Methods of treating hand and foot dermatitis by administering IL-4R antagonist

Abstract

Methods for treating moderate to severe atopic dermatitis in hands and / or feet in a subject are provided. In one aspect, the method comprises administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody or an antigen-binding fragment thereof.

Description

[0001] Reference to the Sequence Listing XML

[0002] This application contains a Sequence Listing that has been electronically submitted in XML format. The Sequence Listing XML is incorporated herein by reference. The XML file, created on October 25, 2023, is named 40848_0117WOU1_SL.xml and is 267,878 bytes in size.

[0003] Cross - Reference to Related Applications

[0004] This application is filed as a PCT international patent application on November 1, 2023, and claims the priority of U.S. Provisional Patent Application No. 63 / 381,908, filed on November 1, 2022, and U.S. Provisional Patent Application No. 63 / 489,377, filed on March 9, 2023. The contents of these two provisional applications are hereby incorporated by reference in their entireties. Technical Field

[0005] The present disclosure relates to the use of interleukin - 4 receptor (IL - 4R) antagonists for the treatment of hand and / or foot dermatitis. Background Art

[0006] Hand - foot dermatitis is a general term that includes irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and patients with a history of concurrent atopic dermatitis (AD) or the presence of concurrent atopic dermatitis (also known as atopic hand - foot dermatitis) (Agner et al., J Eur Acad Dermatol Venereol, 2015, 29:2417 - 2422). The morphological types described in this condition include the following: vesicular (pompholyx), hyperkeratotic, fissured, and nummular (Menne et al., Contact Dermatitis, 2011, 65:3 - 12).

[0007] Compared with the general population, patients with atopic dermatitis (AD) have an increased risk of hand dermatitis of any etiology, with a three- to four-fold increased prevalence compared to controls (Ruff et al., Br J Dermatol, 2018, 178:879-888). The prevalence of hand dermatitis in AD patients has been reported to be approximately 60% (Simpson et al., Dermatitis, 2006, 17:123-127). Similarly, the prevalence of foot dermatitis in AD patients has been reported to be approximately 30% (Holm et al., J Eur Acad Dermatol Venereol, 2016, 30:1760-1767). Atopic dermatitis is a known risk factor for developing hand dermatitis, with approximately 28% of hand dermatitis patients having a history of AD (Petersen et al., Br J Dermatol, 2014, 171:1428-1433). Similarly, approximately 14% of foot dermatitis patients have a history of AD (Agner et al., J Eur Acad Dermatol Venereol, 2015, 29:2417-2422). Other atopic conditions such as allergic rhinitis and asthma are also associated with atopic hand and foot dermatitis (Scalone et al., Br J Dermatol, 2015, 172:187-195).

[0008] Atopic hand dermatitis (also known as atopic hand eczema) presents as erythema, infiltration, desquamation, vesicles, hyperkeratotic areas, and fissures (rhagades) (Coenraads, N Engl J Med, 2012, 367:1829-1837). The lesions are accompanied by significant itching and pain. The morphology often evolves over time, and many patients can have a mixed presentation. In most patients, the same morphological subtypes are found on the hands and feet (Brans et al., Contact Dermatitis, 2015, 73:100-107). This disease tends to be chronic and refractory, has a substantial impact on quality of life (QoL), and is comparable to other skin diseases such as psoriasis (Agner et al., Contact Dermatitis, 2008, 59:43-47). Chronic hand dermatitis is also associated with significant adverse effects on work productivity, mobility impairment, and healthcare costs (Fowler et al., J Am Acad Dermatol, 2006, 54:448-457). It has been shown that 65% of patients with severe hand dermatitis report loss of productivity at work, an average of 10.1 days per patient per month (Politiek et al., Contact Dermatitis, 2016, 75:67-76). In addition, in certain occupations (such as barbers, bakers, and machine workers), up to 18% of patients have to change jobs due to hand dermatitis (Meding et al., Contact Dermatitis, 2005, 65:3-12).

[0009] It is known that severe atopic hand and foot dermatitis can be particularly difficult to treat. The management of hand and foot dermatitis is based on preventive and avoidance strategies, reducing exposure to irritants, and regular use of emollients. Step therapy is used in conjunction with topical treatment as the initial approach, and then progresses to systemic treatment in cases where the response to topical treatment is inadequate (Diepgen et al., Contact Dermatitis, 2007, 57:203 - 210). Short - term topical corticosteroids (TCS) are recommended as the first - line treatment for controlling exacerbations. Long - term application of TCS carries the risks of skin atrophy, dyschromia, acneiform eruptions, as well as risks associated with systemic absorption (e.g., growth retardation, hypothalamic - pituitary axis effects, etc.). Treatment guidelines for hand dermatitis of any etiology recommend continuous long - term treatment for more than 6 weeks only when necessary and under careful medical supervision. For patients with hand and foot AD who require long - term treatment, topical calcineurin inhibitors can be considered, although the evidence for their efficacy is limited. The limited efficacy of topical anti - inflammatory agents is explained by the low permeability / penetration through the hand and foot skin. Overnight occlusion can be advocated to allow sufficient penetration of topical anti - inflammatory drugs. However, in the long run, these measures are often impractical and cumbersome for patients. Currently, there is no systemic treatment specifically approved for hand and foot atopic dermatitis in the United States. Summary of the Invention

[0010] In one aspect, a method for treating hand and / or foot atopic dermatitis is provided. In some embodiments, the method comprises:

[0011] selecting a subject having moderate to severe hand and / or foot atopic dermatitis, wherein the subject has a baseline hand and foot Investigator's Global Assessment (IGA) overall score ≥ 3, and wherein the patient has a history of inadequate response to topical medications for atopic hand and / or foot dermatitis, or the patient is a patient for whom topical treatment of atopic hand and / or foot dermatitis is not medically recommended; and

[0012] administering to the subject one or more doses of an interleukin - 4 receptor (IL - 4R) antagonist.

[0013] In some embodiments, the method comprises:

[0014] selecting a subject having moderate to severe hand and / or foot AD, wherein the subject is selected based on a hand and foot mTLSS ≥ 16; and

[0015] administering to the subject one or more doses of an interleukin - 4 receptor (IL - 4R) antagonist.

[0016] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, e.g., comprising one or more of the CDR, HCVR, and / or LCVR sequences listed in Table 9. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0017] In some embodiments, the subject's baseline IGA hand-foot overall score is 4. In some embodiments, the subject has an inadequate response to topical corticosteroid (TCS) treatment of moderate or higher potency. In some embodiments, the subject has a history of prior use of one or more systemic immunosuppressants.

[0018] In some embodiments, the subject's baseline hand-foot peak pruritus numeric rating score (NRS) ≥ 4.

[0019] In some embodiments, the subject is an adult. In some embodiments, the subject is an adult who has had chronic atopic dermatitis of the hands and / or feet for at least 3 years.

[0020] In some embodiments, the subject is an adolescent. In some embodiments, the subject is an adolescent who has had chronic atopic dermatitis of the hands and / or feet for at least one year.

[0021] In some embodiments, the subject does not have irritant contact dermatitis or allergic contact dermatitis.

[0022] In some embodiments, the subject does not have atopic dermatitis lesions on body sites other than the hands and / or feet. In some embodiments, the subject has mild atopic dermatitis on the body other than the hands and / or feet. In some embodiments, the subject has moderate to severe atopic dermatitis on the body other than the hands and / or feet.

[0023] In some embodiments, the hand-foot score of the subject's modified total lesion severity score (mTLSS) ≥ 16, e.g., ≥ 20 or ≥ 24. In some embodiments, the baseline atopic dermatitis affecting the hand-foot area of the subject is at least 24%.

[0024] In some embodiments, the atopic dermatitis of the subject involves a body surface area (BSA) score < 10% and / or an Eczema Area and Severity Index (EASI) score < 21.

[0025] In some embodiments, the subject has chronic dry and chapped hand and / or foot AD. In some embodiments, the subject has hyperkeratotic hand and / or foot AD. In some embodiments, the subject has pompholyx hand and / or foot AD.

[0026] In some embodiments, the IL-4R antagonist is administered at a dose of about 50 mg to about 600 mg. In some embodiments, the IL-4R antagonist is administered at an initial dose of 100 mg - 600 mg, followed by one or more subsequent doses of 50 mg - 300 mg. In some embodiments, the IL-4R antagonist is administered subcutaneously at an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg subcutaneously. In other embodiments, the IL-4R antagonist is administered subcutaneously at an initial dose of 300 mg, followed by one or more subsequent doses of 300 mg subcutaneously. In some embodiments, the IL-4R antagonist is administered subcutaneously at an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg subcutaneously. In other embodiments, the IL-4R antagonist is administered subcutaneously at an initial dose of 200 mg, followed by one or more subsequent doses of 200 mg subcutaneously. In some embodiments, each subsequent dose is administered one or two weeks after the immediately preceding dose.

[0027] In some embodiments, the subject is an adolescent with a baseline body weight ≥ 60 kg, and the IL-4R antagonist is administered subcutaneously at an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q2W subcutaneously.

[0028] In some embodiments, the subject is an adolescent with a baseline body weight < 60 kg, and the IL-4R antagonist is administered subcutaneously at an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg Q2W subcutaneously.

[0029] In some embodiments, the subject is an adult, and the IL-4R antagonist is administered subcutaneously at an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q2W subcutaneously.

[0030] In some embodiments, the IL-4R antagonist is administered for at least 16 weeks.

[0031] In some embodiments, the IL-4R antagonist is administered in combination with an emollient. In some embodiments, the IL-4R antagonist is administered in combination with a topical AD drug. In some embodiments, the topical AD drug is TCS.

[0032] In some embodiments, treatment with an IL-4R antagonist results in a subject achieving an IGA hand-foot score of 0 or 1 at week 16 after administration of the first dose of the IL-4R antagonist.

[0033] In some embodiments, treatment with an IL-4R antagonist results in an improvement selected from the group consisting of:

[0034] At week 16 after administration of the first dose of the IL-4R antagonist, the peak hand-foot pruritus NRS score is reduced by ≥4 points relative to the subject's baseline peak hand-foot pruritus NRS score;

[0035] At week 16 after administration of the first dose of the IL-4R antagonist, the hand-foot mTLSS score is reduced by at least 50% relative to the subject's baseline hand-foot mTLSS score;

[0036] At week 16 after administration of the first dose of the IL-4R antagonist, the peak hand-foot pruritus NRS score is reduced by at least 50% relative to the subject's baseline peak hand-foot pruritus NRS score;

[0037] At week 16 after administration of the first dose of the IL-4R antagonist, the peak hand-foot pain NRS score is reduced by ≥4 points relative to the subject's baseline peak hand-foot pain NRS score;

[0038] At week 16 after administration of the first dose of the IL-4R antagonist, the hand eczema severity index (HECSI) score is reduced by at least 50% relative to the subject's baseline HECSI score;

[0039] Achieve HECSI-75 at week 16 after administration of the first dose of the IL-4R antagonist;

[0040] At week 16 after administration of the first dose of the IL-4R antagonist, the percentage of the hand and foot surface area affected by AD is reduced by at least 15% relative to the subject's baseline percentage of the hand and foot surface area affected by AD; and

[0041] At week 16 after administration of the first dose of the IL-4R antagonist, the hand eczema quality of life questionnaire (QoLHEQ) score is reduced by at least 40% relative to the subject's baseline QoLHEQ score.

[0042] In some embodiments, treatment with an IL-4R antagonist reduces the need for rescue therapy.

[0043] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:9 and a light chain having the amino acid sequence of SEQ ID NO:10. In some embodiments, the IL-4R antagonist is dupilumab.

[0044] In some embodiments, the IL-4R antagonist is contained in a container selected from the group consisting of: glass vials, syringes, pre-filled syringes, pen delivery devices, and auto-injectors. In some embodiments, the IL-4R antagonist is contained in a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose pre-filled syringe. In some embodiments, the IL-4R antagonist is contained in a pen delivery device. In some embodiments, the IL-4R antagonist is contained in an auto-injector.

[0045] In another aspect, there is provided a pharmaceutical composition for treating atopic dermatitis of the hands and / or feet. In some embodiments, the pharmaceutical composition comprises an interleukin-4 receptor (IL-4R) antagonist. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof, e.g., comprising one or more of the CDR, HCVR, and / or LCVR sequences listed in Table 9. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0046] In another aspect, the present disclosure provides interleukin-4 receptor (IL-4R) antagonists for use in preparing a medicament for treating atopic dermatitis of the hand and / or foot. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, e.g., comprising one or more of the CDR, HCVR, and / or LCVR sequences listed in Table 9. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3, HCDR2 comprises the amino acid sequence of SEQ ID NO:4, HCDR3 comprises the amino acid sequence of SEQ ID NO:5, LCDR1 comprises the amino acid sequence of SEQ ID NO:6, LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence of SEQ ID NO:8.

[0047] Other embodiments will be apparent from reading the following detailed description. Detailed Description

[0048] Definitions

[0049] Before describing the present 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 should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present invention will be limited only by the appended claims.

[0050] All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined.

[0051] As used herein, when referring to a specifically recited numerical value, the term "about" means that the value may vary from the recited value by no more than 1%. By way of 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.).

[0052] As used herein, the terms "treat", "treating", etc. mean to relieve symptoms, eliminate the cause of the symptoms, or prevent or slow the appearance of symptoms of the condition or disorder, either temporarily or permanently.

[0053] As used herein, "atopic dermatitis" or "AD" refers to an inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and squamous and dry eczematous lesions. The terms "hand-foot atopic dermatitis", "hand and / or foot atopic dermatitis", "hand-foot AD", "hand and / or foot AD", and "atopic dermatitis of the hand and / or foot" refer to atopic dermatitis localized to one or both hands and / or one or both feet. In some embodiments, a subject with atopic dermatitis localized to the hand and / or foot has one or more symptoms of atopic dermatitis in other parts of the body. In some embodiments, a subject with atopic dermatitis localized to the hand and / or foot does not have symptoms (e.g., lesions) of atopic dermatitis in other parts of the body.

[0054] As used herein, the term "subject in need" refers to a human or non-human animal having hand and / or foot atopic dermatitis (e.g., moderate to severe hand and / or foot AD, or severe hand and / or foot AD). In some embodiments, the term "subject in need" refers to an adult patient. In some embodiments, the term "subject in need" refers to an adolescent patient who is ≥12 years old and <18 years old. The terms "subject" and "patient" are used interchangeably herein.

[0055] As used herein, the term "TCS" includes Group I, II, III, and IV topical corticosteroids. According to the World Health Organization's Anatomical Therapeutic Chemical Classification System, corticosteroids are classified as weak (Group I), moderately potent (Group II), 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 as potent as hydrocortisone and include clobetasol propionate and halcinonide. Group III TCS (potent) are 50 to 100 times as potent as hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone 17-butyrate, mometasone furoate, and methylprednisolone aceponate. Group II TCS (moderately potent; also interchangeably referred to herein as "medium potency") are 2 to 25 times as potent as hydrocortisone and include, but are not limited to, clobetasone butyrate and triamcinolone acetonide. Group I TCS (mild; also interchangeably referred to herein as "low potency") includes hydrocortisone.

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

[0057] Treatment methods

[0058] In one aspect, methods are provided for treating hand and / or foot atopic dermatitis (AD) in a subject or improving hand and / or foot AD-related parameters in a subject. In some embodiments, the methods include administering to a subject having moderate to severe hand and / or foot AD one or more doses of an interleukin-4 receptor (IL-4R) antagonist.

[0059] In some embodiments, a method for treating a subject having hand and / or foot AD includes:

[0060] (a) Selecting a subject based on having one or more of the following characteristics:

[0061] (i) A baseline IGA hand and foot score ≥ 3 (e.g., an IGA hand and foot score of 4);

[0062] (ii) A baseline mTLSS hand and foot score ≥ 16;

[0063] (iii) A baseline hand and foot peak pruritus NRS ≥ 4 (e.g., a hand and foot peak pruritus NRS score ≥ 6); (iv) A baseline hand and foot peak pain NRS ≥ 6;

[0064] (v) A baseline sleep NRS ≥ 5; and / or

[0065] (vi) A baseline atopic dermatitis involvement of the hands and feet area of at least 24% (e.g., at least 25%, at least 30%, at least 35% or more);

[0066] (b) Administering to the subject identified in step (a) one or more doses of an IL-4R antagonist.

[0067] In some embodiments, a method for treating a subject having hand and / or foot AD includes:

[0068] (a) Selecting a subject based on having one or more of the following characteristics:

[0069] (i) A baseline IGA hand and foot score ≥ 3 (e.g., an IGA hand and foot score of 4);

[0070] (ii) A baseline mTLSS hand and foot score ≥ 16;

[0071] (iii) A baseline hand and foot peak pruritus NRS ≥ 4 (e.g., a hand and foot peak pruritus NRS score ≥ 6); (iv) A baseline hand and foot peak pain NRS ≥ 6;

[0072] (v) A baseline sleep NRS ≥ 5; and / or

[0073] (vi) A baseline atopic dermatitis involvement of the hands and feet area of at least 24% (e.g., at least 25%, at least 30%, at least 35% or more);

[0074] (b) Select the subjects identified in step (a) based on an overall BSA score < 25% (e.g., < 20%, < 15% or < 10%), an overall IGA ≤ 2 and / or an overall EASI < 21 (e.g., < 16); and

[0075] (c) Administer to the subjects identified in step (b) one or more doses of an IL-4R antagonist.

[0076] In some embodiments, the subject has chronic hand and / or foot dermatitis. In some embodiments, the subject was diagnosed with chronic hand and / or foot dermatitis at least 3 years before the start of treatment in patients ≥ 18 years old, or at least 1 year before the start of treatment in patients ≥ 12 years old to < 18 years old.

[0077] In some embodiments, the subject has only moderate to severe hand atopic dermatitis. In some embodiments, the subject has only moderate to severe foot atopic dermatitis. In some embodiments, the subject has moderate to severe hand and foot atopic dermatitis.

[0078] In some embodiments, the subject has at least two hand / foot anatomical regions with moderate to severe disease, e.g., both hands, one hand and one foot, or both feet. In some embodiments, the disease severity of the hand / foot anatomical regions is evaluated by the IGA hand / foot score, e.g., evaluated by the hand / foot IGA tool in Table 2. In some embodiments, the baseline IGA hand / foot score of the subject to be treated is ≥ 3, e.g., the IGA hand / foot score is 3 or the IGA hand / foot score is 4. In some embodiments, the baseline IGA hand / foot scores of at least 2 hand / foot anatomical regions of the subject to be treated are each ≥ 3 (i.e., the IGA hand / foot score is 3 or 4). In some embodiments, the disease severity of the hand / foot anatomical regions is evaluated by the modified total lesion sign score (mTLSS) of the hand and foot. In some embodiments, the baseline mTLSS hand / foot score of the subject to be treated is ≥ 16. In some embodiments, for each mTLSS characteristic of erythema, desquamation / flaking, lichenification, vesiculation / erosion, edema, and fissure in the total mTLSS hand score, the baseline score of the subject to be treated is 2 or 3. In some embodiments, for each mTLSS characteristic of erythema, desquamation / flaking, lichenification, vesiculation / erosion, edema, and fissure in the total mTLSS foot score, the baseline score of the subject to be treated is 2 or 3. In some embodiments, for each mTLSS characteristic of erythema, desquamation / flaking, lichenification, vesiculation / erosion, edema, and fissure in the total mTLSS hand / foot score, the baseline score of the subject to be treated is 2 or 3.

[0079] In some embodiments, the baseline hand and foot peak pruritus numerical rating scale (NRS) score of the subject is ≥4. In some embodiments, the baseline hand and foot peak pruritus NRS score of the subject is ≥6.

[0080] In some embodiments, the subject to be treated according to the methods disclosed herein is a subject with moderate to severe hand and / or foot AD who has an inadequate response to topical therapies (e.g., TCS with or without topical calcineurin inhibitor [TCI]), or for whom topical therapies are not recommended (e.g., due to intolerance, adverse side effects, or safety risks). In some embodiments, the subject has an inadequate response to high-potency TCS, or the subject is a subject for whom high-potency TCS is not recommended. As used herein, "inadequate response" to a topical therapy means failure to achieve and maintain remission or low disease activity, as determined by the clinical judgment of the treating physician, despite treatment with a daily regimen of moderate to higher-potency TCS (± topical calcineurin inhibitor [TCI], as appropriate) for at least 28 days or the longest duration recommended by the product prescribing information (e.g., 14 days for ultra-high-potency TCS), whichever is shorter.

[0081] In some embodiments, a subject is considered to have an "inadequate response" to a topical therapy if the subject has a recent history (e.g., within 3 months or within 6 months) of treatment with a systemic immunosuppressant (e.g., cyclosporine, methotrexate, systemically administered corticosteroids, alitretinoin, etc.) for atopic hand and / or foot dermatitis.

[0082] In some embodiments, the subject is a subject for whom topical therapies (e.g., high-potency TCS) are not recommended. In some embodiments, the subject exhibits intolerance to topical therapies (e.g., TCS such as high-potency TCS). In some embodiments, the subject has a history of adverse side effects or safety risks associated with topical therapies (e.g., TCS such as high-potency TCS). As evaluated by the investigator or the treating physician of the patient, the adverse side effects or safety risks of treating atopic hand and / or foot dermatitis are those adverse side effects or safety risks that exceed the potential therapeutic benefits and include intolerance to the treatment, hypersensitivity reactions, marked hand and foot skin atrophy, and systemic effects.

[0083] In some embodiments, the subject does not have allergic contact dermatitis. In some embodiments, the subject does not have irritant contact dermatitis. In some embodiments, the subject does not have protein contact dermatitis. In some embodiments, the subject undergoes a patch test (e.g., with a standard allergen series, e.g., the American Contact Dermatitis Society Core Allergen Series, the European Baseline Series, the Australian Baseline Series, a patch test panel, or a Thin-Layer Rapid Use Epicutaneous (TRUE) patch test) before starting treatment to confirm that the subject does not have allergic contact dermatitis. In some embodiments, the subject to be treated is selected based on the absence of allergic contact dermatitis, or based on a negative patch test to confirm that the subject does not have allergic contact dermatitis.

[0084] In some embodiments, the subject does not have atopic dermatitis lesions on body parts other than the hands and / or feet. In some embodiments, the subject experiences exacerbation of AD lesions on body parts other than the hands and / or feet. In some embodiments, the subject has AD lesions on body parts other than the hands and / or feet (e.g., more than 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the body other than the hands and / or feet). In some embodiments, a subject with atopic hand and / or foot dermatitis also has AD lesions on body parts other than the hands and / or feet, but has a low overall BSA score (e.g., less than 20%, less than 15%, or less than 10%) over the entire body. In some embodiments, a subject with atopic hand and / or foot dermatitis also has AD lesions on body parts other than the hands and / or feet, but has a low total body EASI (i.e., the overall EASI over the entire body), e.g., EASI < 21, or EASI < 16. In some embodiments, a subject with atopic hand and / or foot dermatitis also has AD lesions on body parts other than the hands and / or feet, but has a low total body IGA (i.e., the overall IGA over the entire body), e.g., IGA ≤ 2, or IGA < 2.

[0085] In some embodiments, the subject to be treated has a BSA score < 10%. In some embodiments, the subject to be treated has an EASI < 21. In some embodiments, the subject to be treated has an IGA ≤ 2. In some embodiments, the subject to be treated has a BSA score < 10% and an EASI < 21. In some embodiments, the subject to be treated has a BSA score < 10% and an IGA ≤ 2. In some embodiments, the subject to be treated has a BSA score < 10%, an EASI < 21, and an IGA ≤ 2.

[0086] In some embodiments, the subject has chronic dry cracked hand and / or foot AD. In some embodiments, the subject has hyperkeratotic hand and / or foot AD. In some embodiments, the subject has pompholyx hand and / or foot AD.

[0087] In some embodiments, the subject is ≥12 years old. In some embodiments, the subject is an adult. In some embodiments, the subject is an adolescent who is ≥12 years old and <17 years old.

[0088] In some embodiments, the subject to be treated has or has had an accompanying type 2 inflammatory disorder. As used herein, "type 2 inflammatory disorder" is a disease, condition, or disorder associated with a T helper cell 2 (Th2)-mediated immune response (Gandhi et al., Nat Rev Drug Discov., 2016, 15(1):35-50). Non-limiting examples of type 2 inflammatory disorders include asthma, chronic rhinosinusitis, allergic rhinitis, allergic fungal rhinosinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), unified airway disease, eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), gastroesophageal reflux disease (GERD), atopic conjunctivitis, atopic dermatitis, vasculitis, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps (CRSwNP), aspirin hypersensitivity, non-steroidal anti-inflammatory drug (NSAID) hypersensitivity (e.g., NSAID-exacerbated respiratory disease or NSAID-ERD), perennial allergic rhinitis (PAR), chronic eosinophilic pneumonia (CEP), and exercise-induced bronchospasm. In some embodiments, the subject has an accompanying atopic disease or disorder selected from the group consisting of food allergy, atopic dermatitis, asthma, chronic rhinosinusitis, allergic rhinitis, or allergic conjunctivitis.

[0089] In some embodiments, treatment with an IL-4R antagonist improves, alleviates, or reduces one or more symptoms of the subject's hand and / or foot AD, the symptoms including but not limited to pruritus, xerosis (dry skin), eczematous lesions, erythema, papule formation, edema, exudation / crusting, epidermal exfoliation, lichenification, sleep disturbance, anxiety, and depression.

[0090] In some embodiments, treatment with an IL-4R antagonist improves one or more AD-related parameters in a subject. Examples of "AD-related parameters" include, but are not limited to: Investigator's Global Assessment (IGA) of hands and feet; Modified Total Lesion Severity Score (mTLSS) of hands and feet; Numerical Rating Scale (NRS) for pruritus of hands and feet; NRS for skin pain of hands and feet; NRS for sleep; Atopic dermatitis area affecting hands and feet; Dermatology Life Quality Index (DLQI); Patient's Global Impression of Severity (PGIS); Patient's Global Impression of Change (PGIC); Hospital Anxiety and Depression Scale (HADS); Hand Eczema Severity Index (HECSI); Hand Eczema Quality of Life Questionnaire (QoLHEQ); Patient-Oriented Eczema Measure (POEM); Eczema Area and Severity Index (EASI); Investigator's Global Assessment (IGA); Atopic dermatitis area affecting body surface area (BSA); Patient-assessed EQ-5D; and Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questionnaire (WPAI+CIQ). "Improvement of an AD-related parameter" means an improvement (e.g., decrease) of one or more parameters (e.g., IGA of hands and feet, mTLSS of hands and feet, NRS for pruritus of hands and feet, NRS for skin pain of hands and feet, etc.) relative to baseline. The term "baseline" with respect to an AD-related parameter means the numerical value of the AD-related parameter of the subject before administration of the pharmaceutical composition disclosed herein or at the start of administration of the pharmaceutical composition disclosed herein. In some embodiments, the AD-related parameter is a measurement (e.g., questionnaire) specific to the assessment of the hands and / or feet. In some embodiments, the AD-related parameter is a measurement (e.g., questionnaire) based on general AD (i.e., not specific only to the hands and / or feet).

[0091] To determine whether an AD-related parameter has "improved", the parameter is quantified at baseline and at one or more time points after administration of the pharmaceutical composition of the present disclosure. For example, the AD-related parameter can be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85 after initial treatment with the pharmaceutical composition of the present disclosure; or at the end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24 or longer. The difference between the parameter value at a specific time point after the start of treatment and the parameter value at baseline is used to determine whether there is an "improvement" (e.g., decrease) in the AD-related parameter. The AD-related parameters are described in U.S. Patent Publication No. US2014 / 0072583, which is incorporated herein in its entirety.

[0092] In some embodiments, the AD-related parameters are evaluated by the patient. In some embodiments, the AD-related parameters are evaluated by a physician or caregiver.

[0093] In some embodiments, subjects with hand and / or foot AD are selected for treatment based on having one or more of the following characteristics:

[0094] (i) Baseline IGA hand-foot score ≥ 3 (e.g., IGA hand-foot score of 4);

[0095] (ii) Baseline mTLSS hand-foot score ≥ 16;

[0096] (iii) Baseline hand-foot peak pruritus NRS ≥ 4 (e.g., hand-foot peak pruritus NRS score ≥ 6);

[0097] (iv) Baseline hand-foot peak pain NRS ≥ 6;

[0098] (v) Baseline sleep NRS ≥ 5; and / or

[0099] (vi) Baseline atopic dermatitis involvement of the hands and feet is at least 24% (e.g., at least 25%, at least 30%, at least 35% or more).

[0100] In some embodiments, subjects with hand and / or foot AD are selected for treatment based on having one or more of the above characteristics (i) to (vi), and are further selected based on an overall (i.e., total body) BSA score < 25% (e.g., < 20%, < 15% or < 10%) and / or an overall EASI < 21 (e.g., < 16).

[0101] In some embodiments, subjects with hand and / or foot AD are selected for treatment based on a baseline mTLSS hand-foot score ≥ 16. In some embodiments, subjects with hand and / or foot AD are selected for treatment based on a baseline mTLSS hand-foot score ≥ 16 and a baseline atopic dermatitis involvement of the hands and feet of at least 24%. In some embodiments, subjects with hand and / or foot AD are selected for treatment based on a baseline mTLSS hand-foot score ≥ 16 and one or more of a baseline hand-foot peak pruritus NRS ≥ 4, a baseline hand-foot peak pain NRS ≥ 6, or a baseline sleep NRS ≥ 5.

[0102] In some embodiments, subjects with hand and / or foot AD are selected for treatment based on a baseline mTLSS hand / foot score ≥ 16 and an overall BSA score < 25%. In some embodiments, subjects with hand and / or foot AD are selected for treatment based on a baseline mTLSS hand / foot score ≥ 16, a baseline atopic dermatitis involvement of the hands and feet of at least 24%, and an overall BSA score < 25%. In some embodiments, subjects with hand and / or foot AD are selected for treatment based on one or more of a baseline mTLSS hand / foot score ≥ 16; a baseline hand / foot peak pruritus NRS ≥ 4, a baseline hand / foot peak pain NRS ≥ 6, or a baseline sleep NRS ≥ 5, and an overall BSA score < 25%.

[0103] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the IGA hand / foot score of the subject relative to baseline. The method for determining the IGA hand / foot score of a subject is described in the Examples section and Table 2 below. In some embodiments, the baseline IGA hand / foot score of the subject to be treated is ≥ 3 (e.g., the IGA hand / foot score is 3 or the IGA hand / foot score is 4). In some embodiments, subjects are selected for treatment based on a baseline IGA hand / foot score ≥ 3 (e.g., the IGA hand / foot score is 3 or the IGA hand / foot score is 4). In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the IGA hand / foot score of at least 1 point relative to baseline (e.g., relative to a baseline IGA hand / foot score ≥ 3 or a baseline IGA hand / foot score = 4). In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease to an IGA hand / foot score of 0 or 1 relative to baseline (e.g., relative to an IGA hand / foot score ≥ 3 or an IGA hand / foot score = 4).

[0104] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the mTLSS hand-foot score of a subject relative to baseline. The method for determining the mTLSS hand-foot score of a subject is described in the Examples section below and in Table 1. In some embodiments, the baseline mTLSS hand-foot score of the subject to be treated is ≥16. In some embodiments, subjects are selected for treatment based on a baseline mTLSS hand-foot score ≥16. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the mTLSS hand-foot score relative to baseline of at least 2 points, at least 3 points, at least 4 points, at least 5 points, or more. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the mTLSS hand-foot score relative to baseline of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90%.

[0105] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the peak hand-foot pruritus NRS score of a subject relative to baseline. The method for determining the peak hand-foot pruritus NRS score of a subject is described in the Examples section below. In some embodiments, the peak hand-foot pruritus NRS score is the weekly average of the daily peak hand-foot pruritus NRS scores. In some embodiments, the baseline peak hand-foot pruritus NRS of the subject to be treated is ≥4. In some embodiments, subjects are selected for treatment based on a baseline peak hand-foot pruritus NRS ≥4. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the peak hand-foot pruritus NRS score relative to baseline of at least 1 point, 2 points, 3 points, or 4 points. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the peak hand-foot pruritus NRS score relative to baseline of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90%.

[0106] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in improvement in the peak hand and foot pain NRS score of a subject relative to baseline. The method for determining the peak hand and foot pain NRS score of a subject is described in the Examples section below. In some embodiments, the peak hand and foot pain NRS score is the weekly average of the daily peak hand and foot itch NRS scores. In some embodiments, the baseline peak hand and foot pain NRS of the subject to be treated is ≥6. In some embodiments, subjects are selected for treatment based on a baseline peak hand and foot pain NRS ≥6. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the peak hand and foot pain NRS score of at least 1 point, 2 points, 3 points, or 4 points relative to baseline. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the peak hand and foot pain NRS score of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% relative to baseline.

[0107] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in improvement in the sleep NRS score of a subject relative to baseline. The method for determining the sleep NRS score of a subject is described in the Examples section below. In some embodiments, the sleep NRS score is the weekly average of the daily sleep NRS scores. In some embodiments, the baseline sleep NRS of the subject to be treated is ≥5. In some embodiments, subjects are selected for treatment based on a baseline sleep NRS ≥5. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the sleep NRS score of at least 1 point relative to baseline. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the sleep NRS score of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% relative to baseline.

[0108] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in improvement in the atopic dermatitis involvement of the hands and feet area score of a subject relative to baseline (e.g., a decrease in the percentage of the AD-involved hand and foot surface area). In some embodiments, the baseline atopic dermatitis involvement of the hands and feet area of the subject to be treated is at least 24%, e.g., at least 25%, at least 30%, at least 35% or higher. In some embodiments, subjects are selected for treatment based on a baseline atopic dermatitis involvement of the hands and feet area of at least 24% (e.g., at least 25%, at least 30%, at least 35% or more). In some embodiments, by week 3, week 4, week 8, week 12 or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a decrease in the hand and foot surface area affected by AD of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50% or at least 60% relative to baseline.

[0109] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the Hand Eczema Severity Index (HECSI) score of a subject relative to baseline. The method for determining the HECSI score of a subject is described in the Examples section below. In some embodiments, the baseline HECSI score of the subject to be treated is ≥46, for example, at least 50, at least 55, at least 60, at least 65, at least 70 or higher. In some embodiments, subjects are selected for treatment based on a baseline HECSI score ≥46 (e.g., at least 50, at least 55, at least 60, at least 65, at least 70 or higher). In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a reduction in the HECSI score of at least 15, 20, 25, 30 or more points relative to baseline. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in a reduction in the HECSI score of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80% or at least 90% relative to baseline. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in the subject achieving HECSI-50 (i.e., a reduction in the HECSI score of at least 50%). In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in the subject achieving HECSI-75 (i.e., a reduction in the HECSI score of at least 75%). In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in the subject achieving HECSI-90 (i.e., a reduction in the HECSI score of at least 90%).

[0110] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the health-related quality of life of a subject relative to baseline, e.g., as measured by DLQI or QoLHEQ. In some embodiments, by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist, treatment with the IL-4R antagonist results in an improvement in the health-related quality of life measurement of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80% or at least 90% relative to baseline.

[0111] In some embodiments, treatment with an IL-4R antagonist reduces the need for rescue therapy (e.g., for exacerbations of AD, for lesions that persist or worsen under routine treatment, or for intolerable symptoms). In some embodiments, treatment with an IL-4R antagonist reduces the need for topical rescue therapy (e.g., topical corticosteroids such as mid-potency TCS or high-potency TCS, TCI, crisaborole, or topical JAK inhibitors). In some embodiments, treatment with an IL-4R antagonist reduces the need for systemic rescue therapy (e.g., systemic corticosteroids or systemic immunosuppressants).

[0112] Interleukin-4 receptor antagonist

[0113] In some embodiments, the methods of the present disclosure include administering to a subject in need thereof (e.g., a subject having moderate to severe hand and / or foot atopic dermatitis) an interleukin-4 receptor (IL-4R) antagonist or a pharmaceutical composition comprising an IL-4R antagonist. As used herein, an "IL-4R antagonist" (also referred to herein as an "IL-4R inhibitor", "IL-4R blocker", or "IL-4Rα antagonist") is any agent that binds to or interacts with IL-4Rα or an IL-4R ligand and inhibits or attenuates the normal biological signaling function of the type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO:11. The type 1 IL-4 receptor is a dimer receptor comprising an IL-4Rα chain and a γc chain. The type 2 IL-4 receptor is a dimer receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. The type 1 IL-4 receptor interacts with and is stimulated by IL-4, while the type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, an IL-4R antagonist that can be used in the methods of the present disclosure can act by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4-mediated signaling and IL-13-mediated signaling. Accordingly, the IL-4R antagonists of the present disclosure can prevent the interaction of IL-4 and / or IL-13 with the type 1 receptor or the type 2 receptor.

[0114] Non-limiting examples of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptibodies" (e.g., engineered molecules comprising the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, an IL-4R antagonist also includes an antigen-binding protein that specifically binds to IL-4 and / or IL-13.

[0115] Anti-IL-4Rα Antibodies and Antigen-Binding Fragments Thereof

[0116] In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. As used herein, the term "antibody" includes an immunoglobulin molecule comprising four polypeptide chains (two heavy (H) chains and two light (L) chains) interconnected by disulfide bonds and multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H ) and a heavy chain constant region. The heavy chain constant region comprises three domains: C H 1, C H 2, and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and a light chain constant region. The light chain constant region comprises one domain (C L 1). The V H region and the V L region can be further subdivided into hypervariable regions known as complementarity-determining regions (CDRs), which are interspersed with more conserved regions known as framework regions (FRs). Each V H and V L is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-IL-4R antibody (or its antigen-binding portion) are identical to the germline sequences. In some embodiments, one or more FRs of the anti-IL-4R antibody (or its antigen-binding portion) are naturally modified or artificially modified.

[0117] The term "antibody" as used herein also includes antigen-binding fragments of the intact antibody molecule. The terms "antigen-binding portion of an antibody", "antigen-binding fragment of an antibody", etc. as used herein include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody can be derived from whole antibody molecules, for example, using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding the variable domains of the antibody and optionally the constant domains of the antibody. Such DNA is known and / or can be readily obtained from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable domains and / or constant domains in a suitable configuration, or to introduce codons, generate cysteine residues, modify, add, or delete amino acids, etc.

[0118] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs) such as CDR3 peptides) or restricted FR3-CDR3-FR4 peptides. As used herein, other engineered molecules (such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetra-bodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains) are also encompassed by the term "antigen-binding fragment."

[0119] Antigen-binding fragments of an antibody generally include at least one variable domain. The variable domain can have any size or amino acid composition and will generally include at least one CDR that is contiguous or in-frame with one or more framework sequences. In antigen-binding fragments having a V H domain associated with a V L domain, the V H and V L domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer and contain V H -V H 、V H -V L or V L -V L dimers. Alternatively, the antigen-binding fragment of an antibody can contain a monomeric V H or V L domain.

[0120] In certain embodiments, the antigen-binding fragment of an antibody can contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found within the antigen-binding fragments of the antibodies of the present disclosure include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) VH -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C L . In any configuration of the variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains can be directly connected to each other or can be linked by a full-length or partial hinge or linker region. The hinge region can consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which results in a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. Additionally, antigen-binding fragments of the antibodies of the present disclosure can comprise homodimers or heterodimers (or other multimers) of each other and / or with one or more monomeric V H or V L domains (e.g., via disulfide bonds) that are non-covalently associated.

[0121] The constant region of an antibody is important for the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, in some embodiments, the isotype of the antibody can be selected based on whether antibody-mediated cytotoxicity is desired.

[0122] As used herein, the term "antibody" also encompasses multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies generally comprise at least two distinct variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Using conventional techniques available in the art, any form of multispecific antibody can be adapted to the context of the antibodies or antigen-binding fragments of antibodies of the present disclosure. For example, in some embodiments, the methods of the present disclosure include the use of bispecific antibodies, wherein one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or conjugated to a therapeutic moiety. Exemplary bispecific forms that can be used in the context of the present disclosure include, but are not limited to, for example, scFv-based or diabody bispecific forms, IgG-scFv fusions, dual variable domain (DVD)-Ig, tetravalent hybridomas, knob-in-hole, common light chain (e.g., common light chain with knob-in-hole, etc.), CrossMab, CrossFab, (SEED)bodies, leucine zippers, Duobodies, IgG1 / IgG2, dual action Fab (DAF)-IgG, and Mab 2 Bispecific forms (for a review of the foregoing forms, see, e.g., Klein et al., 2012, mAbs, 4:6, 1-11, and references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugates, e.g., wherein unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates, which are then self-assembled into multimeric complexes with defined composition, valency, and geometry. (See, e.g., Kazane et al., J. Am. Chem. Soc. [e-pub: Dec. 4, 2012].).

[0123] In some embodiments, the antibodies used in the methods of the present disclosure are human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of the present disclosure can contain amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation), e.g., in the CDRs, and specifically, in CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto a human framework sequence.

[0124] The antibodies used in the disclosed methods can be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant combinatorial human antibody library (described further below), antibodies isolated from a transgenic animal (e.g., a mouse) having human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, created, or isolated by any other means that involves splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using a transgenic animal that is transgenic with respect to human Ig sequences, to in vivo somatic mutagenesis) and thus the amino acid sequences of the V H and V L regions, although derived from and related to human germline V H and V L sequences, may be sequences that do not naturally occur within the human antibody germline repertoire in vivo.

[0125] An "isolated antibody" means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally occurs or is naturally produced, is an "isolated antibody". Isolated antibodies also include antibodies in situ within recombinant cells. An isolated antibody is an antibody that has undergone at least one purification or isolation step. According to certain embodiments, an isolated antibody can be substantially free of other cellular material and / or chemicals.

[0126] According to certain embodiments, the antibodies used in the methods of the present disclosure specifically bind to IL-4Rα. As used herein, the term "specifically bind" as used herein means that an antibody or an antigen-binding fragment thereof forms a relatively stable complex with an antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, etc. In some embodiments, an antibody that "specifically binds" IL-4Rα binds to IL-4Rα or a portion thereof with an equilibrium dissociation constant (K D ) 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 1 nM, less than about 0.5 nM, less than about 0.25 nM, less than about 0.1 nM, or less than about 0.05 nM, as measured in a surface plasmon resonance assay (e.g., BIAcore TM , Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) may also specifically bind to another antigen, e.g., an ortholog of the target antigen. For example, in some embodiments, an isolated antibody that specifically binds human IL-4Rα exhibits cross-reactivity with other antigens, such as IL-4Rα molecules from other (non-human) species.

[0127] In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof, comprising a heavy-chain variable region (HCVR), a light-chain variable region (LCVR), and / or complementarity-determining regions (CDRs), the complementarity-determining regions comprising any of the amino acid sequences of the anti-IL-4R antibody listed in U.S. Patent No. 7,608,693, which patent is incorporated herein by reference. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof, comprising a heavy-chain complementarity-determining region (HCDR) having a heavy-chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light-chain complementarity-determining region (LCDR) having a light-chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof, comprising three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence GFTFRDYA (SEQ ID NO:3), HCDR2 comprises the amino acid sequence ISGSGGNT (SEQ ID NO:4), HCDR3 comprises the amino acid sequence AKDRLSITIRPRYYGLDV (SEQ ID NO:5), LCDR1 comprises the amino acid sequence QSLLYSIGYNY (SEQ ID NO:6), LCDR2 comprises the amino acid sequence LGS, and LCDR3 comprises the amino acid sequence MQALQTPYT (SEQ ID NO:8).

[0128] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCDR1 comprising the amino acid sequence GFTFRDYA (SEQ ID NO:3), an HCDR2 comprising the amino acid sequence ISGSGGNT (SEQ ID NO:4), an HCDR3 comprising the amino acid sequence AKDRLSITIRPRYYGLDV (SEQ ID NO:5), an LCDR1 comprising the amino acid sequence QSLLYSIGYNY (SEQ ID NO:6), an LCDR2 comprising the amino acid sequence LGS, and an LCDR3 comprising the amino acid sequence MQALQTPYT (SEQ ID NO:8), and further comprises an HCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO:1 and an LCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO:2. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises an HCVR having SEQ ID NO:1 and an LCVR having SEQ ID NO:2.

[0129] In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9. In some embodiments, the anti-IL-4R antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0130] An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10 is the fully human anti-IL-4R antibody called dupilumab. According to certain exemplary embodiments, the methods of the present disclosure include using dupilumab. As used herein, "dupilumab" also includes biogenerics of dupilumab. As used herein, the term "biogeneric" with respect to dupilumab refers to an anti-IL-4R antibody or IL-4R binding protein or fragment thereof that, when administered at the same molar dose (single or multiple doses) under similar experimental conditions, does not exhibit a significant difference in the rate and / or extent of absorption compared to dupilumab. In some embodiments, the term refers to an antigen-binding protein that binds to IL-4R and that does not have a clinically meaningful difference from dupilumab in terms of its safety, purity, and / or potency.

[0131] Other anti-IL-4Rα antibodies that can be used in the context of the methods of the present disclosure include, for example, the antibody known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or MEDI 9314, or any anti-IL-4Rα antibody listed in U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, U.S. Patent No. 8,877,189, U.S. Patent No. 10,774,141, or International Patent Publication Nos. WO2020 / 096381, WO 2020 / 182197, WO2020 / 239134, WO 2021 / 213329, WO2022 / 052974, WO2022 / 136669 or WO2022 / 136675, the content of each of said patents being incorporated herein by reference.

[0132] In some embodiments, the anti-IL-4Rα antibody or antigen-binding fragment thereof for use in the methods of the present disclosure comprises one or more of the CDR, HCVR and / or LCVR sequences listed in Table 9 below.

[0133] In some embodiments, the anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:32 (SCB-VH-59), SEQ ID NO:33 (SCB-VH-60), SEQ ID NO:34 (SCB-VH-61), SEQ ID NO:35 (SCB-VH-62), SEQ ID NO:36 (SCB-VH-63), SEQ ID NO:37 (SCB-VH-64), SEQ ID NO:38 (SCB-VH-65), SEQ ID NO:39 (SCB-VH-66), SEQ ID NO:40 (SCB-VH-67), SEQ ID NO:41 (SCB-VH-68), SEQ ID NO:42 (SCB-VH-69), SEQ ID NO:43 (SCB-VH-70), SEQ ID NO:44 (SCB-VH-71), SEQ ID NO:45 (SCB-VH-72), SEQ ID NO:46 (SCB-VH-73), SEQ ID NO:47 (SCB-VH-74), SEQ ID NO:48 (SCB-VH-75), SEQ ID NO:49 (SCB-VH-76), SEQ ID NO:50 (SCB-VH-77), SEQ ID NO:51 (SCB-VH-78), SEQ ID NO:52 (SCB-VH-79), SEQ ID NO:53 (SCB-VH-80), SEQ ID NO:54 (SCB-VH-81), SEQ ID NO:55 (SCB-VH-82), SEQ ID NO:56 (SCB-VH-83), SEQ ID NO:57 (SCB-VH-84), SEQ ID NO:58 (SCB-VH-85), SEQ ID NO:59 (SCB-VH-86), SEQ ID NO:60 (SCB-VH-87), SEQ ID NO:61 (SCB-VH-88), SEQ ID NO:62 (SCB-VH-89), SEQ ID NO:63 (SCB-VH-90), SEQ ID NO:64 (SCB-VH-91), SEQ ID NO:65 (SCB-VH-92) or SEQ ID NO:66 (SCB-VH-93);and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO:12 (SCB-VL-39), SEQ ID NO:13 (SCB-VL-40), SEQ ID NO:14 (SCB-VL-41), SEQ ID NO:15 (SCB-VL-42), SEQ ID NO:16 (SCB-VL-43), SEQ ID NO:17 (SCB-VL-44), SEQ ID NO:18 (SCB-VL-45), SEQ ID NO:19 (SCB-VL-46), SEQ ID NO:20 (SCB-VL-47), SEQ ID NO:21 (SCB-VL-48), SEQ ID NO:22 (SCB-VL-49), SEQ ID NO:23 (SCB-VL-50), SEQ ID NO:24 (SCB-VL-51), SEQ ID NO:25 (SCB-VL-52), SEQ ID NO:26 (SCB-VL-53), SEQ ID NO:27 (SCB-VL-54), SEQ ID NO:28 (SCB-VL-55), SEQ ID NO:29 (SCB-VL-56), SEQ ID NO:30 (SCB-VL-57), or SEQ ID NO:31 (SCB-VL-58). In some embodiments, the anti-IL-4Rα antibody comprises: an HCVR comprising the amino acid sequence of SEQ ID NO:64 (SCB-VH-91), and an LCVR comprising the amino acid sequence of SEQ ID NO:17 (SCB-VL-44), SEQ ID NO:27 (SCB-VL-54), or SEQ ID NO:28 (SCB-VL-55).;

[0134] In some embodiments, the anti-IL-4Rα antibody comprises an amino acid sequence pair selected from the group consisting of: SEQ ID NO:67 / 68 (MEDI-1-VH / MEDI-1-VL); SEQ ID NO:69 / 70 (MEDI-2-VH / MEDI-2-VL); SEQ ID NO:71 / 72 (MEDI-3-VH / MEDI-3-VL); SEQ ID NO:73 / 74 (MEDI-4-VH / MEDI-4-VL); SEQ ID NO:75 / 76 (MEDI-5-VH / MEDI-5-VL); SEQ ID NO:77 / 78 (MEDI-6-VH / MEDI-6 / VL); SEQ ID NO:79 / 80 (MEDI-7-VH / MEDI-7-VL); SEQ ID NO:81 / 82 (MEDI-8-VH / MEDI-8-VL); SEQ ID NO:83 / 84 (MEDI-9-VH / MEDI-9-VL); SEQ ID NO:85 / 86 (MEDI-10-VH / MEDI-10-VL); SEQ ID NO:87 / 88 (MEDI-11-VH / MEDI-11 / VL); SEQ ID NO:89 / 90 (MEDI-12-VH / MEDI-12-VL); SEQ ID NO:91 / 92 (MEDI-13-VH / MEDI-13-VL); SEQ ID NO:93 / 94 (MEDI-14-VH / MEDI-14-VL); SEQ ID NO:95 / 96 (MEDI-15-VH / MEDI-15-VL); SEQ ID NO:97 / 98 (MEDI-16-VH / MEDI-16 / VL); SEQ ID NO:99 / 100 (MEDI-17-VH / MEDI-17-VL); SEQ ID NO:101 / 102 (MEDI-18-VH / MEDI-18-VL); SEQ ID NO:103 / 104 (MEDI-19-VH / MEDI-19-VL); SEQ ID NO:105 / 106 (MEDI-20-VH / MEDI-20-VL); SEQ ID NO:107 / 108 (MEDI-21-VH / MEDI-21-VL); SEQ ID NO:109 / 110 (MEDI-22-VH / MEDI-22-VL); SEQ ID NO:111 / 112 (MEDI-23-VH / MEDI-23-VL); SEQ ID NO:113 / 114 (MEDI-24-VH / MEDI-24-VL);SEQ ID NO: 115 / 116 (MEDI-25-VH / MEDI-25-VL); SEQ ID NO: 117 / 118 (MEDI-26-VH / MEDI-26-VL); SEQ ID NO: 119 / 120 (MEDI-27-VH / MEDI-27-VL); SEQ ID NO: 121 / 122 (MEDI-28-VH / MEDI-28-VL); SEQ ID NO: 123 / 124 (MEDI-29-VH / MEDI-29-VL); SEQ ID NO: 125 / 126 (MEDI-30-VH / MEDI-30-VL); SEQ ID NO: 127 / 128 (MEDI-31-VH / MEDI-31-VL); SEQ ID NO: 129 / 130 (MEDI-32-VH / MEDI-32-VL); SEQ ID NO: 131 / 132 (MEDI-33-VH / MEDI-33-VL); SEQ ID NO: 133 / 134 (MEDI-34-VH / MEDI-34-VL); SEQ ID NO: 135 / 136 (MEDI-35-VH / MEDI-35-VL); SEQ ID NO: 137 / 138 (MEDI-36-VH / MEDI-36-VL); SEQ ID NO: 139 / 140 (MEDI-37-VH / MEDI-37-VL); SEQ ID NO: 141 / 142 (MEDI-38-VH / MEDI-38-VL); SEQ ID NO: 143 / 144 (MEDI-39-VH / MEDI-39-VL); SEQ ID NO: 145 / 146 (MEDI-40-VH / MEDI-40-VL); SEQ ID NO: 147 / 148 (MEDI-41-VH / MEDI-41-VL); SEQ ID NO: 149 / 150 (MEDI-42-VH / MEDI-42-VL); and SEQ ID NO: 151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).;

[0135] In some embodiments, the anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:153 (AJOU-1-VH), SEQ ID NO:154 (AJOU-2-VH), SEQ ID NO:155 (AJOU-3-VH), SEQ ID NO:156 (AJOU-4-VH), SEQ ID NO:157 (AJOU-5-VH), SEQ ID NO:158 (AJOU-6-VH), SEQ ID NO:159 (AJOU-7-VH), SEQ ID NO:160 (AJOU-8-VH), SEQ ID NO:161 (AJOU-9-VH), SEQ ID NO:162 (AJOU-10-VH), SEQ ID NO:163 (AJOU-69-VH), SEQ ID NO:164 (AJOU-70-VH), SEQ ID NO:165 (AJOU-71-VH), SEQ ID NO:166 (AJOU-72-VH), or SEQ ID NO:167 (AJOU-83-VH); and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO:168 (AJOU-33-VL), SEQ ID NO:169 (AJOU-34-VL), SEQ ID NO:170 (AJOU-35-VL), SEQ ID NO:171 (AJOU-36-VL), SEQ ID NO:172 (AJOU-37-VL), SEQ ID NO:173 (AJOU-38-VL), SEQ ID NO:174 (AJOU-39-VL), SEQ ID NO:175 (AJOU-40-VL), SEQ ID NO:176 (AJOU-41-VL), SEQ ID NO:177 (AJOU-42-VL), SEQ ID NO:178 (AJOU-77-VL), SEQ ID NO:179 (AJOU-78-VL), SEQ ID NO:180 (AJOU-79-VL), SEQ ID NO:181 (AJOU-80-VL), SEQ ID NO:182 (AJOU-86-VL), SEQ ID NO:183 (AJOU-87-VL), SEQ ID NO:184 (AJOU-88-VL), SEQ ID NO:185 (AJOU-89-VL), SEQ ID NO:186 (AJOU-90-VL), or SEQ ID NO:187 (AJOU-91-VL).

[0136] In some embodiments, the anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO: 188 (REGN-VH-3), SEQ ID NO: 189 (REGN-VH-19), SEQ ID NO: 190 (REGN-VH-35), SEQ ID NO: 191 (REGN-VH-51), SEQ ID NO: 192 (REGN-VH-67), SEQ ID NO: 193 (REGN-VH-83), SEQ ID NO: 194 (REGN-VH-99), SEQ ID NO: 195 (REGN-VH-115), SEQ ID NO: 196 (REGN-VH-147), or SEQ ID NO: 197 (REGN-VH-163); and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO: 198 (REGN-VL-11), SEQ ID NO: 199 (REGN-VL-27), SEQ ID NO: 200 (REGN-VL-43), SEQ ID NO: 201 (REGN-VL-59), SEQ ID NO: 202 (REGN-VL-75), SEQ ID NO: 203 (REGN-VL-91), SEQ ID NO: 204 (REGN-VL-107), SEQ ID NO: 205 (REGN-VL-123), SEQ ID NO: 206 (REGN-VL-155), or SEQ ID NO: 207 (REGN-VL-171).

[0137] In some embodiments, the anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO: 208 (STSA-C27-VH), SEQ ID NO: 209 (STSA-C27-6-33-VH), SEQ ID NO: 210 (STSA-C27-7-33-VH), SEQ ID NO: 211 (STSA-C27-24-56-VH), SEQ ID NO: 212 (STSA-C27-47-56-VH), SEQ ID NO: 213 (STSA-C27-33-33-VH), SEQ ID NO: 214 (STSA-C27-56-56-VH), SEQ ID NO: 215 (STSA-C27-78-78-VH), SEQ ID NO: 216 (STSA-C27-82-58-VH), SEQ ID NO: 217 (STSA-C27-54-54-VH), SEQ ID NO: 218 (STSA-C27-36-36-VH), SEQ ID NO: 219 (STSA-C27-53-53-VH), SEQ ID NO: 220 (STSA-C27-67-67-VH), SEQ ID NO: 221 (STSA-C27-55-55-VH), SEQ ID NO: 222 (STSA-C27-59-59-VH), SEQ ID NO: 223 (STSA-C27-58-58-VH), SEQ ID NO: 224 (STSA-C27-52-52-VH), or SEQ ID NO: 225 (STSA-C27-Y2-Y2-VH);and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO: 226 (STSA-C27-VL), SEQ ID NO: 227 (STSA-C27-6-33-VL), SEQ ID NO: 228 (STSA-C27-7-33-VL), SEQ ID NO: 229 (STSA-C27-24-56-VL), SEQ ID NO: 230 (STSA-C27-47-56-VL), SEQ ID NO: 231 (STSA-C27-33-33-VL), SEQ ID NO: 232 (STSA-C27-56-56-VL), SEQ ID NO: 233 (STSA-C27-78-78-VL), SEQ ID NO: 234 (STSA-C27-82-58-VL), SEQ ID NO: 235 (STSA-C27-54-54-VL), SEQ ID NO: 236 (STSA-C27-36-36-VL), SEQ ID NO: 237 (STSA-C27-53-53-VL), SEQ ID NO: 238 (STSA-C27-67-67-VL), SEQ ID NO: 239 (STSA-C27-55-55-VL), SEQ ID NO: 240 (STSA-C27-59-59-VL), SEQ ID NO: 241 (STSA-C27-58-58-VL), SEQ ID NO: 242 (STSA-C27-52-52-VL) or SEQ ID NO: 243 (STSA-C27-Y2-Y2-VL);

[0138] In some embodiments, the anti-IL-4Rα antibody comprises (i) an HCVR comprising the amino acid sequence of SEQ ID NO:244 (Y0188-1VH), SEQ ID NO:245 (Y0188-2 VH), SEQ ID NO:246 (Y0188-3 VH), SEQ ID NO:247 (Y0188-4VH), SEQ ID NO:248 (Y0188-6VH), SEQ ID NO:249 (Y0188-8 VH), SEQ ID NO:250 (Y0188-9VH), SEQ ID NO:251 (Y0188-10 VH), SEQ ID NO:252 (Y0188-14 VH), SEQ ID NO:253 (HV3-15-14VH), SEQ ID NO:254 (HV3-48-14VH), SEQ ID NO:255 (HV3-73*2-14VH), SEQ ID NO:256 (HV3-72-14VH), SEQ ID NO:257 (Y01-14 VH), SEQ ID NO:258 (162-14VH), or SEQ ID NO:259 (VH73-14 VH); and (ii) an LCVR comprising the amino acid sequence of SEQ ID NO:260 (Y0188-1 VL), SEQ IDNO:261 (Y0188-2 VL), SEQ ID NO:262 (Y0188-3VL), SEQ ID NO:263 (Y0188-4 VL), SEQ IDNO:264 (Y0188-6 VL), SEQ ID NO:265 (Y0188-8 VL), SEQ ID NO:266 (Y0188-9 VL), SEQ IDNO:267 (Y0188-10 VL), SEQ ID NO:268 (Y0188-14 VL), SEQ ID NO:269 (Y01-14 VL), SEQID NO:270 (164-14VL), SEQ ID NO:271 (KV4-14VL), SEQ ID NO:272 (KV1-27-14VL), SEQ IDNO:273 (KV1-9-14VL), SEQ ID NO:274 (KV1-NL1-14 VL), or SEQ ID NO:275 (KV1D-43-14VL).

[0139] In some embodiments, the anti-IL-4Rα antibodies used in the methods of the present disclosure can have pH-dependent binding characteristics. For example, compared to neutral pH, the anti-IL-4Rα antibodies used as disclosed herein can exhibit reduced binding to IL-4Rα at acidic pH. Alternatively, compared to neutral pH, the anti-IL-4Rα antibodies used as disclosed herein can exhibit enhanced binding to its antigen at acidic pH. The phrase "acidic pH" includes pH values less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or less.

[0140] As used herein, the phrase "neutral pH" refers to a pH of from about 7.0 to about 7.4. The phrase "neutral pH" includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

[0141] In certain cases, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" is expressed as the ratio of the K D value of the antibody binding to IL-4Rα at acidic pH to the K D value of the antibody binding to IL-4Rα at neutral pH (and vice versa). For example, for the purposes of the present disclosure, if an antibody or its antigen-binding fragment exhibits an acidic / neutral K D ratio of about 3.0 or greater, the antibody or its antigen-binding fragment can be considered to exhibit "reduced binding to IL-4Rα at acidic pH compared to neutral pH". In certain exemplary embodiments, the acidic / neutral K D ratio of the antibodies or antigen-binding fragments of the present disclosure can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or greater.

[0142] Antibody populations can be screened, for example, by reduced (or enhanced) binding to a particular antigen at an acidic pH compared to neutral pH to obtain antibodies with pH-dependent binding characteristics. Additionally, modifying the antigen-binding domain at the amino acid level can generate antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids (e.g., within a CDR) of the antigen-binding domain with histidine residues, antibodies can be obtained that have reduced antigen binding at acidic pH relative to neutral pH.

[0143] Preparation of human antibodies

[0144] 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 disclosure to prepare human antibodies that specifically bind to human IL-4R.

[0145] Using the VELOCIMMUNE TM technology (see, for example, US 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, a high-affinity chimeric antibody against IL-4R having a human variable region and a murine constant region is initially isolated. The technology involves generating transgenic mice having a genome that includes human heavy and light chain variable regions operably linked to the endogenous murine constant region locus such that the mice produce antibodies comprising human variable regions and murine constant regions in response to antigen stimulation. The DNA encoding the heavy and light chain variable regions of the antibody is isolated and operably linked to DNA encoding human heavy and light chain constant regions. Subsequently, the DNA is expressed in cells capable of expressing fully human antibodies.

[0146] Typically, the mice are challenged with the antigen of interest, and lymphocytes (such as B cells) are recovered from the antibody-expressing mice. The lymphocytes can be fused with a myeloma cell line to prepare an immortalized hybridoma cell line, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific for the antigen of interest. The DNA encoding the heavy and light chain variable regions can be isolated and ligated to the desired heavy and light chain isotype constant regions. Such antibody proteins can be produced in cells such as CHO cells. Alternatively, the DNA encoding the antigen-specific chimeric antibody or the light and heavy chain variable domains can be directly isolated from antigen-specific lymphocytes.

[0147] First, a high-affinity chimeric antibody having a human variable region and a murine constant region is isolated. The antibody is characterized and selected using standard procedures known to those of skill in the art to obtain desired characteristics, including affinity, selectivity, epitope, etc. The murine constant region is replaced with a desired human constant region to generate the fully human antibodies of the present disclosure, such as wild-type or modified IgG1 or IgG4. Although the constant region selected may vary depending on the particular use, the high-affinity antigen-binding and target-specificity characteristics reside in the variable region.

[0148] Generally, when measured by binding to an antigen immobilized on a solid phase or in solution phase, the antibodies useful in the methods of the present disclosure have high affinity as described above. The murine constant region is replaced with a desired human constant region to generate the fully human antibodies of the present disclosure. Although the constant region selected may vary depending on the particular use, the high-affinity antigen-binding and target-specificity characteristics reside in the variable region.

[0149] In one embodiment, a human antibody or antigen-binding fragment thereof that specifically binds to IL-4R and can be used in the methods disclosed herein comprises three heavy-chain CDRs (HCDR1, HCDR2, and HCDR3) contained within a heavy-chain variable region (HCVR) having the amino acid sequence of SEQ ID NO:1, and three light-chain CDRs (LCVR1, LCVR2, and LCVR3) contained within a light-chain variable region (LCVR) having the amino acid sequence of SEQ ID NO:2. Methods and techniques for identifying CDRs within the HCVR and LCVR amino acid sequences are well known in the art and can be used to identify the CDRs within the specified 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. Generally, the Kabat definition is based on sequence differences, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia methods. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases can also be used to identify CDR sequences within antibodies.

[0150] Pharmaceutical composition

[0151] In one aspect, the present disclosure provides methods that include administering an IL-4R antagonist to a subject, where the IL-4R antagonist (e.g., an anti-IL-4R antibody) is included in a pharmaceutical composition that includes one or more pharmaceutically acceptable vehicles, carriers, and / or excipients. A variety of pharmaceutically acceptable carriers and excipients are well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA). In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, intrathecal, transdermal, topical, or subcutaneous administration.

[0152] Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, such as by infusion or bolus injection, absorption through the epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.), and can be administered in combination with other bioactive agents. In some embodiments, the pharmaceutical composition as disclosed herein is administered intravenously. In some embodiments, the pharmaceutical composition as disclosed herein is administered subcutaneously.

[0153] In some embodiments, the pharmaceutical composition includes an injectable preparation, such as dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, infusion, etc. These injectable preparations can be prepared by known methods. For example, an injectable preparation can be prepared, for example, by dissolving, suspending, or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injection. As the aqueous medium for injection, there are, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, etc., which can be used in combination with suitable solubilizers (such as alcohols (e.g., ethanol), polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc.). As the oily medium, for example, sesame oil, soybean oil, etc. are used, which can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. The injectable preparation thus prepared can be filled into suitable ampoules.

[0154] The dosage of the antibody administered to a subject according to the methods of the present disclosure can vary depending on the age and size of the subject, symptoms, condition, route of administration, etc. The dosage is typically calculated based on body weight or body surface area. Depending on the severity of the condition, the frequency and duration of treatment can be adjusted. The effective dosage and schedule for administering a pharmaceutical composition comprising an anti-IL-4R antibody can be determined empirically; for example, the progress of the subject can be monitored by regular evaluation and the dosage adjusted accordingly. In addition, interspecies scaling of dosages can be performed using methods well known in the art (e.g., Mordenti et al., 1991, Pharmaceut. Res. 8:1351). Specific exemplary dosages of anti-IL4R antibodies that can be used in the context of the present disclosure and dosing regimens involving such dosages are disclosed elsewhere herein.

[0155] In some embodiments, the IL-4R antagonist or pharmaceutical composition of the present disclosure is contained in a container. Accordingly, in another aspect, there is provided a container comprising an IL-4R antagonist or pharmaceutical composition as disclosed herein. For example, in some embodiments, the pharmaceutical composition is contained within a container selected from the group consisting of glass vials, syringes, pen delivery devices, and autoinjectors.

[0156] In some embodiments, the pharmaceutical composition of the present disclosure is delivered subcutaneously or intravenously using a standard needle and syringe. In some embodiments, the syringe is a prefilled syringe. In some embodiments, a pen delivery device or autoinjector is used to deliver the pharmaceutical composition of the present disclosure (e.g., for subcutaneous delivery). The pen delivery device can be reusable or disposable. Typically, a reusable pen delivery device utilizes a replaceable cartridge containing the pharmaceutical composition. Once the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be used again. In a disposable pen delivery device, there is no replaceable cartridge. In fact, a disposable pen delivery device is prefilled with the pharmaceutical composition in a reservoir within the device. Once the pharmaceutical composition in the reservoir is emptied, the entire device is discarded.

[0157] Examples of suitable pen and autoinjector delivery devices include, but are not limited to, AUTOPEN TM (Owen Mumford, Inc., Woodstock, UK), DISETRONIC TM Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30TM Pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN TM I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (Novo Nordisk, Copenhagen, Denmark), BD TM Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN TM , OPTIPEN PRO TM , OPTIPEN STARLET TM and OPTICLIK TM (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen delivery devices for subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to, SOLOSTAR TM Pen (sanofi-aventis), FLEXPEN TM (Novo Nordisk) and KWIKPEN TM (Eli Lilly), SURECLICK TM Autoinjector (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.) and HUMIRA TM Pen (Abbott Labs, Abbott Park IL).

[0158] In some embodiments, a controlled release system is used to deliver the pharmaceutical composition. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, a polymeric material can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed near the target of the composition, so that only a fraction of the systemic dose is required (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, Vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533. Other delivery systems are known and can be used to administer the pharmaceutical composition, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432).

[0159] In some embodiments, a pharmaceutical composition comprising an anti-IL-4R antibody is administered using a drug delivery device that is a needle-based injection system as described in Table 1 of Section 5.2 of ISO 11608-1:2014(E). As described in ISO 11608-1:2014(E), needle-based injection systems can generally be divided into multi-dose container systems and single-dose (partially or fully evacuated) container systems. The container can be a replaceable container or an integral non-replaceable container.

[0160] As further described in ISO 11608-1:2014(E), a multi-dose container system can involve a needle-based injection device with a replaceable container. In such a system, each container holds a multi-dose, the size of which can be fixed or variable (preset by the user). Another multi-dose container system can involve a needle-based injection device with an integral non-replaceable container. In such a system, each container holds a multi-dose, the size of which can be fixed or variable (preset by the user).

[0161] As further described in ISO 11608-1:2014(E), a single-dose container system can involve a needle-based injection device with a replaceable container. In one example of such a system, each container holds a single dose such that the entire deliverable volume is expelled (fully emptied). In another example, each container holds a single dose such that a portion of the deliverable volume is expelled (partially emptied). Additionally, as described in ISO 11608-1:2014(E), a single-dose container system can involve a needle-based injection device with an integrated non-replaceable container. In one example of such a system, each container holds a single dose such that the entire deliverable volume is expelled (fully emptied). In another example, each container holds a single dose such that a portion of the deliverable volume is expelled (partially emptied).

[0162] Exemplary sleeve-triggered autoinjectors with manual needle inserts are described in International Publication WO2015 / 004052. Exemplary audible dose-end feedback mechanisms are described in International Publications WO2016 / 193346 and WO2016 / 193348. An exemplary needle safety mechanism after use of an autoinjector is described in International Publication WO2016 / 193352. An exemplary needle sheath remover mechanism for syringes and autoinjectors is described in International Publication WO2016 / 193353. An exemplary support mechanism for supporting the axial position of a syringe is described in International Publication WO2016 / 193355.

[0163] In some embodiments, a pharmaceutical composition for use as described herein is formulated into dosage forms in unit doses suitable for the dose of the active ingredient. Such dosage forms in unit doses include, for example, tablets, pills, capsules, injection solutions (ampoules), suppositories, and the like.

[0164] For example, an exemplary pharmaceutical composition comprising an anti-IL-4R antibody that can be used in the context of the present disclosure is disclosed in U.S. Patent No. 8,945,559.

[0165] Dose and Administration

[0166] In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered to a subject (e.g., a subject having moderate to severe atopic hand and / or foot dermatitis) in a therapeutically effective amount according to the methods of the present disclosure. As used herein with respect to an IL-4R antagonist, the phrase "therapeutically effective amount" means an amount of the IL-4R antagonist that results in one or more of the following: (a) an improvement in one or more AD-related parameters (as mentioned elsewhere herein); and / or (b) a detectable improvement in one or more symptoms or signs of atopic hand and / or foot dermatitis.

[0167] In the case of an anti-IL-4R antibody, a therapeutically effective amount can be from 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 or about 600 mg of anti-IL-4R antibody. In some embodiments, the therapeutically effective amount is from about 50 mg to about 600 mg, or from about 100 mg to about 600 mg, or from about 200 mg to about 600 mg. In certain embodiments, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg of anti-IL-4R antibody is administered to a subject.

[0168] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in a single dose can be expressed as milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-4R antagonist can be administered to a subject at a dose of from about 0.0001 mg / kg to about 10 mg / kg of subject body weight, for example, at a dose of from about 1 mg / kg to about 10 mg / kg, at a dose of from about 2 mg / kg to about 9 mg / kg, or at a dose of from about 3 mg / kg to about 8 mg / kg. In some embodiments, the IL-4R antagonist can be administered to a subject at a dose of about 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg or 10 mg / kg.

[0169] In some embodiments, the methods disclosed herein include administering an IL-4R antagonist to a subject at a dosing frequency of about four times per week, twice per week, once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or a lower frequency, so long as a therapeutic response is achieved.

[0170] In some embodiments, multiple doses of an IL-4R antagonist are administered to a subject over a defined period of time. In some embodiments, the methods of the present disclosure include sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, "sequentially administering" means administering each dose of the IL-4R antagonist to the subject at different time points, such as on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the methods of the present disclosure include sequentially administering a single initial dose of an IL-4R antagonist to a patient, followed by one or more second doses of the IL-4R antagonist, and optionally then one or more third doses of the IL-4R antagonist.

[0171] The terms "initial dose," "second dose," and "third dose" refer to the chronological order of administration of the IL-4R antagonist. Thus, the "initial dose" is the dose administered at the start of a treatment regimen (also referred to as a "loading dose"); the "second dose" is the dose administered after the initial dose; and the "third dose" is the dose administered after the second dose. The initial dose, second dose, and third dose may all contain the same amount of the IL-4R antagonist, but typically may differ from one another in terms of dosing frequency. However, in certain embodiments, the amounts of the IL-4R antagonist contained in the initial dose, second dose, and / or third dose differ from one another during the course of treatment (e.g., up or down adjusted as appropriate). In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered at the start of a treatment regimen as a "loading dose," followed by subsequent doses (e.g., "maintenance doses") administered at a lower frequency. In some embodiments, the initial dose or loading dose and one or more second doses or maintenance doses each contain the same amount of the IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of the IL-4R antagonist, and each of the one or more second doses comprises a second amount of the IL-4R antagonist. For example, the first amount of the IL-4R antagonist may be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x or more of the second amount of the IL-4R antagonist. In some embodiments, one or more maintenance doses of the IL-4R antagonist are administered without a loading dose.

[0172] In some embodiments, the loading dose is a "fractionated dose" administered as two or more doses (e.g., 2, 3, 4, or 5 doses), which are administered on different days. In some embodiments, the loading dose is administered as a fractionated dose, where two or more doses are administered at least about one week apart. In some embodiments, the loading dose is administered as a fractionated dose, where two or more doses are administered about 1, 2, 3, or 4 weeks apart. In some embodiments, the loading dose is evenly divided into two or more doses (e.g., half of the loading dose is administered as a first portion and half of the loading dose is administered as a second portion). In some embodiments, the loading dose is unevenly divided into two or more doses (e.g., more than half of the loading dose is administered as a first portion and less than half of the loading dose is administered as a second portion).

[0173] In some embodiments, each second dose and / or third dose is administered 1 to 14 weeks (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 / 2 or more) after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" means that, in the sequence of multiple administrations, the dose of the IL-4R antagonist is administered to the patient immediately before the next dose in the sequence, without an intervening dose.

[0174] The methods of the present disclosure can include administering to a patient any number of second and / or third doses of an IL-4R antagonist. By way of 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.

[0175] In some embodiments involving multiple second doses, each second dose is administered at the same frequency as the other second doses. For example, each second dose can be administered to a patient 1, 2, 3, or 4 weeks after the immediately preceding dose. Similarly, in some embodiments involving multiple third doses, each third dose is administered at the same frequency as the other third doses. For example, each third dose can be administered to a patient 1, 2, 3, or 4 weeks after the immediately preceding dose. Alternatively, during the course of a treatment regimen, the frequency of second and / or third doses administered to a patient can vary. A physician can also adjust the administration frequency during the course of treatment, depending on the needs of each patient following a clinical examination.

[0176] In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W). In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a loading dose of 600 mg followed by one or more subsequent doses of 300 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.

[0177] In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W). In some embodiments, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises a loading dose of 400 mg followed by one or more subsequent doses of 200 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.

[0178] In some embodiments, for subjects ≥12 years to <18 years of age with moderate to severe hand and foot atopic dermatitis or severe AD, if the subject weighs <60 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W). In some embodiments, if the subject weighs <60 kg, the subject is administered a loading dose of 400 mg followed by one or more subsequent doses of 200 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.

[0179] In some embodiments, for subjects ≥12 years to <18 years of age with moderate to severe hand and foot atopic dermatitis or severe AD, if the subject weighs ≥60 kg, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises administering 300 mg every two weeks (Q2W). In some embodiments, if the subject weighs ≥60 kg, the subject is administered a loading dose of 600 mg, followed by one or more subsequent doses of 300 mg administered every two weeks (Q2W). In some embodiments, no loading dose is administered.

[0180] Combination therapy

[0181] In some embodiments, the methods of the present disclosure comprise administering an IL-4R antagonist (e.g., an anti-IL-4R antibody) according to the present disclosure in combination with one or more additional therapeutic agents to a subject (e.g., a subject with moderate to severe hand and / or foot atopic dermatitis). In some embodiments, the additional therapeutic agent is a topical therapeutic agent, e.g., a TCS or a topical non-steroidal drug such as a TCI, crisaborole, or a topical JAK inhibitor. As used herein, the expression "in combination with" means that the topical therapy (e.g., a TCS) is administered before, after, or simultaneously with the IL-4R inhibitor. The term "in combination with" also includes sequential or concomitant administration of the IL-4R inhibitor and the topical therapy (e.g., a TCS).

[0182] 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 the pharmaceutical composition comprising the IL-4R antagonist is administered. 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 the pharmaceutical composition comprising the IL-4R antagonist is administered. Administering "simultaneously" with a pharmaceutical composition comprising an IL-4R antagonist means administering the additional therapeutic agent to the subject in a separate dosage form within less than about 10 minutes (before, after, or simultaneously) of administering the pharmaceutical composition comprising the IL-4R antagonist, or administering the additional therapeutic agent to the subject in a single combined dosage form formulation comprising both the additional therapeutic agent and the IL-4R antagonist.

[0183] In some embodiments, the additional therapeutic agent is TCS. In some embodiments, the TCS is medium-potency TCS. In some embodiments, the TCS is low-potency TCS. In some embodiments, the additional therapeutic agent is TCI. In some embodiments, the additional therapeutic agent is crisaborole.

[0184] Example

[0185] The following examples are provided to give a complete disclosure and description to those of ordinary skill in the art of how to make and use the methods and compositions of the present disclosure, and are not intended to limit the scope that the inventors regard as their invention. Efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is atmospheric or near atmospheric.

[0186] Example 1: A clinical trial to evaluate the efficacy and safety of dupilumab in adult and adolescent patients with moderate to severe atopic hand and / or foot dermatitis

[0187] Study Design and Objectives

[0188] This was a global, multicenter, randomized, double-blind, parallel-group, placebo-controlled Phase 3 study to investigate the efficacy and safety of dupilumab monotherapy in adult and adolescent patients with moderate to severe atopic hand and / or foot dermatitis (NCT04417894). The study consisted of three periods: a screening period (at least 4 weeks and at most 8 weeks), a randomized treatment period (16 weeks), and a post-treatment follow-up period (12 weeks).

[0189] Dupilumab is a fully human anti-IL-4R antibody that comprises a heavy chain having the amino acid sequence of SEQ ID NO:9 and a light chain having the amino acid sequence of SEQ ID NO:10; an HCVR / LCVR amino acid sequence pair of SEQ ID NO:1 / 2; and heavy and light chain CDR sequences of SEQ ID NO:3-8.

[0190] This study was conducted in accordance with the provisions of the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practices guidelines, and applicable regulatory requirements. The protocol was reviewed and approved by the institutional review board / ethics committee at all sites. At the screening visit, adult patients provided informed consent before any other study procedures. For adolescent patients, the parents or legal guardians provided informed consent, and the patients provided assent.

[0191] Patient Population

[0192] The study population consisted of patients with chronic, moderate to severe atopic hand and / or foot dermatitis who had an inadequate response to medium- to high-potency topical corticosteroids (TCS) or for whom medium- to high-potency TCS were not recommended. Only patients who met the diagnostic criteria for atopic dermatitis (AD) were included in this study. Patients diagnosed with irritant contact dermatitis or allergic contact dermatitis (the major causes of hand and / or foot dermatitis) were excluded from the study. Patients were randomly assigned in a 1:1 ratio, stratified by age (adult vs. adolescent), baseline disease severity (HF-IGA score 3 vs. 4), and geographical region (United States vs. Japan vs. European Union), and received subcutaneous dupilumab or placebo every 2 weeks (q2w) for 16 weeks.

[0193] Inclusion CriteriaPatients must meet the following criteria to be eligible for inclusion in this study: (1) male or female, ≥ 12 years old at the screening visit; (2) patients diagnosed with chronic hand and / or foot dermatitis at least 3 years before the screening visit for patients ≥ 18 years old and at least 1 year before the screening visit for patients ≥ 12 years old and < 18 years old; (3) patients with involvement of at least 2 anatomical regions at screening and baseline. These two anatomical regions can be both hands, one hand and one foot, or both feet. (4) Patients need to have an IGA hand / foot score of 3 or 4 (moderate to severe disease) at screening and baseline. Note: The investigator should assign a single IGA score based on the overall impression of the disease severity of the hands and feet. Patients need to have overall moderate to severe disease of the hands / feet and involvement of at least 2 anatomical regions to be eligible. (5) Patients with a recent history (within 6 months before the screening visit) of inadequate response to topical medications for atopic hand and / or foot dermatitis, or patients for whom topical treatment of atopic hand and / or foot dermatitis is not medically recommended (e.g., intolerance due to significant side effects or safety risks). If the documentation is inadequate, a course of treatment with a daily regimen of medium or higher potency TCS (± TCI, as appropriate) can be provided to potential patients, applied for at least 28 days during the screening period, or for the maximum duration recommended by the product prescribing information (whichever is shorter). As defined above, patients who demonstrate an inadequate response during this period will be eligible for inclusion in the study after appropriate washout. (6) Patients need to meet the Hanifin and Rajka diagnostic criteria (Hanifin, 1980). (7) Baseline hand / foot peak pruritus NRS score for maximum itching intensity ≥ 4; (8) Application of topical emollients (moisturizers) at least 11 times (out of a total of 14 times) within 7 consecutive days (excluding the day of randomization) before the baseline visit; (9) willing and able to comply with outpatient and study-related procedures; (10) provide an informed consent form signed by the study patient or a legal representative; (12) Patients need to comply with skin protection measures throughout the duration of the screening period (minimum 4 weeks but maximum 8 weeks). This includes avoiding known irritants identified as causing exacerbation of AD of the individual's hands and / or feet.

[0194] Inclusion criteria note (5): Inadequate response is defined as failure to achieve and maintain remission or low disease activity, as judged clinically by the treating physician, despite treatment with a daily regimen of medium- to higher-potency TCS (± topical calcineurin inhibitor [TCI], as appropriate) for at least 28 days or the maximum duration recommended in the product prescribing information (e.g., 14 days for ultra-high-potency TCS), whichever is shorter. As evaluated by the investigator or the patient's treating physician, important side effects or safety risks of treating atopic hand and / or foot dermatitis are those that outweigh the potential therapeutic benefits and include intolerance to treatment, hypersensitivity reactions, marked atrophy of the hand and foot skin, and systemic effects. Acceptable documentation includes contemporaneous chart notes documenting topical medication prescriptions and treatment outcomes, or investigator documentation based on communication with the patient's treating physician.

[0195] Inclusion criteria note (6): The diagnosis of AD requires the presence of at least 3 of 4 major criteria: (a) pruritus; (b) dermatitis affecting flexural surfaces in adults; (c) chronic or recurrent dermatitis; (d) personal or family history of cutaneous or respiratory atopy. For patients without AD lesions at screening on body sites other than the hands and feet, study investigators should examine any past history of AD lesions in the typical age-specific distribution pattern in, for example, flexural areas (cutaneous atopy). A past history of respiratory atopic diseases (e.g., asthma, allergic rhinitis) should also be queried. In addition, 3 of 23 minor criteria need to be met. Minor criteria include: features of the so-called "atopic march": pallor or erythema of the face, hypopigmented macules, infraorbital darkening, infraorbital creases or wrinkles, cheilitis, recurrent conjunctivitis, and anterior cervical folds; triggers of atopic dermatitis: foods, emotional factors, environmental factors, and skin irritants such as wool, solvents, and sweat; complications of atopic dermatitis: susceptibility to cutaneous viral and bacterial infections, impaired cell-mediated immunity, immediate skin test reactivity, elevated serum IgE, keratoconus, anterior subcapsular cataract; others: early age of onset, dry skin, ichthyosis, excessive palmar creasing, keratosis pilaris (proximal follicular occlusion), hand and / or foot dermatitis, nipple eczema, white dermographism, and perifollicular accentuation.

[0196] Exclusion CriteriaThe following are the exclusion criteria for this study: (1) Patients with a positive patch test reaction (scored 1+ or above according to the International Contact Dermatitis Research Group [ICDRG] grading scale) to one or more allergens in (a) the baseline patch test series, or (b) extended baseline or supplementary patch test allergens (if such additional tests are conducted by the investigator), or (c) personal products (if tests using such products are conducted by the investigator); in the investigator's opinion, this is considered clinically relevant to the current etiology of hand and / or foot dermatitis. [Note: Patients with a recorded diagnosis of allergic contact dermatitis of the hand and / or foot with a positive patch test reaction at screening will also be excluded from this study, regardless of whether there is a history of current skin exposure to products containing this allergen (current relevance). Patients with a positive reaction interpreted as an irritant reaction based on morphology, time (e.g., positive on day 2, then showing a waning pattern) are still eligible to participate in the study as long as they meet the other eligibility criteria of the study.] (2) Patients with a recorded diagnosis of hand and / or foot protein contact dermatitis. These patients are those who have occupational or non-occupational exposure to proteins (such as food, latex, etc.), have a positive prick test, and present with lesions of hand / foot contact urticaria or dermatitis. (3) Patients who cannot undergo patch testing for any reason (these reasons include but are not limited to patient refusal to undergo patch testing, inability to discontinue systemic immunosuppressants / topical AD medications in the patient during the required washout period before patch testing, lack of clear skin (without lesions) on the upper back and / or upper arm where patch testing is applied, etc.). (4) Patients with a recorded exposure to irritants in an occupational or non-occupational (home / recreational) environment, which, in the investigator's judgment, is considered the main cause of current hand and / or foot dermatitis. (5) Prior exposure to dupilumab. (6) Patients who have used any of the following treatments within 4 weeks before the baseline visit: (a) systemic corticosteroids; (b) immunosuppressive / immunomodulatory drugs (e.g., acitretin, cyclosporine, mycophenolate mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, or methotrexate); (c) phototherapy (including psoralen and UVA [PUVA] or narrowband ultraviolet B [UVB] limited to the hand and / or foot). (7) Treatment with the following biologics other than dupilumab: (a) any cell depleting agent, including but not limited to rituximab: within 6 months before the baseline visit, or until the lymphocyte and CD19+ lymphocyte counts return to normal (whichever is longer); (b) other biologics: within 5 half-lives (if known) or 16 weeks before the baseline visit (whichever is longer). (8) Treatment with TCS or TCI or crisaborole or topical JAK inhibitors within 2 weeks before the hand and foot baseline visit. (9) Treatment with the study drug within 8 weeks before the baseline visit or 5 half-lives (if known) (whichever is longer).(10) Treatment with live (attenuated) vaccines within 4 weeks before baseline visit. (11) Planning or anticipating the use of any prohibited medications and procedures during the study treatment. (12) Known or suspected immunodeficiency, including a history of invasive opportunistic infections (e.g., tuberculosis [TB], histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) (although the infection has resolved), or recurrent infections at an abnormal frequency judged by the investigator. (13) Known history of human immunodeficiency virus (HIV) infection or HIV seropositivity. (14) Current diagnosis of hepatitis B virus infection at screening, as demonstrated by (a) positive hepatitis B surface antigen (HBsAg) or (b) positive total hepatitis B core antibody (HBcAb) confirmed by positive HBV DNA. (15) Current diagnosis of hepatitis C virus infection at screening, as demonstrated by (a) positive HCV Ab and (b) positive HCV RNA. (16) Currently receiving treatment for liver disease (including but not limited to acute or chronic hepatitis, cirrhosis, or liver failure), or having signs of liver disease during the screening period, such as persistent (confirmed by repeated tests at intervals ≥ 2 weeks) elevation of transaminases (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) more than 3 times the upper limit of normal (ULN). (17) Presence of any one or more of the following abnormalities in the laboratory test results at screening: (a) platelets ≤ 100 × 10. 3 / μL; (b) neutrophils < 1.5 × 10 3 / μL. (18) Diagnosed with active helminthic infection. (19) Skin comorbidities in the hands and / or feet that may interfere with study assessment. This includes but is not limited to palmoplantar psoriasis, palmoplantar keratoderma, lichen planus, pityriasis rubra pilaris, herpes simplex, erythema multiforme, tinea manuum / pedis, scabies, granuloma annulare. (20) History of malignancy within 5 years prior to the baseline visit, except for completely treated cervical carcinoma in situ, completely treated and resolved non-metastatic cutaneous squamous cell carcinoma or basal cell carcinoma. (21) Severe concomitant diseases that, in the investigator's judgment, would have an adverse impact on the patient's participation in the study. Examples include but are not limited to patients with a short life expectancy, patients with uncontrolled diabetes (HbA1c ≥ 9%), patients with cardiovascular conditions (e.g., stage III or IV heart failure according to the New York Heart Association classification), patients with severe kidney disease (e.g., patients on dialysis), patients with neurological conditions (e.g., demyelinating diseases), patients with active major autoimmune diseases (e.g., eosinophilic granulomatosis with polyangiitis (EGPA), lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), and patients with other severe endocrine, gastrointestinal, hepatobiliary, metabolic, pulmonary, or lymphatic diseases. (22) Any other medical or psychological conditions (including relevant laboratory abnormalities at screening) that the investigator believes may indicate a new and / or poorly understood disease, may pose an unreasonable risk to the patient due to their participation in this clinical trial, may render the patient's participation unreliable, or may interfere with study assessment. (23) History of alcohol or drug abuse within 2 years prior to the screening visit. (24) Patients committed to an institution by order of a judicial or administrative authority. (25) The patient is a member of the study team or a direct relative. (26) Pregnant or lactating women, or women planning to become pregnant or lactate during the patient's participation in this study. (27) Women of childbearing potential (WOCBP) who are unwilling to use highly effective contraception before the first dose / start of the first treatment, during the study, and for at least 12 weeks after the last dose.

[0197] Study Treatments

[0198] The study drug is administered as follows:

[0199] · Dupilumab, administered subcutaneously Q2W

[0200] - Adults: After a loading dose of 600 mg on Day 1, 300 mg of dupilumab, regardless of body weight.

[0201] - Adolescents: Body weight ≥ 60 kg, after a loading dose of 600 mg on Day 1, 300 mg of dupilumab; body weight < 60 kg, after a loading dose of 400 mg on Day 1, 200 mg of dupilumab.

[0202] · Matching placebo, administered subcutaneously Q2W

[0203] It is recommended that the subcutaneous injection sites of the investigational drug be alternated among different quadrants of the abdomen (avoiding the navel and waist), upper thigh, and upper arm, such that the same site is not injected twice consecutively.

[0204] Background Treatments: During screening, all patients are required to apply a moisturizer to their hands and feet at least twice a day. Patients are recommended to continue using the moisturizer throughout the study (for all 28 weeks, if applicable). All types of moisturizers are permitted, but patients cannot start treatment with a prescription moisturizer or a moisturizer containing additives during the screening period or the study period. If started before the screening visit, patients may continue using a stable dose of such a moisturizer. It is recommended to use a moisturizer without additives, fragrances, perfumes, and other potential sensitizers. In addition, it is recommended that the moisturizer does not contain any compounds with known antipruritic effects (such as pramoxine, lidocaine, prilocaine, capsaicin, etc.).

[0205] Rescue Treatments: In the study, the investigator may decide to provide rescue treatment for the deterioration of hand and / or foot AD in study patients. Rescue treatment is only permitted after day 14 of the study. The investigator is required to perform a hand and foot IGA assessment before starting rescue treatment and to start rescue treatment only in patients with an IGA hand and foot score ≥ 3. If possible, the investigator is encouraged to first consider rescue with topical treatment (e.g., high-potency or ultra-high-potency TCS, TCI, crisaborole, or topical JAK inhibitor) and to escalate to systemic drugs only in patients with an inadequate response to topical treatment for at least 7 days. Rescue treatment with topical therapy can be used according to the prescribing information and local guidelines. If the rescue consists of a topical drug, the patient can continue the study treatment.

[0206] The investigator may also use systemic corticosteroids or non-steroidal systemic immunosuppressive drugs (alitretinoin, cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, JAK inhibitors, etc.) for the rescue of patients with hand and foot AD deterioration. If the rescue consists of these systemic treatments, the patient can continue the study treatment at the discretion of the investigator. All patients are required to complete the scheduled study visits and assessments, regardless of whether they have completed the study treatment or whether they have received rescue treatment for AD. Before administering any rescue treatment, the investigator should make every effort to perform efficacy and safety assessments (e.g., disease severity scoring, safety laboratory tests).

[0207] Outcomes Assessed

[0208] The primary endpoint of the study is the proportion of patients with an IGA (hand and foot) score of 0 or 1 at week 16.

[0209] The key secondary endpoint was the proportion of patients with an improvement (decrease) of ≥4 in the weekly mean of the daily peak pruritus NRS for hands and feet from baseline to Week 16.

[0210] Other secondary endpoints of efficacy included: the percentage change in the modified total lesion severity score (mTLSS) for hand / foot lesions from baseline to Week 16; the proportion of patients with an improvement (decrease) of ≥3 in the weekly mean of the daily peak pruritus NRS for hands and feet from baseline to Week 16; the percentage change in the weekly mean of the daily peak pruritus NRS for hands and feet from baseline to Week 16; the percentage change in the weekly mean of the daily peak pain NRS for hands and feet from baseline to Week 16; the percentage change in the weekly mean of the daily sleep NRS from baseline to Week 16; the change in the percentage of the body surface area of the hands and feet affected by AD from baseline to Week 16; the percentage change in the weekly mean of the daily peak pruritus NRS for hands and feet from baseline to Week 4; the proportion of patients with an improvement (decrease) of ≥4 in the weekly mean of the daily peak pruritus NRS for hands and feet from baseline to Week 4; for patients with hand dermatitis, the percentage change in the Hand Eczema Severity Index (HECSI) score from baseline to Week 16; for patients with hand dermatitis, the proportion of patients with HECSI-75 at Week 16; for patients with hand dermatitis, the proportion of patients with HECSI-50 at Week 16; for patients with hand dermatitis, the proportion of patients with HECSI-90 at Week 16; for patients with hand dermatitis, the change in the Hand Eczema Quality of Life Questionnaire (QOLHEQ) from baseline to Week 16; the change in the Work Productivity and Activity Impairment Questionnaire (WPAI) and the Classroom Impairment Questionnaire (CIQ) from baseline to Week 16.

[0211] The secondary endpoint of safety included: the incidence of treatment-emergent adverse events (TEAEs) by Week 16.

[0212] The secondary endpoints of clinical pharmacology and immunogenicity included: the trough concentration of functional dupilumab in serum at different time points; the incidence and titer of antidrug antibodies (ADAs) that emerged during treatment over time.

[0213] The procedures used to evaluate efficacy (e.g., using hand / foot IGA, mTLSS, daily peak pruritus NRS for hands and feet, daily peak pain NRS for hands and feet, or other assessment methods) are described below or in WO 2021 / 026205, which is incorporated herein by reference.

[0214] Modified Total Lesion Severity Score of Hands and Feet:The modified total lesion severity score (mTLSS) is applicable to the hands and feet; it has previously been used in a registration study of hand dermatitis (Ruzicka et al., Br J Dermatol, 2008, 158:808-817). The investigator assesses the severity of the signs of hand and foot diseases based on this scale; this assessment is limited to the hands and feet and is not affected by the severity of AD lesions in other parts of the body. The mTLSS score is evaluated at screening, at baseline, and on specific dates during and / or after treatment.

[0215] Based on the morphological descriptions of severity provided in Table 1 below, the mTLSS is evaluated by scoring each of the 6 features (erythema, desquamation / flaking, lichenification, vesicle formation / erosion, edema, fissure) on a scale of 0 to 3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe). The scores for the hands and feet are separated. The total hand mTLSS is 0 - 18. The total foot mTLSS is 0 - 18. The total mTLSS score (0 - 36) is calculated as the sum of the total hand score and the total foot score.

[0216] Table 1: mTLSS Score of Hands and Feet

[0217]

[0218]

[0219] a Hyperkeratosis is not explicitly listed as a separate sign, but hyperkeratosis seen in hyperkeratotic eczema should be captured by desquamation, fissure, and skin thickening.

[0220] b When evaluating exaggerated skin markings, excessive palmar creases seen in ichthyosis vulgaris are not considered.

[0221] Investigator's Global Assessment of Hands and Feet: The hand-foot IGA is an adaptation of a physician's global assessment tool that was previously used in a registration study of hand dermatitis (Ruzicka et al., Br J Dermatol 2008; 158:808 - 17). The investigator assesses the severity of the signs of hand and foot diseases based on this scale; this assessment is limited to the hands and feet and is not affected by the severity of AD lesions in other parts of the body. Based on the scoring algorithm shown in Table 2 below, the IGA score is evaluated at screening, at baseline, and on specific dates during and / or after treatment. The assessment of IGA should be based on the investigator's overall impression of the severity of hand and foot diseases according to clinical judgment at the time of assessment. It is not necessary to classify all signs presented by the patient into IGA categories.

[0222] Table 2: IGA of Hands and Feet

[0223]

[0224] Note:

[0225] 1. In case of uncertainty:

[0226] (a) Use the degree to guide the rating of the severity of IGA. For example, patients with obvious erythema and clearly visible desquamation, suffering from a limited degree of the disease, will be classified as moderate IGA.

[0227] (b) Use the severity rating of blisters and fissures (signs that have a greater impact on the patient's QoL) to increase the rating of the severity of IGA. For example, patients with clearly visible blisters and mild but definite erythema should be rated as having a moderate IGA score.

[0228] 2. Non-inflammatory signs of atopic dermatitis (such as post-inflammatory hyperpigmentation or hypopigmentation, dry skin, etc.) should not be used for the assessment of IGA.

[0229] Numeric Rating Scale for Pruritus of Hands and Feet The Itch NRS is a patient-reported assessment tool used to evaluate the intensity of itching (itching) of the hands and feet during a 24-hour recall period. This is an 11-point scale (0 to 10), where 0 means no itching and 10 means the most itching. During the study, patients completed the rating scale at specific time points every day. The Itch NRS score is calculated as the average of the last 7 days, with at least 4 scores per day.

[0230] Numeric Rating Scale for Skin Pain of Hands and Feet : Measure the skin pain of the hands and feet using the Skin Pain NRS. This is an 11-point scale (0 to 10), where 0 means no pain and 10 means the most pain. During the study, patients completed the rating scale at specific time points every day.

[0231] Numeric Rating Scale for Sleep : Measure the sleep quality using the Sleep Quality NRS. This is an 11-point scale (0 to 10), where 0 means the worst sleep and 10 means the best sleep. Patients are asked to choose the number that best describes the sleep quality of the previous night. During the study, patients completed the rating scale at specific time points every day.

[0232] Dermatology Life Quality Index:This questionnaire is based on general AD, not just hand and / or foot AD. For adults, the DLQI is a valid 10-item questionnaire for use in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on QOL (Badia et al., Br J Dermatol, 1999, 141:698 - 702). The format is a simple response to 10 questions (0 to 3, where 0 = "not at all", 1 = "only a little"; 2 = "quite a lot"; and 3 = "very much"), which assess QOL in the past week, with an overall scoring system from 0 to 30; a high score indicates poor QOL. The DLQI is evaluated at specific time points during the study period.

[0233] For adolescents, the CDLQI is a valid questionnaire designed to measure the impact of skin disease on children's QOL (Lewis-Jones et al., Br J Dermatol, 1995, 132:942 - 949). The purpose of the questionnaire is to measure the extent to which the patient's skin problems have affected the patient during a recall period of the past week. To complete the questionnaire, the patient needs to answer 10 questions (the questions focus on areas such as the sensations of disease-related symptoms, the impact of the disease on leisure, school or holidays, relationships, sleep, and side effects of skin disease treatment). The recall period for this tool is 7 days. Nine of the 10 questions are scored from 0 to 3 (where 0 = "not at all" or the question not answered, 1 = "only a little"; 2 = "quite a lot"; and 3 = "very much"). Question 7 has an additional possible response (preventing school attendance), which is scored 3. The patient's CDLQI is the sum of the scores for each question, with a maximum of 30 and a minimum of 0. The higher the score, the greater the impact on QOL. The CDLQI is evaluated at specific time points during the study period.

[0234] Hospital Anxiety and Depression Scale: This questionnaire is based on general AD, not just hand and / or foot AD. The HADS is a tool for screening anxiety and depression in non-psychiatric populations; repeated administration also provides information on changes in the patient's emotional state (Zigmond and Snaith, 1983, Acta Psychiatr.Scand, 67:361 - 70; Herrmann, 1997, J.Psychosom.Res., 42:17 - 41). The HADS consists of 14 items, 7 for anxiety symptoms and 7 for depression symptoms; the possible score range for each subscale is 0 to 21. The following cut-off scores are recommended for both subscales: 7 to 8 indicates possible presence, 10 to 11 indicates probable presence, and 14 to 15 indicates severe anxiety or depression. The questionnaire is administered to the patient at specific time points during the study period.

[0235] Patient-Oriented Eczema Measure:The POEM is a valid 7-item questionnaire for use in clinical practice and clinical trials to assess disease symptoms in children and adults (Charman et al., Archives of Dermatology, 2004, 140:1513-1519). The format is responses to 7 items (dryness, itching, flaking, cracking, lack of sleep, bleeding, and tearing) based on the frequency of these disease symptoms in the past week (i.e., 0 = not a single day, 1 = 1 to 2 days, 2 = 3 to 4 days, 3 = 5 to 6 days, and 4 = every day), with a scoring system of 0 to 28; the total score reflects disease-related morbidity. The POEM questionnaire was evaluated at specific time points during the study period.

[0236] Severity Index of Hand Eczema: HECSI is similar to the scoring systems for AD (EASI) and psoriasis vulgaris (PASI), incorporating both the extent and intensity of the disease. Each hand is divided into 5 regions [fingertips, fingers (excluding fingertips), palm, dorsum of the hand, and wrist]. For each of these regions, the intensity of 6 clinical signs (erythema, induration / papule formation, vesicles, fissures, desquamation, and edema) is graded on the following scale: 0, no skin changes; 1, mild disease; 2, moderate, and 3, severe. For each location (sum of both hands), a score of 0 to 4 is given for the extent of the clinical symptoms in the affected area (0, 0%; 1, 1% to 25%; 2, 26% to 50%; 3, 51% to 75% and 4, 76% to 100%). Finally, the score given for the extent of each location is multiplied by the sum of the intensities of each clinical feature, and a sum called the HECSI score is calculated, ranging from 0 to a maximum severity score of 360. HECSI has previously been validated in patients with hand dermatitis (Held et al., Br J Dermatol, 2005, 152:302-307).

[0237] Quality of Life Questionnaire of Hand Eczema QoLHEQ is a disease-specific tool for assessing the health-related quality of life (HRQOL) of patients with hand eczema (HE) (Ofenloch et al., Br J Dermatol, 2014, 171:304-312). QOLHEQ consists of 30 items and assesses four domains of HRQOL: (a) symptoms, (b) emotions, (c) function, and (d) treatment / prevention. The total QOLHEQ score ranges from 0 - 127. QoLHEQ was evaluated at specific time points during the study period.

[0238] Results

[0239] A total of 133 patients were enrolled in a roughly 1:1 randomization to receive dupilumab every two weeks (n = 67) (300 mg for adults, 200 mg or 300 mg based on body weight for adolescents) or placebo (n = 66). Among these patients, a higher percentage of patients in the dupilumab group completed treatment compared to placebo (94.0% in the dupilumab group; 81.5% in the placebo group; 88.0% of total patients).

[0240] Baseline demographics and disease characteristics are summarized in Tables 3 and 4. Baseline demographics were generally balanced between treatment groups, slightly favoring female patients, consistent with background rates reported in the literature (Table 3). As shown in Table 4, disease severity was balanced across treatment groups. Trial participants had severe chronic disease, with most having disease on both hands and feet. The baseline disease severity in the study population was high, as reflected by measures of signs, symptoms, and quality of life. Approximately two-thirds of patients had either disease limited to the hands and feet or mild disease (EASI < 16). A substantial number of patients had prior use of systemic immunosuppressants, reflecting the heavy burden of the disease on patients' hands and feet.

[0241] Table 3: Baseline Demographics

[0242]

[0243] Table 4: Baseline Disease Characteristics

[0244]

[0245]

[0246] 1 Others included pulpitis, nummular eczema, unspecified, and patient-specified primary morphologies

[0247] 2 Patients who had a patch test within 3 years prior to screening were not required to have a patch test at screening

[0248] As shown in Table 5, the incidence of atopic comorbidities was high in the patient population, highlighting the common type 2 pathophysiology underlying these diseases.

[0249] Table 5: Concurrent Atopic / Allergic Conditions

[0250]

[0251] *Refers to allergies to plants, animals, dust mites, medications, etc.

[0252] Efficacy

[0253] Treatment with dupilumab met all pre-specified efficacy endpoints with highly significant p-values. See Table 6. The primary endpoint evaluated the proportion of patients with clear or almost clear hands and feet at Week 16 (measured by a score of 0 or 1 on the Investigator's Global Assessment [IGA] of hands and feet). At Week 16, 40.3% of patients treated with dupilumab achieved a hands and feet IGA of 0 / 1, compared to only 16.7% of patients treated with placebo. The statistically significant improvement in the primary endpoint was evident at Week 4 and persisted through Week 16.

[0254] The key secondary endpoint measured the proportion of patients with improvement in itching relative to baseline at Week 16 (measured by a decrease of ≥4 points on a 0 - 10 scale on the Peak Pruritus Numerical Rating Scale [PP-NRS]). Improvement in hands and feet itching with dupilumab treatment started rapidly (by Week 1), and persisted until Week 16. At Week 16, 52.2% of patients treated with dupilumab achieved a PP-NRS decrease of ≥4 points, compared to only 13.6% of patients treated with placebo.

[0255] To assess the effect of dupilumab treatment on individual signs of atopic hand and / or foot dermatitis, the proportion of patients reporting no, mild, moderate, or severe erythema, desquamation / flaking, lichenification, vesiculation / erosion, edema, and fissuring was analyzed, as evaluated by the hands and feet mTLSS. Among the 133 patients enrolled, more than 65% of patients treated with dupilumab (n = 67) achieved a no or mild score in each of the evaluated signs / symptoms by Week 16. From baseline to Week 16, the proportion of patients with no or mild hand scores increased in terms of erythema (9% vs 71.6%), desquamation / flaking (16.4% vs 74.7%), lichenification (4.5% vs 65.6%), vesiculation / erosion (43.3% vs 89.6%), edema (44.7% vs 86.6%), and fissuring (23.9% vs 83.5%). From baseline to Week 16, the proportion of patients with no or mild foot scores increased in terms of erythema (56.7% vs 80.6%), desquamation / flaking (56.7% vs 82.1%), lichenification (53.8% vs 82.1%), vesiculation / erosion (76.1% vs 86.6%), edema (76.1% vs 88.1%), and fissuring (77.6% vs 86.6%).

[0256]

[0257] Use of Rescue Medications

[0258] Compared with patients treated with dupilumab, the use of rescue medications was 7-fold higher in patients treated with placebo (at week 16, 14 / 66 (21.2%) in the placebo group vs 2 / 67 (3.0%) in the dupilumab group). See Table 7 below. None of the patients in the dupilumab treatment group required systemic drug rescue.

[0259] Table 7: Rescue Medications Administered During 16-Week Treatment

[0260]

[0261] Safety

[0262] Dupilumab was well tolerated and demonstrated an acceptable safety profile, with no new safety concerns identified. See Table 8. The overall incidence of treatment-emergent adverse events (TEAEs) during the 16-week treatment period was 65.7% for the dupilumab group and 74.2% for the placebo group. The incidence of serious adverse events (SAEs) and AEs leading to permanent treatment discontinuation was low. The incidence of conjunctivitis was higher in the dupilumab group, while the incidence of COVID-19 infection was lower.

[0263] Table 8: Adverse Events Occurring During Treatment

[0264]

[0265]

[0266] Summary

[0267] This phase 3 trial evaluated the efficacy and safety of dupilumab in 133 adolescents and adults with moderate to severe hand and foot atopic dermatitis who were insufficiently responsive or intolerant to topical corticosteroids. Patients with irritant contact dermatitis were excluded from the trial. Atopic and allergic comorbidities were present in 73% and 64% of dupilumab-treated and placebo-treated patients, respectively.

[0268] Patients received dupilumab every two weeks (n = 67) (300 mg for adults, 200 mg or 300 mg based on body weight for adolescents) or placebo (n = 66). At week 16, in patients treated with dupilumab, more than twice as many patients achieved clear or almost clear skin (40%, compared with 17% in the placebo group (p = 0.0030)). For the key secondary endpoint, 52% of the dupilumab-treated group experienced a clinically significant reduction in itching, compared with 14% in the placebo group (p < 0.0001). The disease severity in patients treated with dupilumab improved by an average of 73% compared with baseline, compared with 38% in the placebo group (p < 0.0001). Patients treated with dupilumab also showed significant improvements in skin pain, sleep, and health-related quality of life compared with placebo-treated patients. Dupilumab rapidly improved disease signs and symptoms, significantly reducing itching as early as one week and improving pain and health-related quality of life within two weeks. In addition, patients treated with dupilumab required significantly less rescue medication compared with placebo (3% vs 21%).

[0269] The trial demonstrated safety results similar to the known safety profile of dupilumab in atopic dermatitis. During the 16-week treatment period, the overall incidence of adverse events (AEs) was 66% in the dupilumab group and 74% in the placebo group. AEs that were more commonly observed (≥5%) with dupilumab included conjunctivitis (6% in the dupilumab group, 2% in the placebo group) and herpesvirus infection (6% in the dupilumab group, 3% in the placebo group).

[0270] The scope of the present invention is not limited by the specific embodiments described herein. Indeed, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description and drawings in addition to those described herein. Such modifications are intended to fall within the scope of the appended claims.

[0271] Table 9. Informal Sequence List

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

Claims

1. A method for treating atopic dermatitis (AD) of the hands and / or feet, the method comprising: Subjects with moderate to severe hand and / or foot atopic dermatitis are selected, wherein the subjects have a baseline hand and foot investigator global assessment (IGA) score of ≥ 3, and wherein the subjects have a history of inadequate response of atopic hand and / or foot dermatitis to topical medications, or the subjects are subjects for whom topical treatment of atopic hand and / or foot dermatitis is not medically recommended; and One or more doses of an interleukin-4 receptor (IL-4R) antagonist are administered to the subjects, wherein the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:3, the HCDR2 comprises the amino acid sequence of SEQ ID NO:4, the HCDR3 comprises the amino acid sequence of SEQ ID NO:5, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence LGS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

2. The method according to claim 1, wherein the baseline hand-foot IGA score of the subject is 4.

3. The method according to claim 1, wherein the subject has an inadequate response to treatment with medium or higher potency topical corticosteroids (TCS).

4. The method according to claim 1, wherein the baseline hand-foot peak pruritus numeric rating score (NRS) of the subject is ≥ 4.

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

6. The method according to claim 5, wherein the subject has had chronic atopic dermatitis of the hands and / or feet for at least 3 years.

7. The method according to any one of claims 1 to 4, wherein the subject is an adolescent.

8. The method according to claim 7, wherein the subject has had chronic atopic dermatitis of the hands and / or feet for at least 1 year.

9. The method according to any one of claims 1 to 8, wherein the subject does not have irritant contact dermatitis or allergic contact dermatitis.

10. The method according to any one of claims 1 to 9, wherein the subject does not have atopic dermatitis lesions on body parts other than the hands and / or feet.

11. The method according to any one of claims 1 to 9, wherein the subject has mild atopic dermatitis on the body other than the hands and / or feet.

12. The method according to any one of claims 1 to 9, wherein the subject has moderate to severe atopic dermatitis on the body other than the hands and / or feet.

13. The method according to any one of claims 1 to 12, wherein the modified total lesion severity score (mTLSS) of the subject's hands and feet is ≥ 16.

14. The method according to any one of claims 1 to 13, wherein the baseline atopic dermatitis area involving the hands and feet of the subject is at least 24%.

15. The method according to any one of claims 1 to 14, wherein the atopic dermatitis involves a body surface area (BSA) score of < 10% and / or an eczema area and severity index (EASI) score of < 21 in the subject.

16. The method according to any one of claims 1-11 or 13-15, wherein the subject: (a) Baseline total body IGA score ≤ 2; and / or (b) Baseline total body EASI score < 16.

17. A method for treating atopic dermatitis (AD) of the hands and / or feet, the method comprising: Subjects with moderate to severe hand and / or foot AD are selected, wherein the subjects are selected based on a hand and foot mTLSS of ≥ 16; and One or more doses of an IL-4R antagonist are administered to the subjects, wherein the IL-4R antagonist is an anti-IL-4R antibody or an antigen-binding fragment thereof, comprising three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) and three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:3, the HCDR2 comprises the amino acid sequence of SEQ ID NO:4, the HCDR3 comprises the amino acid sequence of SEQ ID NO:5, the LCDR1 comprises the amino acid sequence of SEQ ID NO:6, the LCDR2 comprises the amino acid sequence LGS, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

8.

18. The method according to claim 17, wherein the subject is further selected based on a baseline hand and foot IGA score ≥ 3 and / or a baseline atopic dermatitis affected hand and foot area of at least 24%.

19. The method according to claim 17 or 18, wherein the subject has a history of inadequate response to topical medications for hand and / or foot AD, or the subject is a subject for whom topical treatment of hand and / or foot AD is not medically recommended.

20. The method according to any one of claims 17 to 19, wherein the subject does not have atopic dermatitis lesions on body parts other than the hands and / or feet.

21. The method according to any one of claims 17 to 19, wherein the subject has mild atopic dermatitis on the body other than the hands and / or feet.

22. The method according to any one of claims 17 to 21, wherein the subject: (a) Baseline BSA score < 10%; (b) Baseline total body IGA score ≤ 2; and / or (c) Baseline total body EASI score < 16.

23. The method according to any one of claims 17 to 22, wherein the subject is an adult.

24. The method according to any one of claims 17 to 22, wherein the subject is an adolescent.

25. The method according to any one of claims 17 to 24, wherein the subject is further selected based on the absence of allergic contact dermatitis and / or the absence of irritant contact dermatitis.

26. The method according to any one of claims 1 to 25, wherein the subject has chronic dry and chapped hand and / or foot AD.

27. The method according to any one of claims 1 to 25, wherein the subject has hyperkeratotic hand and / or foot AD.

28. The method according to any one of claims 1 to 25, wherein the subject has pompholyx hand and / or foot AD.

29. The method according to any one of claims 1 to 28, wherein the IL-4R antagonist is administered at a dose of about 50 mg to about 600 mg.

30. The method according to any one of claims 1 to 29, wherein the IL-4R antagonist is administered at an initial dose of 100 mg - 600 mg, and then at one or more subsequent doses of 50 mg - 300 mg.

31. The method according to any one of claims 1 to 30, wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 600 mg, and then at one or more subsequent doses of 300 mg subcutaneously.

32. The method according to any one of claims 1 to 30, wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 300 mg, and then at one or more subsequent doses of 300 mg subcutaneously.

33. The method according to any one of claims 1 to 30, wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 400 mg, and then at one or more subsequent doses of 200 mg subcutaneously.

34. The method according to any one of claims 1 to 30, wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 200 mg, and then at one or more subsequent doses of 200 mg subcutaneously.

35. The method according to any one of claims 30 to 34, wherein each subsequent dose is administered one or two weeks after the immediately preceding dose.

36. The method according to any one of claims 1-4, 7-22 or 24-30, wherein the subject is an adolescent with a baseline body weight ≥ 60 kg, and wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 600 mg, and then at one or more subsequent doses of 300 mg Q2W subcutaneously.

37. The method according to any one of claims 1-4, 7-22 or 24-30, wherein the subject is an adolescent with a baseline body weight < 60 kg, and wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 400 mg, and then at one or more subsequent doses of 200 mg Q2W subcutaneously.

38. The method according to any one of claims 1-6, 9-23 or 25-30, wherein the subject is an adult, and wherein the IL-4R antagonist is administered subcutaneously at an initial dose of 600 mg, and then at one or more subsequent doses of 300 mg Q2W subcutaneously.

39. The method according to any one of claims 1 to 38, wherein the IL-4R antagonist is administered for at least 16 weeks.

40. The method according to any one of claims 1 to 39, wherein the IL-4R antagonist is administered in combination with an emollient.

41. The method according to any one of claims 1 to 40, wherein the IL-4R antagonist is administered in combination with a topical AD drug.

42. The method according to claim 41, wherein the topical AD drug is a topical corticosteroid (TCS).

43. The method according to any one of claims 1 to 42, wherein treatment with the IL-4R antagonist results in the subject achieving an IGA hand-foot score of 0 or 1 at week 16 after administration of the first dose of the IL-4R antagonist.

44. The method according to any one of claims 1 to 43, wherein treatment with the IL-4R antagonist results in an improvement selected from the group consisting of: at week 16 after administration of the first dose of the IL-4R antagonist, the peak hand-foot pruritus NRS score is reduced by ≥4 points relative to the subject's baseline peak hand-foot pruritus NRS score; at week 16 after administration of the first dose of the IL-4R antagonist, the hand-foot mTLSS score is reduced by at least 50% relative to the subject's baseline hand-foot mTLSS score; at week 16 after administration of the first dose of the IL-4R antagonist, the peak hand-foot pruritus NRS score is reduced by at least 50% relative to the subject's baseline peak hand-foot pruritus NRS score; at week 16 after administration of the first dose of the IL-4R antagonist, the peak hand-foot pain NRS score is reduced by ≥4 points relative to the subject's baseline peak hand-foot pain NRS score; at week 16 after administration of the first dose of the IL-4R antagonist, the hand eczema severity index (HECSI) score is reduced by at least 50% relative to the subject's baseline HECSI score; HECSI-75 is achieved at week 16 after administration of the first dose of the IL-4R antagonist; at week 16 after administration of the first dose of the IL-4R antagonist, the percentage of the hand-foot surface area affected by AD is reduced by at least 15% relative to the subject's baseline percentage of the hand-foot surface area affected by AD; and at week 16 after administration of the first dose of the IL-4R antagonist, the quality of life in hand eczema questionnaire (QoLHEQ) score is reduced by at least 40% relative to the subject's baseline QoLHEQ score.

45. The method according to any one of claims 1 to 44, wherein treatment with the IL-4R antagonist reduces the need for rescue treatment.

46. The method according to any one of claims 1 to 45, wherein the anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

47. The method according to any one of claims 1 to 46, wherein the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

48. The method according to any one of claims 1 to 47, wherein the IL-4R antagonist is dupilumab.

49. The method according to any one of claims 1 to 48, wherein the IL-4R antagonist is contained in a container selected from the group consisting of: glass vials, syringes, pre-filled syringes, pen-type delivery devices, and auto-injectors.

50. The method according to claim 49, wherein the IL-4R antagonist is contained in a pre-filled syringe.

51. The method according to claim 50, wherein the pre-filled syringe is a single-dose pre-filled syringe.

52. The method according to claim 49, wherein the IL-4R antagonist is contained in an auto-injector.

53. The method according to claim 49, wherein the IL-4R antagonist is contained in a pen-type delivery device.

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