method of claim 104, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

107. The method of claim 104, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises a HCVR having the amino acid sequence of SEQ ID NO: 162 and a LCVR having the amino acid sequence of SEQ ID NO:

164.

108. 103. The method of any one of claims 93 to 102, wherein the safe therapeutic dose is 500 mg or less.

109. 103. The method of any one of claims 93-102, wherein the safe therapeutic dose is selected from the group consisting of 75 mg, 150 mg, and 300 mg.

110. 1. A therapeutic dosage form of a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist, comprising administering the dosage form to a human comprising: (a) Area under the plasma concentration versus time curve (AUC) calculated using the trapezoidal method from time zero to real time from about 4 mg·h / ml to about 20 mg·h / ml ｌａｓｔ ). (b) a maximum observed plasma concentration (C) of about 15 μg / ml to about 42 μg / ml ｍａｘ ). (c) a time to a first maximum plasma concentration (t ｍａｘ ). (d) Approximately 5,000,000ng / h ＊ mL~about 25,000,000ng / h ＊ the area under the plasma concentration versus time curve (AUC) in mL extrapolated to infinity, and (e) A terminal half-life time (t １／２ Ｚ ) The dosage form provides one or more of the following:

111. The IL-4R antagonist specifically binds to IL-4R and is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 166 / 16 111. The dosage form of claim 110, which is an antibody or antigen-binding fragment comprising heavy and light chain CDR sequences derived from a HCVR / LCVR sequence pair selected from the group consisting of: 8, 170 / 178, 186 / 188, 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

112. The dosage form of claim 111, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

113. The dosage form of claim 111, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

114. The dosage form of claim 111, wherein the antibody or antigen-binding fragment that specifically binds to IL-4R comprises a HCVR having the amino acid sequence of SEQ ID NO:162 and a LCVR having the amino acid sequence of SEQ ID NO:

164.

115. 115. The dosage form of any one of claims 110 to 114, having a safe therapeutic dose of 500 mg or less.

116. 116. The dosage form of any one of claims 110 to 115, wherein the safe therapeutic dose is selected from the group consisting of 75 mg, 150 mg, and 300 mg.

117. 1. A method for comparing interleukin-4 receptor (IL-4R) antagonists produced by a first method and a proposed equivalent second method, comprising obtaining information regarding the safety of the antagonists following administration of the antagonist produced by the first method to a first human and following administration of the antagonist produced by the second method to a second human, the information comprising: including one or more events selected from the group consisting of anaphylactic or acute allergic reactions requiring immediate treatment, severe injection site reactions lasting more than 24 hours, severe infection, any parasitic infection, an increase in alanine aminotransferase (ALT) 2-fold or greater than the upper limit of normal (ULN), QTc > 500 ms, pregnancy, overdose, and herpes simplex type II virus infection; and If the information is not significantly different for the antagonist produced by the first method and the antagonist produced by the second method, the two methods are determined to be acceptable for producing equivalent antagonists; and If the information is determined to be significantly different for the antagonist produced by the first method and the antagonist produced by the second method, then the two methods are determined to be unacceptable for producing equivalent antagonists. The method.

118. 118. The method of claim 117, wherein the infection is an upper respiratory tract infection, pharyngitis, or sinusitis.

119. 118. The method of claim 117, wherein the injection site reaction is erythema, pain, nodule, hematoma, or pruritus.

120. 120. The method of claim 119, wherein the pain is greater than 2mm VAS, for example, between 3mm and 30mm VAS.

121. 120. The method of claim 119, wherein the erythema has a diameter of 9 mm or more.

122. 1. A method for comparing an interleukin-4 receptor (IL-4R) antagonist produced by a first method and a proposed equivalent second method, comprising obtaining information regarding the therapeutic dose of the antagonist following administration of a dose of the antagonist produced by the first method to a first human and following administration of a dose of the antagonist produced by the second method to a second human, the information comprising: (a) Area under the plasma concentration versus time curve (AUC) calculated using the trapezoidal method from time zero to real time from about 4 mg·h / ml to about 20 mg·h / ml ｌａｓｔ ). (b) a maximum observed plasma concentration (C) of about 15 μg / ml to about 42 μg / ml ｍａｘ ). (c) a time to a first maximum plasma concentration (t ｍａｘ ). (d) Approximately 5,000,000ng / h ＊ mL~about 25,000,000ng / h ＊ the area under the plasma concentration versus time curve (AUC) in mL extrapolated to infinity, and (e) A terminal half-life time (t １／２ Ｚ ) If the information is not significantly different for the antagonist produced by the first method and the antagonist produced by the second method, the two methods are determined to be acceptable for producing equivalent antagonists; and If the information is determined to be significantly different for the antagonist produced by the first method and the antagonist produced by the second method, then the two methods are determined to be unacceptable for producing equivalent antagonists. The method.

123. 1. A method of monitoring the effectiveness of treatment of moderate to severe AD in a subject, comprising the steps of: (a) determining the expression levels of one or both of TARC and serum IgE in a biological sample obtained from the subject prior to treatment with an IL-4R antagonist; (b) determining the expression levels of one or both of TARC and serum IgE in a biological sample obtained from the subject after treatment with an IL-4R antagonist; (c) comparing the levels determined in step (a) with the levels determined in step (b); and (d) concluding that the treatment is effective if the level determined in step (b) is lower than the level determined in step (a), or concluding that the treatment is not effective if the level determined in step (b) is the same as or higher than the level determined in step (a).

124. 124. The method of claim 123, wherein the level in step (b) is determined 1 week, 2 weeks, 3 weeks, 4 weeks, or 5 weeks after determining the level in step (a).

125. A method of monitoring a subject's response to treatment with an IL-4R antagonist, wherein the subject has moderate to severe AD, comprising: (a) obtaining information regarding expression levels of one or both of TARC and IgE in a biological sample from the subject following administration of an IL-4R antagonist to the subject; and (b) providing an indication that treatment should be continued if the expression levels of TARC or IgE are decreased compared to levels prior to treatment with the IL-4R antagonist.

126. IL-4R antagonists for use in the treatment and / or prevention of atopic dermatitis.

127. A pharmaceutical composition comprising an anti-IL-4R antibody or an antigen-binding fragment thereof for use in the treatment and / or prevention of atopic dermatitis.

128. 128. The pharmaceutical composition of claim 127, wherein the pharmaceutical composition comprises between 75 mg and 600 mg of the antibody or antigen-binding fragment thereof.

129. 129. The pharmaceutical composition of claim 128, wherein the pharmaceutical composition comprises 300 mg of the antibody or antigen-binding fragment thereof.

130. The antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 166 / 168, 170 / 178, 186 / 188, 130. The pharmaceutical composition of any one of claims 127 to 129, comprising heavy and light chain complementarity determining region (CDR) sequences derived from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair selected from the group consisting of 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

131. The pharmaceutical composition of claim 130, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

132. The pharmaceutical composition of claim 131, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

133. The pharmaceutical composition of claim 132, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 162 and an LCVR having the amino acid sequence of SEQ ID NO:

164.

134. The pharmaceutical composition according to any one of claims 127 to 133, wherein the pharmaceutical composition is administered subcutaneously or intravenously to a subject suffering from atopic dermatitis.

135. The pharmaceutical composition of any one of claims 127-134, wherein the second therapeutic agent is administered before, after, or simultaneously with the pharmaceutical composition.

136. The pharmaceutical composition of claim 135, wherein the second therapeutic agent is selected from the group consisting of a TNF inhibitor, an IL-1 inhibitor, an IL-5 inhibitor, an IL-8 inhibitor, an IgE inhibitor, a topical corticosteroid (TCS), a calcineurin inhibitor, an NSAID, and IFNγ.

137. 137. The pharmaceutical composition of claim 136, wherein the second therapeutic agent is selected from the group consisting of a Group I TCS, a Group II TCS, and a Group III TCS.

138. 137. The pharmaceutical composition of claim 136, wherein the TCS is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate and hydrocortisone butyrate.

139. A pharmaceutical composition comprising an anti-IL-4R antibody or an antigen-binding fragment thereof for use in treating AD in a subject, wherein the treatment results in an improvement in an AD-related parameter.

140. Improvement in AD-related parameters, (a) at least 40% reduction from baseline in Investigator Global Assessment (IGA) score; (b) at least 40% reduction from baseline in atopic dermatitis body surface area lesion (BSA) score; (c) at least 55% reduction from baseline in Eczema Area and Severity Index (EASI) score; and (d) at least 40% reduction from baseline in SCORAD score; (e) at least a 25% reduction from baseline in the 5-D itch scale; and (f) at least 45% reduction from baseline in pruritus numeric rating scale (NRS) score 140. The pharmaceutical composition of claim 139, selected from the group consisting of:

141. 141. The pharmaceutical composition of claim 139 or 140, wherein the subject is resistant, non-responsive, or does not respond adequately to treatment with TCS or a calcineurin inhibitor.

142. A pharmaceutical composition comprising an anti-IL-4R antibody or an antigen-binding fragment thereof for use in treating AD in a subject who has elevated levels of AD-associated biomarkers selected from one or both of TARC or serum IgE prior to or at the time of treatment.

143. The treatment improves the level of the biomarker by 4, 8, 1, or 2 days after treatment compared to the level of the biomarker in the subject before treatment. A pharmaceutical composition comprising an anti-IL-4R antibody or an antigen-binding fragment thereof for use in treating AD in a subject, wherein the pharmaceutical composition results in a reduction of an AD-associated biomarker in the subject by day 5, 22, 25, 29 or 36, and the AD-associated biomarker is selected from one or both of TARC or serum IgE.

144. A pharmaceutical composition comprising an anti-IL-4R antibody or antigen-binding fragment thereof for use in improving an AD-related parameter or for reducing the level of an AD-related biomarker in a subject, administered sequentially to a subject as a single initial dose followed by one or more secondary doses.

145. 145. The pharmaceutical composition of claim 144, wherein the pharmaceutical composition comprises between 75 mg and 600 mg of the antibody or antigen-binding fragment thereof.

146. The pharmaceutical composition of claim 145, wherein the pharmaceutical composition comprises 300 mg of the antibody or antigen-binding fragment thereof.

147. 147. The pharmaceutical composition of any one of claims 144 to 146, wherein the one or more second doses are administered weekly.

148. The pharmaceutical composition according to any one of claims 139 to 147, wherein the pharmaceutical composition is administered subcutaneously or intravenously.

149. The antibody or antigen-binding fragment thereof is selected from the group consisting of SEQ ID NOs: 2 / 10, 18 / 20, 22 / 24, 26 / 34, 42 / 44, 46 / 48, 50 / 58, 66 / 68, 70 / 72, 74 / 82, 90 / 92, 94 / 96, 98 / 106, 114 / 116, 118 / 120, 122 / 130, 138 / 140, 142 / 144, 146 / 154, 162 / 164, 166 / 168, 170 / 178, 186 / 188, 149. The pharmaceutical composition of any one of claims 139 to 148, comprising heavy and light chain complementarity determining region (CDR) sequences derived from a heavy chain variable region (HCVR) / light chain variable region (LCVR) sequence pair selected from the group consisting of 190 / 192, 194 / 202, 210 / 212, 214 / 216, 218 / 226, 234 / 236, 238 / 240, 242 / 250, 258 / 260 and 262 / 264.

150. The pharmaceutical composition of claim 149, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR sequences derived from the HCVR / LCVR sequence pair of SEQ ID NOs: 162 / 164.

151. The pharmaceutical composition of claim 150, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining region (HCDR) sequences comprising SEQ ID NOs: 148, 150, 152, respectively, and three light chain complementarity determining region (LCDR) sequences comprising SEQ ID NOs: 156, 158 and 160, respectively.

152. The pharmaceutical composition of claim 151, wherein the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO: 162 and an LCVR having the amino acid sequence of SEQ ID NO: 164.

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