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

Abstract

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

Description

[Technical Field]

[0001] Reference to sequence table XML This application contains a Sequence Listing that has been submitted electronically in XML format. This Sequence Listing XML is incorporated herein by reference. The XML file was created on October 25, 2023, is named 40848_0117WOU1_SL.xml, and is 267,878 bytes in size.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application was filed on November 1, 2023 as a PCT international patent application claiming priority to 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 each of which are incorporated herein by reference.

[0003] The present disclosure relates to the use of interleukin-4 receptor (IL-4R) antagonists to treat dermatitis of the hands and / or feet. [Background technology]

[0004] Hand and foot dermatitis is an umbrella term that includes patients with a history of or the presence of irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), and concurrent atopic dermatitis (AD), also known as atopic hand and foot dermatitis (Agner, et al., J Eur Acad Dermatol Venereol, 2015, 29:2417-2422). Morphological types described for this condition include: vesicular (dyshidrotic), hyperkeratotic, fissured, and nummular (Menne, et al., Contact Dermatitis, 2011, 65:3-12).

[0005] Patients with atopic dermatitis (AD) are at increased risk for hand dermatitis of any etiology compared to the general population, 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 patients with AD has been reported to be approximately 60% (Simpson, et al., Dermatitis, 2006, 17:123-127). Similarly, the prevalence of foot dermatitis in patients with AD 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 the development of hand dermatitis, with approximately 28% of patients with hand dermatitis having a history of AD (Petersen, et al., Br J Dermatol, 2014, 171:1428-1433). Similarly, a history of AD is present in approximately 14% of patients with foot dermatitis (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).

[0006] Atopic hand and foot dermatitis (also known as atopic hand and foot eczema) presents with redness, infiltration, scaling, vesicles, areas of hyperkeratosis, and fissures (cracks) (Coenraads, N Engl J Med, 2012, 367:1829-1837). Lesions are associated with significant itching and pain. The morphology tends to evolve over time, and many patients may have mixed symptoms. In the majority of patients, the same morphological subtype is found on the hands and feet (Brans, et al., Contact Dermatitis, 2015, 73:100-107). The disease tends to be chronic and refractory, with a substantial impact on quality of life (QoL), comparable to other skin disorders 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, disability, and medical costs (Fowler, et al., J Am Acad Dermatol, 2006, 54:448-457). Sixty-five percent of patients with severe hand dermatitis reported lost productivity at work, averaging 10.1 days / patient / month (Politiek, et al., Contact Dermatitis, 2016, 75:67-76). Furthermore, in certain occupations, such as hairdressers, bakers, and mechanics, up to 18% of patients had to change jobs due to hand dermatitis (Meding, et al., Contact Dermatitis, 2005, 65:3-12).

[0007] Severe atopic hand and foot dermatitis is known to be particularly difficult to treat. Management of hand and foot dermatitis is based on prevention and avoidance strategies, reducing exposure to irritants and regular use of emollients. Step therapy is used, initiating treatment with topical medications and then progressing to systemic medications in cases of inadequate response to topical medications (Diepgen, et al., Contact Dermatitis, 2007, 57:203-210). A short course of topical corticosteroids (TCS) is recommended as first-line treatment to control flare-ups. Long-term application of TCS carries the risk of skin atrophy, pigmentation abnormalities, acneiform eruptions, and 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 beyond six weeks only if necessary and under careful medical supervision. Topical calcineurin inhibitors may be considered for patients with AD of the hands and feet who require long-term treatment, but evidence of their effectiveness is limited. The limited effectiveness of topical anti-inflammatory agents is explained by the low penetration / permeation of topical agents through the skin of the hands and feet. Overnight occlusion may be advocated to allow sufficient penetration of topical anti-inflammatory drugs. However, in the long term, such measures are often impractical and cumbersome for patients. Currently, there are no systemic treatments approved in the United States specifically indicated for atopic dermatitis of the hands and feet. Summary of the Invention

[0008] In one aspect, a method for treating atopic dermatitis of the hands and / or feet is provided. In some embodiments, the method includes: Selecting subjects with moderate to severe atopic dermatitis of the hands and / or feet, wherein the subjects have a baseline Investigator Global Assessment (IGA) composite score of ≥ 3, and the patient has a history of poor response of atopic hand and / or foot dermatitis to topical medications or is a patient for whom topical treatment of atopic hand and / or foot dermatitis is medically inadvisable; and Administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist.

[0009] In some embodiments, the method includes: Selecting a subject with moderate to severe AD of the hands and / or feet, wherein the subject is selected based on having a mTLSS for the hands and feet > 16; and Administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist.

[0010] In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody, or antigen-binding fragment thereof, comprising one or more CDR, HCVR, and / or LCVR sequences, for example, as shown 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.

[0011] In some embodiments, the subject has a baseline IGA global hand and foot score of 4. In some embodiments, the subject is inadequately responsive to treatment with medium or higher potency topical corticosteroids (TCS). In some embodiments, the subject has a history of prior use of one or more systemic immunosuppressants.

[0012] In some embodiments, the subject has a baseline Hands and Feet Peak Pruritus Numerical Rating Score (NRS) of ≧4.

[0013] 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 three years.

[0014] 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.

[0015] In some embodiments, the subject does not have irritant or allergic contact dermatitis.

[0016] In some embodiments, the subject does not have atopic dermatitis lesions on any part of the body other than the hands and / or feet. In some embodiments, the subject has mild atopic dermatitis on any part of the body other than the hands and / or feet. In some embodiments, the subject has moderate to severe atopic dermatitis on any part of the body other than the hands and / or feet.

[0017] In some embodiments, the subject has a modified Total Lesion Sign Score (mTLSS) for hands and feet score ≧16, e.g., ≧20 or ≧24. In some embodiments, the subject has a baseline hand and foot area of ​​at least 24% atopic dermatitis involvement.

[0018] In some embodiments, the subject has an atopic dermatitis (BSA) score <10% body surface area involvement and / or an Eczema Area and Severity Index (EASI) score <21.

[0019] 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 dyshidrotic hand and / or foot AD.

[0020] 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 as an initial dose of 100 to 600 mg, followed by one or more subsequent doses of 50 to 300 mg. In some embodiments, the IL-4R antagonist is administered subcutaneously as an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg. In other embodiments, the IL-4R antagonist is administered subcutaneously as an initial dose of 300 mg, followed by one or more subsequent doses of 300 mg. In some embodiments, the IL-4R antagonist is administered subcutaneously as an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg. In other embodiments, the IL-4R antagonist is administered subcutaneously as an initial dose of 200 mg, followed by one or more subsequent doses of 200 mg. In some embodiments, each subsequent dose is administered one or two weeks after the immediately preceding dose.

[0021] In some embodiments, the subject is an adolescent with a baseline weight of ≧60 kg, and the IL-4R antagonist is administered subcutaneously as an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q2W.

[0022] In some embodiments, the subject is an adolescent with a baseline weight <60 kg and the IL-4R antagonist is administered subcutaneously as an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg Q2W.

[0023] In some embodiments, the subject is an adult and the IL-4R antagonist is administered subcutaneously as an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q2W.

[0024] In some embodiments, the IL-4R antagonist is administered for at least 16 weeks.

[0025] 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 medication. In some embodiments, the topical AD medication is TCS.

[0026] In some embodiments, treatment with an IL-4R antagonist results in the subject achieving an IGA Hand and Foot score of 0 or 1 by week 16 after administration of the first dose of the IL-4R antagonist.

[0027] In some embodiments, treatment with an IL-4R antagonist results in an improvement selected from the group consisting of: a ≧4 point reduction in the Hands and Feet Peak Pruritus NRS compared to the subject's baseline Hands and Feet Peak Pruritus NRS score by week 16 after administration of the first dose of the IL-4R antagonist; a reduction in the mTLSS for Hand and Feet score of at least 50% compared to the baseline mTLSS for Hand and Feet score for the subject by week 16 after administration of the first dose of the IL-4R antagonist; a reduction in Hand and Foot Peak Pruritus NRS score of at least 50% compared to the subject's baseline Hand and Foot Peak Pruritus NRS score by 16 weeks after administration of the first dose of the IL-4R antagonist; a ≧4 point reduction in Hands and Feet Peak Pain NRS compared to the subject's baseline Hands and Feet Peak Pain NRS score by week 16 after administration of the first dose of the IL-4R antagonist; a reduction in the Hand Eczema Severity Index (HECSI) score of at least 50% compared to the subject's baseline HECSI score by week 16 after administration of the first dose of the IL-4R antagonist; Achievement of HECSI-75 by week 16 after administration of the first dose of the IL-4R antagonist; A reduction of at least 15% in the percent surface area of ​​hands and feet involved with AD compared to the subject's baseline percent surface area of ​​hands and feet involved with AD by 16 weeks after administration of the first dose of the IL-4R antagonist; and At least a 40% reduction in the Quality of Life Questionnaire for Hand Eczema (QoLHEQ) score by week 16 after administration of the first dose of the IL-4R antagonist, compared to the subject's baseline QoLHEQ score.

[0028] In some embodiments, treatment with an IL-4R antagonist reduces the need for rescue therapy.

[0029] In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the IL-4R antagonist is dupilumab.

[0030] In some embodiments, the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an auto-injector. 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.

[0031] In another aspect, pharmaceutical compositions for treating atopic dermatitis of the hands and / or feet are provided. 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 an antigen-binding fragment thereof, comprising one or more CDR, HCVR, and / or LCVR sequences, for example, as set forth 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.

[0032] In another aspect, provided herein is an interleukin-4 receptor (IL-4R) antagonist for the preparation of a medicament for the treatment of atopic dermatitis of the hands and / or feet. In some embodiments, the IL-4R antagonist is an anti-IL-4R antibody, or an antigen-binding fragment thereof, comprising one or more CDR, HCVR, and / or LCVR sequences, e.g., as set forth 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.

[0033] Other embodiments will be apparent from consideration of the detailed description that follows. DETAILED DESCRIPTION OF THE INVENTION

[0034] definition Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present invention will be limited only by the appended claims.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0036] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101, and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0037] As used herein, the terms "treat," "treating," or the like, mean to relieve symptoms, eliminate the cause of symptoms on either a temporary or permanent basis, or prevent or delay the onset of symptoms of the named disorder or condition.

[0038] "Atopic dermatitis" or "AD," as used herein, refers to an inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and by scaly and dry eczematous lesions. The terms "hand and foot atopic dermatitis," "hand and / or foot atopic dermatitis," "hand and foot AD," "hand and / or foot AD," and "hand and / or foot atopic dermatitis" 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 hands and / or feet also has one or more symptoms of atopic dermatitis elsewhere on the body. In some embodiments, a subject with atopic dermatitis localized to the hands and / or feet does not have symptoms of atopic dermatitis (e.g., lesions) elsewhere on the body.

[0039] As used herein, the term "subject in need thereof" refers to a human or non-human animal with atopic dermatitis of the hands and / or feet (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 thereof" refers to an adult patient. In some embodiments, the term "subject in need thereof" refers to an adolescent patient ≥ 12 years of age and < 18 years of age. The terms "subject" and "patient" are used interchangeably herein.

[0040] The term "TCS," as used herein, includes Group I, Group II, Group III, and Group IV topical corticosteroids. According to the World Health Organization's Anatomical Therapeutic Classification System, corticosteroids are classified into weak (Group I), moderately potent (Group II), potent (Group III), and very potent (Group IV) based on their activity relative to hydrocortisone. Group IV TCS (very potent) are up to 600 times more potent than hydrocortisone and include clobetasol propionate and halcinonide. Group III TCS (potent) are 50 to 100 times more potent than hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolone valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Group II TCS (moderately potent, also referred to interchangeably herein as "mid-potency") are 2-25 times more potent than hydrocortisone and include, but are not limited to, clobetasone butyrate and triamcinolone acetonide. Group I TCS (mild, also referred to interchangeably herein as "low-potency") include hydrocortisone.

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

[0042] Treatment method In one aspect, methods are provided for treating atopic dermatitis (AD) of the hands and / or feet or improving hand and / or foot AD-related parameters in a subject. In some embodiments, the methods comprise administering one or more doses of an interleukin-4 receptor (IL-4R) antagonist to a subject with moderate to severe hand and / or foot AD.

[0043] In some embodiments, the method for treating a subject with hand and / or foot AD includes: (a) Selecting subjects on the basis of having one or more of the following characteristics: (i) baseline IGA Hand and Foot score ≥ 3 (e.g., IGA Hand and Foot score 4); (ii) baseline mTLSS Hand and Foot score ≥ 16; (iii) baseline Hand and Foot Peak Pruritus NRS ≥ 4 (e.g., Hand and Foot Peak Pruritus NRS score ≥ 6); (iv) baseline hand and foot peak pain NRS ≥ 6; (v) baseline sleep NRS ≥ 5, and / or (vi) baseline hand and foot area involvement of atopic dermatitis of at least 24%, e.g., at least 25%, at least 30%, at least 35%, or more; (b) administering to the subject identified in step (a) one or more doses of an IL-4R antagonist.

[0044] In some embodiments, the method for treating a subject with hand and / or foot AD includes: (a) Selecting subjects on the basis of having one or more of the following characteristics: (i) baseline IGA Hand and Foot score ≥ 3 (e.g., IGA Hand and Foot score 4); (ii) baseline mTLSS Hand and Foot score ≥ 16; (iii) baseline Hand and Foot Peak Pruritus NRS ≥ 4 (e.g., Hand and Foot Peak Pruritus NRS score ≥ 6); (iv) baseline hand and foot peak pain NRS ≥ 6; (v) baseline sleep NRS ≥ 5, and / or (vi) baseline hand and foot area involvement of atopic dermatitis of at least 24%, e.g., at least 25%, at least 30%, at least 35%, or more; (b) selecting the subjects identified in step (a) based on having 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 (c) administering to the subject identified in step (b) one or more doses of an IL-4R antagonist.

[0045] In some embodiments, the subject has chronic hand and / or foot dermatitis that was diagnosed at least 3 years prior to initiation of treatment for patients ≥ 18 years of age, or at least 1 year prior to initiation of treatment for patients ≥ 12 to < 18 years of age.

[0046] In some embodiments, the subject has moderate to severe atopic dermatitis on the hands only. In some embodiments, the subject has moderate to severe atopic dermatitis on the feet / legs only. In some embodiments, the subject has moderate to severe atopic dermatitis on both the hands and feet / legs.

[0047] In some embodiments, the subject has at least two anatomical regions of the hand / foot with moderate to severe disease, e.g., in both hands, one hand and one foot, or both feet. In some embodiments, the extent of disease in an anatomical region of the hand / foot is assessed by an IGA hand and foot score, e.g., as assessed by IGA for the Hand and Foot Tool in Table 2. In some embodiments, the subject to be treated has a baseline IGA hand and foot score of ≥ 3, e.g., an IGA hand and foot score of 3 or an IGA hand and foot score of 4. In some embodiments, the subject to be treated has a baseline IGA hand and foot score of ≥ 3 (i.e., an IGA hand and foot score of 3 or 4) separately for at least two anatomical regions of the hand / foot. In some embodiments, the extent of disease in an anatomical region of the hand / foot is assessed by the modified Total Lesion Sign Score for Hands and Feet (mTLSS). In some embodiments, the subject to be treated has a baseline mTLSS hand and foot score of ≥ 16. In some embodiments, the subject to be treated has a baseline score of 2 or 3 for each of the mTLSS features erythema, scaling / scaling, lichenification, vesiculation / erosion, edema, and fissures in the total mTLSS hand score. In some embodiments, the subject to be treated has a baseline score of 2 or 3 for each of the mTLSS features erythema, scaling / scaling, lichenification, vesiculation / erosion, edema, and fissures in the total mTLSS foot score. In some embodiments, the subject to be treated has a baseline score of 2 or 3 for each of the mTLSS features erythema, scaling / scaling, lichenification, vesiculation / erosion, edema, and fissures in the total mTLSS hand and foot score.

[0048] In some embodiments, the subject has a baseline Hands and Feet Peak Pruritus Numerical Rating Scale (NRS) score of ≧4. In some embodiments, the subject has a baseline Hands and Feet Peak Pruritus NRS score of ≧6.

[0049] In some embodiments, subjects treated according to the methods disclosed herein have moderate to severe hand and / or foot AD that is inadequately responsive to topical treatment (e.g., TCS with or without a topical calcineurin inhibitor (TCI)), or for whom topical treatment is inadvisable (e.g., due to intolerance, adverse side effects, or safety risks). In some embodiments, the subject is inadequately responsive to high-potency TCS, or for whom high-potency TCS is inadvisable. As used herein, an "inadequate response" to topical treatment refers to a failure to achieve and maintain remission or a state of low disease activity, according to the clinical judgment of the attending physician, despite treatment with a daily regimen of a moderate to higher potency TCS (± a topical calcineurin inhibitor [TCI], if appropriate) administered for at least 28 days or for the maximum period recommended by the product's prescribing information (e.g., 14 days for an extra-potent TCS), whichever is shorter.

[0050] In some embodiments, a subject is considered "poorly responsive" to topical treatment if they have a recent history (e.g., within 3 months or within 6 months) of treatment with a systemic immunosuppressant (e.g., cyclosporine, methotrexate, systemic corticosteroids, alitretinoin, etc.) for atopic hand and / or foot dermatitis.

[0051] In some embodiments, the subject is one for whom topical treatment (e.g., high-potency TCS) is not advisable. In some embodiments, the subject is intolerant to topical treatment, e.g., TCS, such as high-potency TCS. In some embodiments, the subject has a medical history indicating adverse side effects or safety risks from topical treatment, e.g., TCS, such as high-potency TCS. The adverse side effects or safety risks from treating atopic hand and / or foot dermatitis outweigh the potential therapeutic benefits and include intolerance to the treatment, hypersensitivity reactions, significant skin atrophy of the hands and feet, and systemic effects as assessed by the investigator or the patient's physician.

[0052] 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., a standard series of allergens, e.g., the American Contact Dermatitis Society Core Allergen Series, European Baseline Series, Australian Baseline Series, Patch Test Panel, or Thin Rapid Use Epidermal (TRUE) patch test) prior to the start of treatment to confirm that the subject does not have allergic contact dermatitis. In some embodiments, subjects to be treated are selected based on not having allergic contact dermatitis, or based on having a negative patch test to confirm that the subject does not have allergic contact dermatitis.

[0053] In some embodiments, the subject does not have atopic dermatitis lesions on parts of the body other than the hands and / or feet. In some embodiments, the subject experiences a flare-up of AD lesions on parts of the body other than the hands and / or feet. In some embodiments, the subject has AD lesions on parts of the body 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, the subject with atopic hand and / or foot dermatitis also has AD lesions on parts of the body other than the hands and / or feet, but has a low overall BSA score over the whole body (e.g., less than 20%, less than 15%, or less than 10%). In some embodiments, the subject with atopic hand and / or foot dermatitis also has AD lesions on parts of the body other than the hands and / or feet, but has a low whole-body EASI (i.e., overall EASI over the whole body), for example, an EASI<21, or an EASI<16. In some embodiments, a subject with atopic hand and / or foot dermatitis also has AD lesions on parts of the body other than the hands and / or feet, but has a low systemic IGA (i.e., overall IGA over the entire body), e.g., an IGA≦2, or an IGA<2.

[0054] In some embodiments, the subject being treated has a BSA score <10%. In some embodiments, the subject being treated has an EASI <21. In some embodiments, the subject being treated has an IGA <2. In some embodiments, the subject being treated has a BSA score <10% and an EASI <21. In some embodiments, the subject being treated has a BSA score <10% and an IGA <2. In some embodiments, the subject being treated has a BSA score <10%, an EASI <21, and an IGA <2.

[0055] 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 dyshidrotic hand and / or foot AD.

[0056] 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 > 12 and < 17 years old.

[0057] In some embodiments, the subject being treated has or has had a concomitant type 2 inflammatory condition. As used herein, a "type 2 inflammatory condition" is a disease, disorder, or condition associated with a T helper 2 (Th2)-mediated immune response (Gandhi, et al., Nat Rev Drug Discov., 2016, 15(1):35-50). Non-limiting examples of type 2 inflammatory diseases include asthma, chronic sinusitis, allergic rhinitis, allergic fungal sinusitis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), 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), and atopic dermatitis. These conditions include aspirin hypersensitivity, nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (e.g., NSAIDs, exacerbated respiratory disease, or allergic rhinitis (NSAID-ERD), perennial allergic rhinitis (PAR), chronic eosinophilic pneumonia (CEP), and exercise-induced bronchospasm. In some embodiments, the subject has a concomitant atopic disease or condition selected from the group consisting of food allergy, atopic dermatitis, asthma, chronic sinusitis, allergic rhinitis, or allergic conjunctivitis.

[0058] In some embodiments, treatment with an IL-4R antagonist improves, alleviates, or reduces one or more symptoms of hand and / or foot AD in a subject, including, but not limited to, pruritus, xerosis (dry skin), eczematous lesions, erythema, papules, edema, oozing / crusting, excoriation, lichenification, sleep disorders, anxiety, and depression.

[0059] 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, the following: Investigator Global Assessment (IGA) of Hands and Feet, Modified Total Lesion Sign Score for Hands and Feet (mTLSS), Hand and Foot Pruritus Numerical Rating Scale (NRS), Hand and Foot Skin Pain NRS, Sleep NRS, Atopic Dermatitis Hand and Foot Area Involvement, Dermatology Quality of Life Index (DLQI), Patient Global Impression of Severity (PGIS), Patient 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 Measurement (POEM), Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Atopic Dermatitis Body Surface Area Involvement (BSA), Patient-Rated EQ-5D, and Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questionnaire (WPAI+CIQ). "Improvement in AD-related parameters" means an improvement (e.g., a decrease) from baseline in one or more parameters (e.g., IGA for hands and feet, mTLSS for hands and feet, pruritus NRS for hands and feet, skin pain NRS for hands and feet, etc.). The term "baseline," as used with respect to an AD-related parameter, refers to the value of the AD-related parameter for a subject before or at the start of administration of a pharmaceutical composition disclosed herein. In some embodiments, the AD-related parameter is a measure (e.g., questionnaire) specific for assessing the hands and / or feet. In some embodiments, the AD-related parameter is a general AD-based measure (e.g., questionnaire) (i.e., not specific for only the hands and / or feet).

[0060] To determine whether an AD-related parameter is "improved," the parameter is quantified at baseline and at one or more time points after administration of a pharmaceutical composition of the present disclosure. For example, AD-related parameters may be measured on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, day 15, day 22, day 25, day 29, day 36, day 43, day 50, day 57, day 64, day 71, day 85, or at the end of week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, or more after initial treatment with a pharmaceutical composition of the present disclosure. The difference between the value of the parameter at a particular time point after initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an "improvement" (e.g., a decrease) in the AD-related parameter. AD-related parameters are described in U.S. Patent Publication No. 2014 / 0072583, which is incorporated herein in its entirety.

[0061] In some embodiments, the AD-related parameters are assessed by the patient, hi some embodiments, the AD-related parameters are assessed by a physician or by a caregiver.

[0062] In some embodiments, subjects with hand and / or foot AD are selected for treatment based on having one or more of the following characteristics: (i) baseline IGA Hand and Foot score ≥ 3 (e.g., IGA Hand and Foot score 4); (ii) baseline mTLSS Hand and Foot score ≥ 16; (iii) baseline Hand and Foot Peak Pruritus NRS ≥ 4 (e.g., Hand and Foot Peak Pruritus NRS score ≥ 6); (iv) baseline hand and foot peak pain NRS ≥ 6; (v) baseline sleep NRS ≥ 5, and / or (vi) baseline hand and foot area involvement of atopic dermatitis of at least 24%, e.g., at least 25%, at least 30%, at least 35%, or more).

[0063] In some embodiments, subjects with hand and / or foot AD are selected for treatment based on having one or more of characteristics (i)-(vi) above, and are further selected based on having an overall (i.e., whole-body) BSA score <25% (e.g., <20%, <15%, or <10%) and / or an overall EASI <21 (e.g., <16).

[0064] In some embodiments, subjects with hand and / or foot AD are selected for treatment based on having a baseline mTLSS Hand and Foot score of ≥ 16. In some embodiments, subjects with hand and / or foot AD are selected for treatment based on having a baseline mTLSS Hand and Foot score of ≥ 16 and baseline hand and foot area involvement of atopic dermatitis of at least 24%. In some embodiments, subjects with hand and / or foot AD are selected for treatment based on having a baseline mTLSS Hand and Foot score of ≥ 16 and one or more of a baseline Hand and Foot Peak Pruritus NRS of ≥ 4, a baseline Hand and Foot Peak Pain NRS of ≥ 6, or a baseline Sleep NRS of ≥ 5.

[0065] In some embodiments, subjects with hand and / or foot AD are selected for treatment based on having a baseline mTLSS Hand and Foot score of ≥ 16 and an overall BSA score < 25%. In some embodiments, subjects with hand and / or foot AD are selected for treatment based on having a baseline mTLSS Hand and Foot score of ≥ 16, baseline hand and foot area involvement of atopic dermatitis 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 having one or more of a baseline mTLSS Hand and Foot score of ≥ 16, a baseline Hand and Foot Peak Pruritus NRS of ≥ 4, a baseline Hand and Foot Peak Pain NRS of ≥ 6, or a baseline Sleep NRS of ≥ 5, and an overall BSA score < 25%.

[0066] 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 and Foot score for the subject compared to baseline. Methods for determining the IGA Hand and Foot score for a subject are described in the Examples section below and in Table 2. In some embodiments, the subject being treated has a baseline IGA Hand and Foot score of ≥ 3 (e.g., an IGA Hand and Foot score of 3 or an IGA Hand and Foot score of 4). In some embodiments, the subject is selected for treatment based on having a baseline IGA Hand and Foot score of ≥ 3 (e.g., an IGA Hand and Foot score of 3 or an IGA Hand and Foot score of 4). In some embodiments, treatment with an IL-4R antagonist results in a reduction in the IGA Hand and Foot score of at least 1 point from baseline (e.g., from a baseline IGA Hand and Foot score of ≥ 3 or a baseline IGA Hand and Foot score = 4) by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in a reduction of an IGA Hand and Foot score from baseline (e.g., from an IGA Hand and Foot score ≧3 or an IGA Hand and Foot score = 4) to 0 or 1 by 3, 4, 8, 12, or 16 weeks after administration of the first dose of the IL-4R antagonist.

[0067] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the mTLSS Hands and Feet score for the subject compared to baseline. Methods for determining the mTLSS Hands and Feet score for a subject are described in the Examples section below and in Table 1. In some embodiments, the subject to be treated has a baseline mTLSS Hands and Feet score of ≧16. In some embodiments, the subject is selected for treatment based on having a baseline mTLSS Hands and Feet score of ≧16. In some embodiments, treatment with an IL-4R antagonist results in a reduction from baseline in the mTLSS Hands and Feet score of at least 2 points, at least 3 points, at least 4 points, at least 5 points, or more by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, or at least a 90% reduction from baseline in mTLSS Hand and Foot score by 3 weeks, 4 weeks, 8 weeks, 12 weeks, or 16 weeks after administration of the first dose of the IL-4R antagonist.

[0068] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the Hands and Feet Peak Pruritus NRS score for a subject compared to baseline. Methods for determining a subject's Hands and Feet Peak Pruritus NRS score are described in the Examples section below. In some embodiments, the Hands and Feet Peak Pruritus NRS score is the weekly average of the daily Hands and Feet Peak Pruritus NRS scores. In some embodiments, the treated subject has a baseline Hands and Feet Peak Pruritus NRS of ≧4. In some embodiments, the subject is selected for treatment based on having a baseline Hands and Feet Peak Pruritus NRS of ≧4. In some embodiments, treatment with an IL-4R antagonist results in a reduction from baseline in the Hands and Feet Peak Pruritus NRS score of at least 1, 2, 3, or 4 points by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, or at least a 90% reduction from baseline in the Hands and Feet Peak Pruritus NRS score by 3 weeks, 4 weeks, 8 weeks, 12 weeks, or 16 weeks after administration of the first dose of the IL-4R antagonist.

[0069] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the Hand and Foot Peak Pain NRS score for the subject compared to baseline. Methods for determining the Hand and Foot Peak Pain NRS score for a subject are described in the Examples section below. In some embodiments, the Hand and Foot Peak Pain NRS score is a weekly average of the daily Hand and Foot Peak Pain NRS scores. In some embodiments, the subject to be treated has a baseline Hand and Foot Peak Pain NRS of ≧6. In some embodiments, the subject is selected for treatment based on having a baseline Hand and Foot Peak Pain NRS of ≧6. In some embodiments, treatment with an IL-4R antagonist results in a reduction in the Hand and Foot Peak Pain NRS score from baseline of at least 1, 2, 3, or 4 points by 3, 4, 8, 12, or 16 weeks after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, or at least a 90% reduction from baseline in Hand and Foot Peak Pain NRS score by 3 weeks, 4 weeks, 8 weeks, 12 weeks, or 16 weeks after administration of the first dose of the IL-4R antagonist.

[0070] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in the sleep NRS score for the subject compared to baseline. Methods for determining the sleep NRS score for a subject are described in the Examples section below. In some embodiments, the sleep NRS score is a weekly average of the daily sleep NRS scores. In some embodiments, the treated subject has a baseline sleep NRS of ≧5. In some embodiments, the subject is selected for treatment based on having a baseline sleep NRS of ≧5. In some embodiments, treatment with an IL-4R antagonist results in a reduction of at least 1 point from baseline in the sleep NRS score by 3 weeks, 4 weeks, 8 weeks, 12 weeks, or 16 weeks after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, or at least a 90% reduction from baseline in sleep NRS score by 3 weeks, 4 weeks, 8 weeks, 12 weeks, or 16 weeks after administration of the first dose of the IL-4R antagonist.

[0071] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in hand and foot area involvement in the atopic dermatitis score for the subject compared to baseline (e.g., a reduction in the percentage of surface area of ​​hand and foot involvement associated with AD). In some embodiments, the subject being treated has a baseline hand and foot area involvement of at least 24%, e.g., at least 25%, at least 30%, at least 35%, or more of atopic dermatitis. In some embodiments, the subject is selected for treatment based on having a baseline hand and foot area involvement of at least 24%, e.g., at least 25%, at least 30%, at least 35%, or more of atopic dermatitis. In some embodiments, treatment with an IL-4R antagonist results in at least a 10%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 40%, at least a 50%, or at least a 60% reduction from baseline in the surface area of ​​the AD-affected hands and feet by 3, 4, 8, 12, or 16 weeks after administration of the first dose of the IL-4R antagonist.

[0072] 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 for the subject compared to baseline. Methods for determining the HECSI score for a subject are described in the Examples section below. In some embodiments, the subject being treated has a baseline HECSI score of ≧46, e.g., at least 50, at least 55, at least 60, at least 65, at least 70, or higher. In some embodiments, the subject is selected for treatment based on having a baseline HECSI score of ≧46, e.g., at least 50, at least 55, at least 60, at least 65, at least 70, or higher. In some embodiments, treatment with an IL-4R antagonist results in a reduction in the HECSI score from baseline of at least 15, 20, 25, 30, or more points by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, or at least a 90% reduction from baseline in the HECSI score by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in the subject achieving a HECSI-50 (i.e., at least a 50% reduction in the HECSI score) by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist. In some embodiments, treatment with an IL-4R antagonist results in the subject achieving HECSI-75 (i.e., at least a 75% reduction in HECSI score) by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist.In some embodiments, treatment with an IL-4R antagonist results in the subject achieving a HECSI-90 (i.e., at least a 90% reduction in HECSI score) by week 3, week 4, week 8, week 12, or week 16 after administration of the first dose of the IL-4R antagonist.

[0073] In some embodiments, treatment with an IL-4R antagonist according to the methods of the present disclosure results in an improvement in health-related quality of life for a subject compared to baseline, as measured, for example, by DLQI or QoLHEQ. In some embodiments, treatment with an IL-4R antagonist results in at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least a 75%, at least a 80%, or at least a 90% improvement from baseline in a health-related quality of life measure by 3 weeks, 4 weeks, 8 weeks, 12 weeks, or 16 weeks after administration of the first dose of the IL-4R antagonist.

[0074] In some embodiments, treatment with an IL-4R antagonist reduces the need for rescue therapy (e.g., due to AD flare-ups, due to lesions that persist or worsen under daily treatment, or due to intolerable symptoms). In some embodiments, treatment with an IL-4R antagonist reduces the need for local rescue therapy (e.g., topical corticosteroids, such as mid-potency or high-potency TCS, TCIs, 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).

[0075] Interleukin-4 receptor antagonist In some embodiments, the methods of the present disclosure comprise administering to a subject in need thereof (e.g., a subject with moderate to severe atopic dermatitis of the hands and / or feet) 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 type 1 and / or type 2 IL-4 receptors. Human IL-4Rα has the amino acid sequence of SEQ ID NO: 11. Type 1 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and a γc chain. Type 2 IL-4 receptor is a dimeric receptor comprising an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptor interacts with and is stimulated by IL-4, while type 2 IL-4 receptor interacts with and is stimulated by both IL-4 and IL-13. Thus, IL-4R antagonists that can be used in the methods of the present disclosure can function by blocking IL-4-mediated signaling, IL-13-mediated signaling, or both IL-4- and IL-13-mediated signaling. IL-4R antagonists of the present disclosure can thus prevent the interaction of IL-4 and / or IL-13 with the type 1 or type 2 receptor.

[0076] Non-limiting examples of categories of IL-4R antagonists include small molecule IL-4R inhibitors, anti-IL-4R aptamers, peptide-based IL-4R inhibitors (e.g., "peptibody" molecules), "receptor-bodies" (e.g., engineered molecules containing the ligand-binding domain of an IL-4R component), and antibodies or antigen-binding fragments of antibodies that specifically bind to human IL-4Rα. As used herein, IL-4R antagonists also include antigen-binding proteins that specifically bind to IL-4 and / or IL-13.

[0077] Anti-IL-4Rα antibodies and their antigen-binding fragments In certain exemplary embodiments of the present disclosure, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof. The term "antibody," as used herein, includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (herein referred to as HCVR or VL). H The heavy chain constant region comprises three domains: C H 1. C H 2, and C H Each light chain comprises a light chain variable region (herein referred to as LCVR or V L The light chain constant region comprises one domain (C L 1) V H Area and V L The regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) are identical to human germline sequences. In some embodiments, one or more FRs of an anti-IL-4R antibody (or antigen-binding portion thereof) are naturally or artificially modified.

[0078] The term "antibody," as used herein, also includes antigen-binding fragments of intact antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from intact antibody molecules using any suitable standard method, such as proteolytic or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, e.g., phage antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to place one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids, etc.

[0079] 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 mimicking the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed by the term "antigen-binding fragment" as used herein.

[0080] Antigen-binding fragments of antibodies typically contain at least one variable domain, which may be of any size or amino acid composition and generally contains at least one CDR adjacent to, or in frame with, one or more framework sequences. L V associated with the domain H In an antigen-binding fragment having a domain, V H Domain and V L The domains can be arranged relative to each other in any suitable configuration. For example, the variable region is a dimer and the V H -V H , V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may comprise a dimer of monomeric V H or V L It may include a domain.

[0081] In certain embodiments, an antigen-binding fragment of an antibody may comprise at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) a V H -C H 1, (ii) V H -C H 2, (iii) V H -C H 3, (iv) V H -C H 1-C H 2. (v) V H -C H 1-C H 2-C H 3. (vi) V H -C H 2-C H 3, (vii)V H -C L , (viii) V L -C H 1, (ix)V L -C H 2. (x)V L -C H 3. (xi) VL -C H 1-C H 2, (xii)V L -C H 1-C H 2-C H 3, (xiii)V L -C H 2-C H 3, and (xiv) V L -C L In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. A hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that provide a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the present disclosure may be linked to each other and / or to one or more monomeric V H Or V L It may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations listed above in non-covalent association with the domains (e.g., via disulfide bonds).

[0082] The constant region of an antibody is important in 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 it is desirable for the antibody to mediate cytotoxicity.

[0083] The term "antibody," as used herein, also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies typically contain at least two different variable domains, each capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in the context of the antibodies or antigen-binding fragments of antibodies of the present disclosure using routine techniques available in the art. For example, in some embodiments, the methods of the present disclosure include the use of bispecific antibodies in which one arm of the immunoglobulin is specific for IL-4Rα or a fragment thereof and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present disclosure include, but are not limited to, for example, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, Quadroma, knob-into-hole, common light chain (e.g., common light chain with knob-into-hole), CrossMab, CrossFab, (SEED) body, leucine zipper, duobody, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab 2 Bispecific antibodies include bispecific formats (for a review of such formats, 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 conjugation, e.g., using unnatural amino acids with orthogonal chemical reactivity to generate site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with defined composition, valency, and geometry. (See, e.g., Kazane, et al., J. Am. Chem. Soc. [Epub: December 4, 2012]).

[0084] In some embodiments, the antibodies used in the methods of the present disclosure are human antibodies. The term "human antibody," as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies of the present disclosure may nevertheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example, in the CDRs, particularly CDR3. However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0085] The antibody used in the methods of the present disclosure may be a recombinant human antibody. The term "recombinant human antibody," as used herein, is intended to include all human antibodies prepared, expressed, generated, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector (described further below) transfected into a host cell, antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, generated, or isolated by any other means, including splicing human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, when animals transgenic for human Ig sequences are used), thus improving the V H Area and V L The amino acid sequence of the region is human germline V H Sequence and V LThese are sequences that, while derived from and related to sequences, may not naturally occur within the human antibody germline repertoire in vivo.

[0086] An "isolated antibody" refers to an antibody that has been identified, 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 the tissue or cell in which it is naturally present or produced, is an "isolated antibody." An isolated antibody also includes an antibody in situ within a recombinant cell. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0087] According to certain embodiments, the antibody used in the methods of the present disclosure specifically binds to IL-4Rα. As used herein, the term "specifically binds" means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. In some embodiments, an antibody that "specifically binds" to IL-4Rα has an equilibrium dissociation constant (K) of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 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™, Biacore Life Sciences division of GE Healthcare, Piscataway, NJ). D) binds to IL-4Rα or a portion thereof. In some embodiments, an antibody that specifically binds to a target antigen (e.g., IL-4Rα) can 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 to human IL-4Rα exhibits cross-reactivity to other antigens, such as IL-4Rα molecules from other (non-human) species.

[0088] 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 a complementarity-determining region (CDR) comprising any of the amino acid sequences of the anti-IL-4R antibodies set forth in U.S. Patent No. 7,608,693, 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) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1, and a light chain complementarity-determining region (LCDR) of the 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 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).

[0089] 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 HCDR3 comprising the amino acid sequence MQALQTPYT (SEQ ID NO: 7). SEQ ID NO: 8), and further comprises a HCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 1 and a LCVR having at least 85% sequence identity (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-4R antibody or antigen-binding fragment thereof comprises a HCVR comprising SEQ ID NO: 1 and a LCVR comprising SEQ ID NO: 2.

[0090] 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.

[0091] An exemplary antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10 is the fully human anti-IL-4R antibody known as dupilumab. According to certain exemplary embodiments, the methods of the present disclosure include the use of dupilumab. As used herein, "dupilumab" also includes bioequivalents of dupilumab. The term "bioequivalent," as used herein with reference to dupilumab, refers to an anti-IL-4R antibody or IL-4R binding protein, or fragment thereof, that is a pharmaceutical equivalent or pharmaceutical substitute, whose rate and / or extent of absorption is not significantly different from that of dupilumab when administered at the same molar dose under similar experimental conditions, either in a single dose or multiple doses. In some embodiments, the term refers to an antigen-binding protein that binds to IL-4R that has no clinically meaningful differences from dupilumab in safety, purity, and / or efficacy.

[0092] Other anti-IL-4Rα antibodies that can be used in the context of the disclosed methods include, for example, AMG317 (Corren, et al., 2010, Am J Respir Crit Care Med., 181(8):788-796), or MEDI 9314, or any of the anti-IL-4Rα antibodies set forth in U.S. Patent No. 7,186,809, U.S. Patent No. 7,605,237, U.S. Patent No. 7,638,606, U.S. Patent No. 8,092,804, U.S. Patent No. 8,679,487, U.S. Patent No. 8,877,189, U.S. Patent No. 10,774,141, or International Patent Publication Nos. WO2020 / 096381, WO2020 / 182197, WO2020 / 239134, WO2021 / 213329, WO2022 / 052974, WO2022 / 136669, or WO2022 / 136675, the contents of each of which are incorporated herein by reference.

[0093] In some embodiments, anti-IL-4Rα antibodies or antigen-binding fragments thereof for use in the methods of the disclosure comprise one or more CDR, HCVR, and / or LCVR sequences shown in Table 9 below.

[0094] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of i) SEQ ID NO:32 (SCB-VH-59), SEQ ID NO:33 (SCB-VH-60), SEQ ID NO:34 (SCB-VH-61), SEQ ID NO:35 (SCB-VH-62), SEQ ID NO:36 (SCB-VH-63), SEQ ID NO:37 (SCB-VH-64), SEQ ID NO:38 (SCB-VH-65), SEQ ID NO:39 (SCB-VH-66), SEQ ID NO:40 (SCB-VH-67), SEQ ID NO:41 (SCB-VH-68), SEQ ID NO:42 (SCB-VH-69), SEQ ID NO:43 (SCB-VH-70), SEQ ID NO:44 (SCB-VH-71), SEQ ID NO:45 (SCB-VH-72), SEQ ID NO:46 (SCB-VH-73), SEQ ID NO:47 (SCB-VH-74), SEQ ID NO:48 (SCB-VH-75), SEQ ID NO:49 (SCB-VH-80), SEQ ID NO:50 (SCB-VH-81), SEQ ID NO:51 (SCB-VH-82), SEQ ID NO:52 (SCB-VH-83), SEQ ID NO:53 (SCB-VH-84), SEQ ID NO:54 (SCB-VH-85), SEQ ID NO:55 (SCB-VH-86), SEQ ID NO:56 (SCB-VH-87), SEQ ID NO:57 (SCB-VH-88), SEQ ID NO:58 (SCB-VH-89), SEQ ID NO:59 (SCB-VH-90), SEQ ID NO:60 (SCB-VH 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 HCVRs 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), 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),In some embodiments, the anti-IL-4Rα antibody comprises an HCVR comprising the amino acid sequence of 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).

[0095] In some embodiments, the anti-IL-4Rα antibody comprises a pair of amino acid sequences selected from the group consisting of SEQ ID NOs: 67 / 68 (MEDI-1-VH / MEDI-1-VL), SEQ ID NOs: 69 / 70 (MEDI-2-VH / MEDI-2-VL), SEQ ID NOs: 71 / 72 (MEDI-3-VH / MEDI-3-VL), SEQ ID NOs: 73 / 74 (MEDI-4-VH / MEDI-4-VL), SEQ ID NOs: 75 / 76 (MEDI-5-VH / MEDI-5-VL), SEQ ID NOs: 77 / 78 (MEDI-6-VH / MEDI-6-VL), SEQ ID NOs: 79 / 80 (MEDI-8-VH / MEDI-8-VL), SEQ ID NOs: 81 / 82 (MEDI-8-VH / MEDI-8-VL), SEQ ID NOs: 83 / 84 (MEDI-8-VH / MEDI-8-VL), SEQ ID NOs: 85 / 86 (MEDI-8-VH / MEDI-8-VL), SEQ ID NOs: 87 / 88 (MEDI-8-VH / MEDI-8-VL), SEQ ID NOs: 89 / 90 (MEDI-9-VH / MEDI-9-VL), SEQ ID NOs: 91 / 92 (MEDI-9-VH / MEDI-9-VL), SEQ ID NOs: 92 / 93 (MEDI-9-VH / MEDI-9-VL), SEQ ID NOs: 93 / 94 (MEDI-9-VH / MEDI-9-VL), SEQ ID NOs: 94 / 95 (MEDI-9-VH / MEDI-9-VL), SEQ ID NOs: 95 / 96 (MEDI-9-VH / MEDI-7-VH / MEDI-7-VL), SEQ ID NOs: 81 / 82 (MEDI-8-VH / MEDI-8-VL), SEQ ID NOs: 83 / 84 (MEDI-9-VH / MEDI-9-VL), SEQ ID NOs: 85 / 86 (MEDI-10-VH / MEDI-10-VL), SEQ ID NOs: 87 / 88 (MEDI-11-VH / MEDI-11-VL), SEQ ID NOs: 89 / 90 (MEDI-12-VH / MEDI-12-VL), SEQ ID NOs: 91 / 92 (MEDI-13-VH / MEDI-13-VL), SEQ ID NOs: 93 / 94 (MEDI-14-VH / MEDI-14-VL) L), 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), Sequence numbers 109 / 110 (MEDI-22-VH / MEDI-22-VL), sequence numbers 111 / 112 (MEDI-23-VH / MEDI-23-VL), sequence numbers 113 / 114 (MEDI-24-VH / MEDI-24-VL), sequence numbers 115 / 116 (MEDI-25-VH / MEDI-25-VL), sequence numbers 117 / 118 (MEDI-26-VH / MEDI-26-VL), sequence numbers 119 / 120 (MEDI-27-VH / MEDI-27-VL), sequence numbers 121 / 122 (MEDI-28-VH / MEDI-28-VL),SEQ ID NOs: 123 / 124 (MEDI-29-VH / MEDI-29-VL), SEQ ID NOs: 125 / 126 (MEDI-30-VH / MEDI-30-VL), SEQ ID NOs: 127 / 128 (MEDI-31-VH / MEDI-31-VL), SEQ ID NOs: 129 / 130 (MEDI-32-VH / MEDI-32-VL), SEQ ID NOs: 131 / 132 (MEDI-33-VH / MEDI-33-VL), SEQ ID NOs: 133 / 134 (MEDI-34-VH / MEDI-34-VL), SEQ ID NOs: 135 / 136 (MEDI-35-VH / MEDI-35-VL), SEQ ID NOs: 137 / 138 (MEDI-36-VH / MEDI-36-VL) SEQ ID NOs: 139 / 140 (MEDI-37-VH / MEDI-37-VL), SEQ ID NOs: 141 / 142 (MEDI-38-VH / MEDI-38-VL), SEQ ID NOs: 143 / 144 (MEDI-39-VH / MEDI-39-VL), SEQ ID NOs: 145 / 146 (MEDI-40-VH / MEDI-40-VL), SEQ ID NOs: 147 / 148 (MEDI-41-VH / MEDI-41-VL), SEQ ID NOs: 149 / 150 (MEDI-42-VH / MEDI-42-VL), and SEQ ID NOs: 151 / 152 (MEDI-37GL-VH / MEDI-37GL-VL).

[0096] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of i) 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- (i) an HCVR 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-VH), SEQ ID NO: 175 (AJOU-40-VH), SEQ ID NO: 176 (AJOU-41-VH), SEQ ID NO: 177 (AJOU-42-VH), SEQ ID NO: 178 (AJOU-43-VH), SEQ ID NO: 179 (AJOU-44-VH), SEQ ID NO: 180 (AJOU-45-VH), SEQ ID NO: 181 (AJOU-46-VH), SEQ ID NO: 182 (AJOU-47-VH), SEQ ID NO: 183 (AJOU-48-VH), SEQ ID NO: 184 (AJOU-49-VH), SEQ ID NO: 185 (AJOU-50-VH), SEQ ID NO: 186 (AJOU-51-VH), SEQ ID NO: 187 (AJOU-52-VH), SEQ ID NO: 188 (AJOU-53-VH), SEQ ID NO: 189 (AJOU-54-VH), SEQ ID NO: 190 (AJOU-55-VH), SEQ ID NO: 191 (AJOU-56-VH), SEQ ID NO: 192 (AJOU-57-V Sequence number 170 (AJOU-35-VL), sequence number 171 (AJOU-36-VL), sequence number 172 (AJOU-37-VL), sequence number 173 (AJOU-38-VL), sequence number 174 (AJOU-39-VL), sequence number 175 (AJOU-40-VL), sequence number 176 (AJOU-41-VL), sequence number 177 (AJOU-42-VL), sequence number 178 (AJOU-77-VL), sequence number 179 (AJOU-40-VL), sequence number 180 (AJOU-41-VL), sequence number 181 (AJOU-42-VL), sequence number 182 (AJOU-42-VL), sequence number 183 (AJOU-42-VL), sequence number 184 (AJOU-42-VL), sequence number 185 (AJOU-42-VL), sequence number 186 (AJOU-42-VL), sequence number 187 (AJOU-42-VL), sequence number 188 (AJOU-42-VL), sequence number 189 (AJOU-42-VL), sequence number 190 (AJOU-42-VL), sequence number 191 (AJOU-42-VL), sequence number 192 (AJOU-42-VL), sequence number 193 (AJOU-42-VL), sequence number 194 (AJOU-42-VL), sequence number 195 (AJOU-42-VL), sequence number 196 (AJOU-42-VL), sequence number 197 (AJOU-42-VL), sequence number 198 (AJOU-42-VL), sequence number 199 (AJOU-42-VL), sequence and an LCVR comprising the amino acid sequence of SEQ ID NO: 180 (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).

[0097] In some embodiments, the anti-IL-4Rα antibody (i) comprises 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 HCVR 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).

[0098] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of: (i) 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-C27-80-80-80-VH), SEQ ID NO: 217 (STSA-C27-81-81-81-VH), SEQ ID NO: 218 (STSA-C27-82-82-82-VH), SEQ ID NO: 219 (STSA-C27-83-83-83-VH), SEQ ID NO: 220 (STSA-C27-84-84-84-VH), SEQ ID NO: 221 (STSA-C27-85-85-85-VH), SEQ ID NO: 222 (STSA-C27-86-86-86-VH), SEQ ID NO: 223 (STSA-C27-87-87-87-VH), SEQ ID NO: 224 (STSA-C27-88-88-VH), SEQ ID NO: 225 (STSA-C27-89-89-89-VH), A-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 (ST and (ii) an HCVR 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), or 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 an LCVR comprising the amino acid sequence of SEQ ID NO: 243 (STSA-C27-Y2-Y2-VL).

[0099] In some embodiments, the anti-IL-4Rα antibody is selected from the group consisting of i) SEQ ID NO:244 (Y0188-1 VH), SEQ ID NO:245 (Y0188-2 VH), SEQ ID NO:246 (Y0188-3 VH), SEQ ID NO:247 (Y0188-4 VH), SEQ ID NO:248 (Y0188-6 VH), SEQ ID NO:249 (Y0188-8 VH), SEQ ID NO:250 (Y0188-9 VH), SEQ ID NO:251 (Y0188-10 VH), SEQ ID NO:252 (Y0188-14 VH), SEQ ID NO:253 (HV3-15-14 VH), SEQ ID NO:254 (HV3-48-14 VH), SEQ ID NO:255 (HV3-73*2-14 VH), SEQ ID NO:256 (HV3-72-14 VH), SEQ ID NO:257 (Y0188-14 VH), SEQ ID NO:258 (Y0188-14 VH), SEQ ID NO:259 (Y0188-14 VH), SEQ ID NO:260 (Y0188-14 VH), SEQ ID NO:261 (Y0188-14 VH), SEQ ID NO:262 (Y0188-14 VH), SEQ ID NO:263 (Y0188-14 VH), SEQ ID NO:264 (Y0188-14 VH), SEQ ID NO:265 (Y0188-14 VH), SEQ ID NO:266 (Y0188-14 VH), SEQ ID NO:267 (Y0188-14 VH), SEQ ID NO:268 (Y and (ii) an HCVR comprising the amino acid sequence of SEQ ID NO:260 (Y0188-1 VL), SEQ ID NO:261 (Y0188-2 VL), SEQ ID NO:262 (Y0188-3 VL), SEQ ID NO:263 (Y0188-4 VL), SEQ ID NO:264 (Y0188-6 VL), SEQ ID NO:265 (Y0188-8 VL), SEQ ID NO:266 (Y0188-9 VL), SEQ ID NO:267 (Y0188-10 VL), SEQ ID NO:268 (Y0188-14 VL), SEQ ID NO:269 (Y01-14 VL), SEQ ID NO:270 (164-14 VL), SEQ ID NO:271 (KV4-14 VL), SEQ ID NO: 272 (KV1-27-14 VL), SEQ ID NO: 273 (KV1-9-14 VL), SEQ ID NO: 274 (KV1-NL1-14 VL), or SEQ ID NO: 275 (KV1D-43-14 VL).

[0100] In some embodiments, the anti-IL-4Rα antibodies used in the methods of the present disclosure may have pH-dependent binding properties. For example, an anti-IL-4Rα antibody for use disclosed herein may exhibit reduced binding to IL-4Rα at acidic pH compared to neutral pH. Alternatively, an anti-IL-4Rα antibody for use disclosed herein may exhibit enhanced binding to its antigen at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values ​​below about 6.2, e.g., 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 lower. As used herein, the expression "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0101] In certain instances, "reduced binding to IL-4Rα at acidic pH compared to neutral pH" refers to the K D values ​​and the K of antibodies binding to IL-4Rα at neutral pH D For example, an antibody or antigen-binding fragment thereof is defined for purposes of this disclosure as having an acidic / neutral K of about 3.0 or greater. D When a ratio is presented, it can be taken as indicating "reduced binding to IL-4Rα at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K for an antibody or antigen-binding fragment of the present disclosure D The ratio 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 more.

[0102] Antibodies with pH-dependent binding properties may be obtained, for example, by screening a population of antibodies for decreased (or increased) binding to a particular antigen at acidic pH compared to neutral pH. In addition, modification of the antigen-binding domain at the amino acid level may produce antibodies with pH-dependent properties. For example, substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues may result in an antibody with decreased antigen binding at acidic pH compared to neutral pH.

[0103] Preparation of human antibodies 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 generate human antibodies that specifically bind to human IL-4R.

[0104] Using VELOCIMMUNE™ technology (see, e.g., U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, a high-affinity chimeric antibody against IL-4R is first isolated and has a human variable region and a mouse constant region. VELOCIMMUNE® technology involves the generation of transgenic mice whose genomes contain human heavy and light chain variable regions operably linked to endogenous mouse constant region loci, such that the mice produce antibodies containing human variable regions and mouse constant regions in response to antigenic challenge. DNA encoding the antibody heavy and light chain variable regions is isolated and operably linked to DNA encoding human heavy and light chain constant regions. The DNA is then expressed in cells capable of expressing fully human antibodies.

[0105] Generally, VELOCIMMUNE® mice are challenged with an antigen of interest, and lymphocytes (e.g., B cells) are collected from the mice that express antibodies. The lymphocytes may be fused with a myeloma cell line to prepare immortal hybridoma cell lines, which are then screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the heavy and light chain variable regions may be isolated and linked to the desired heavy and light chain isotype constant regions. Such antibody proteins may be produced in cells, such as CHO cells. Alternatively, DNA encoding the antigen-specific chimeric antibody or the light and heavy chain variable domains may be isolated directly from antigen-specific lymphocytes.

[0106] First, a high-affinity chimeric antibody is isolated, having a human variable region and a mouse constant region. The antibody is characterized and selected for desirable properties, including affinity, selectivity, epitope, etc., using standard procedures known to those skilled in the art. The mouse constant region is replaced with a desired human constant region to generate a fully human antibody of the present disclosure, e.g., wild-type or modified IgG1 or IgG4. While the constant region selected can vary according to the specific use, the high-affinity antigen-binding and target specificity properties reside in the variable region.

[0107] Generally, antibodies that can be used in the methods of the present disclosure have high affinity, as described above, as measured by binding to antigen immobilized either on a solid phase or in solution. The mouse constant region is replaced with a desired human constant region to generate a fully human antibody of the present disclosure. While the constant region selected can vary according to the specific use, the high affinity antigen binding and target specificity properties reside in the variable region.

[0108] 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 HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the identified HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary rules that can be used to identify CDR boundaries include, for example, the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani, et al., J. Mol. Biol. 273:927-948 (1997); and Martin, et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within antibodies.

[0109] Pharmaceutical Composition In one aspect, the present disclosure provides a method comprising administering to a subject an IL-4R antagonist, wherein the IL-4R antagonist (e.g., an anti-IL-4R antibody) is contained within a pharmaceutical composition comprising one or more pharmaceutically acceptable solvents, 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.

[0110] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions may be administered by any conventional route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other biologically active agents. In some embodiments, the pharmaceutical compositions disclosed herein are administered intravenously. In some embodiments, the pharmaceutical compositions disclosed herein are administered subcutaneously.

[0111] In some embodiments, the pharmaceutical composition includes an injectable preparation, such as a dosage form for intravenous injection, subcutaneous injection, intradermal injection, and intramuscular injection, infusion, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparation can be prepared by dissolving, suspending, or emulsifying the antibody or salt thereof described above in a sterile aqueous or oily medium conventionally used for injection. Aqueous media for injection include, for example, saline, isotonic solutions containing glucose, and other auxiliary agents, which may be used in combination with suitable solubilizing agents such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. Oily media include, for example, sesame oil, soybean oil, etc., which may be used in combination with solubilizing agents such as benzyl benzoate, benzyl alcohol, etc. The injection solution thus prepared can be filled into suitable ampoules.

[0112] The dose of an antibody administered to a subject according to the methods of the present disclosure may vary depending on the subject's age and size, symptoms, condition, route of administration, and the like. Doses are typically calculated according to body weight or body surface area. The frequency and duration of treatment can be adjusted depending on the severity of the condition. Effective dosages and schedules for administering pharmaceutical compositions containing anti-IL-4R antibodies may be determined empirically; for example, the subject's progress can be monitored by periodic evaluation, and the dosage adjusted accordingly. Furthermore, 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 doses of anti-IL4R antibodies that can be used in the context of the present disclosure, and dosing regimens including the same, are disclosed elsewhere herein.

[0113] In some embodiments, the IL-4R antagonist or pharmaceutical composition of the present disclosure is contained within a container. Thus, in another aspect, a container is provided comprising an IL-4R antagonist or pharmaceutical composition disclosed herein. For example, in some embodiments, the pharmaceutical composition is contained within a container selected from the group consisting of a glass vial, a syringe, a pen delivery device, and an auto-injector.

[0114] In some embodiments, the pharmaceutical compositions of the present disclosure are delivered using a standard needle and syringe, e.g., subcutaneously or intravenously. In some embodiments, the syringe is a pre-filled syringe. In some embodiments, a pen delivery device or auto-injector is used to deliver the pharmaceutical compositions of the present disclosure (e.g., for subcutaneous delivery). The pen delivery device can be reusable or disposable. Typically, reusable pen delivery devices utilize a replaceable cartridge containing the pharmaceutical composition. Once the pharmaceutical composition in the cartridge is administered and the cartridge is emptied, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In disposable pen delivery devices, there is no replaceable cartridge. Rather, the disposable pen delivery device comes pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0115] Examples of suitable pen and autoinjector delivery devices include, but are not limited to, the AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), the DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), the HUMALOG MIX 75 / 25™ pen, the HUMALOG™ pen, the HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), the NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), the NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), the BD™ pen (Becton Dickinson, Franklin Lakes, NJ), the OPTIPEN™, the OPTIPEN PRO™, the OPTIPEN Examples of disposable pen delivery devices having application in the subcutaneous delivery of pharmaceutical compositions of the present disclosure include, but are not limited to, the SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), the SURECLICK™ autoinjector (Amgen, Thousand Oaks, CA), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ pen (Abbott Labs, Abbott Park, IL).

[0116] In some embodiments, the pharmaceutical composition is delivered using a controlled-release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, a polymeric material may 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 may be placed in proximity to the target of the composition, thus requiring only a fraction of the systemic dose (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 pharmaceutical compositions, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis, etc. (See, e.g., Wu, et al., 1987, J. Biol. Chem. 262:4429-4432).

[0117] In some embodiments, a pharmaceutical composition comprising an anti-IL-4R antibody is administered using a drug delivery device that is a needle-based injection system as described in Table 1 of Section 5.2 of ISO 11608-1:2014(E). As described in ISO 11608-1:2014(E), needle-based injection systems can be broadly distinguished between multi-dose container systems and single-dose (with partial or complete exclusion) container systems. The container may be an exchangeable container or a one-piece, non-exchangeable container.

[0118] As further described in ISO 11608-1:2014(E), a multi-dose container system may include a needle-based injection device with an exchangeable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user). Another multi-dose container system may include a needle-based injection device with a unitary, non-exchangeable container. In such a system, each container holds multiple doses, the size of which may be fixed or variable (pre-set by the user).

[0119] As further described in ISO 11608-1:2014(E), a single-dose container system may include a needle-based injection device with an exchangeable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (full discharge). In a further example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partial discharge). Also, as described in ISO 11608-1:2014(E), a single-dose container system may include a needle-based injection device with a unitary, non-exchangeable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (full discharge). In a further example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partial discharge).

[0120] An exemplary sleeve-trigger autoinjector with manual needle insertion is described in International Publication WO 2015 / 004052. Exemplary audible end-of-dose feedback mechanisms are described in International Publication WO 2016 / 193346 and WO 2016 / 193348. An exemplary needle safety mechanism after use of the autoinjector is described in International Publication WO 2016 / 193352. An exemplary needle sheath removal mechanism for a syringe autoinjector is described in International Publication WO 2016 / 193353. An exemplary support mechanism for supporting the axial position of a syringe is described in International Publication WO 2016 / 193355.

[0121] In some embodiments, the pharmaceutical compositions for use as described herein are prepared in dosage forms in unit doses that are compatible with the dosage of the active ingredient.Such dosage forms in unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0122] Exemplary pharmaceutical compositions comprising anti-IL-4R antibodies that can be used in the context of the present disclosure are disclosed, for example, in US Pat. No. 8,945,559.

[0123] Dosage and Administration In some embodiments, an IL-4R antagonist (e.g., an anti-IL-4R antibody) is administered in a therapeutically effective amount to a subject (e.g., a subject with moderate to severe atopic hand and / or foot dermatitis) according to the methods of the present disclosure. As used herein with reference to an IL-4R antagonist, the phrase "therapeutically effective amount" means an amount of IL-4R antagonist that results in one or more of: (a) an improvement in one or more AD-related parameters (as referred to elsewhere herein), and / or (b) a detectable improvement in one or more symptoms or signs of atopic hand and / or foot dermatitis.

[0124] In the case of an anti-IL-4R antibody, the therapeutically effective amount is about 0.05 mg to about 600 mg, for example, about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg The amount of the anti-IL-4R antibody can be about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. In some embodiments, the therapeutically effective amount is about 50 mg to about 600 mg, or about 100 mg to about 600 mg, or about 200 mg to about 600 mg. In specific 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 an anti-IL-4R antibody is administered to a subject.

[0125] The amount of IL-4R antagonist (e.g., anti-IL-4R antibody) contained in an individual dose may be expressed in units of milligrams of antibody per kilogram of the subject's body weight (i.e., mg / kg). For example, the IL-4R antagonist may be administered to a subject at a dose of about 0.0001 to about 10 mg / kg of the subject's body weight, e.g., at a dose of about 1 mg / kg to about 10 mg / kg, at a dose of about 2 mg / kg to about 9 mg / kg, or at a dose of about 3 mg / kg to about 8 mg / kg. In some embodiments, the IL-4R antagonist may 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.

[0126] In some embodiments, the methods disclosed herein comprise 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 12 weeks, or less frequently, so long as a therapeutic response is achieved.

[0127] In some embodiments, multiple doses of an IL-4R antagonist are administered to a subject over a defined time course. In some embodiments, the methods of the present disclosure comprise sequentially administering multiple doses of an IL-4R antagonist to a subject. As used herein, "sequentially administering" means that each dose of the IL-4R antagonist is administered to the subject at different time points, for example, on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). In some embodiments, the methods of the present disclosure comprise sequentially administering to a patient a single initial dose of an IL-4R antagonist, followed by one or more secondary doses of the IL-4R antagonist, and optionally, one or more tertiary doses of the IL-4R antagonist.

[0128] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the temporal order of administration of an IL-4R antagonist. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also referred to as a "loading dose"), a "secondary dose" is a dose administered after the initial dose, and a "tertiary dose" is a dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-4R antagonist, but may generally differ from one another with respect to the frequency of administration. In certain embodiments, however, the amount of IL-4R antagonist contained in the initial, secondary, and / or tertiary doses varies from one another during the course of treatment (e.g., adjusted up or down, if appropriate). In certain embodiments, one or more doses (e.g., 1, 2, 3, 4, or 5) are administered as a "loading dose" at the beginning of a treatment regimen, followed by subsequent doses (e.g., "maintenance doses") administered on a less frequent basis. In some embodiments, the initial dose or loading dose and the one or more secondary or maintenance doses each comprise the same amount of IL-4R antagonist. In other embodiments, the initial dose comprises a first amount of IL-4R antagonist, and the one or more secondary doses each comprise a second amount of IL-4R antagonist. For example, the first amount of IL-4R antagonist can be 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x or more of the second amount of IL-4R antagonist. In some embodiments, the one or more maintenance doses of IL-4R antagonist are administered without a loading dose.

[0129] In some embodiments, the loading dose is a "split dose" administered as two or more doses (e.g., 2, 3, 4, or 5 doses) administered on separate days. In some embodiments, the loading dose is administered as a split dose, where the two or more doses are administered at least about one week apart. In some embodiments, the loading dose is administered as a split dose, where the two or more doses are administered about one week, two weeks, three weeks, or four weeks apart. In some embodiments, the loading dose is evenly divided across 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 unequally divided across 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).

[0130] In some embodiments, each secondary and / or tertiary 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 weeks or more) after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" refers to the dose of an IL-4R antagonist administered to a patient prior to administration of the immediately next dose in a multiple administration sequence, without any intervening doses.

[0131] The methods of the present disclosure can include administering any number of secondary and / or tertiary doses of an IL-4R antagonist to a patient. For example, in certain embodiments, only a single secondary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to a patient. Similarly, in certain embodiments, only a single tertiary dose is administered to a patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to a patient.

[0132] In some embodiments comprising multiple secondary doses, each secondary dose is administered at the same frequency as the other secondary doses. For example, each secondary dose can be administered to the patient one week, two weeks, three weeks, or four weeks after the immediately preceding dose. Similarly, in some embodiments comprising multiple tertiary doses, each tertiary dose is administered at the same frequency as the other tertiary doses. For example, each tertiary dose can be administered to the patient one week, two weeks, three weeks, or four weeks after the immediately preceding dose. Alternatively, the frequency with which the secondary and / or tertiary doses are administered to the patient can vary over the course of the treatment regimen. The frequency of administration can also be adjusted by the physician during the course of treatment, depending on the needs of each individual patient after clinical examination.

[0133] In some embodiments, the 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, the 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.

[0134] In some embodiments, the 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, the 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.

[0135] In some embodiments, for subjects ≥12 to <18 years of age with moderate to severe atopic dermatitis of the hands and / or feet or severe AD, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 200 mg administered every two weeks (Q2W) if the subject weighs <60 kg. In some embodiments, the subject is administered a loading dose of 400 mg, followed by one or more subsequent doses of 200 mg administered Q2W if the subject weighs <60 kg. In some embodiments, no loading dose is administered.

[0136] In some embodiments, for subjects ≥12 to <18 years of age with moderate to severe atopic dermatitis of the hands and / or feet or severe AD, a therapeutically effective amount of an IL-4R antagonist (e.g., an anti-IL-4R antibody) comprises 300 mg administered every two weeks (Q2W) if the subject weighs ≥60 kg. In some embodiments, the subject is administered a loading dose of 600 mg, followed by one or more subsequent doses of 300 mg administered Q2W if the subject weighs ≥60 kg. In some embodiments, no loading dose is administered.

[0137] Combination treatment In some embodiments, the methods of the present disclosure include administering to a subject (e.g., a subject with moderate to severe atopic dermatitis of the hands and / or feet) 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. In some embodiments, the additional therapeutic agent is a topical therapeutic agent, such as TCS, or a topical nonsteroidal medication, such as a TCI, crisaborole, or a topical JAK inhibitor. As used herein, the phrase "in combination with" means that the topical treatment (e.g., TCS) is administered before, after, or simultaneously with the IL-4R inhibitor. The term "in combination with" also includes sequential or simultaneous administration of an IL-4R inhibitor and a topical treatment (e.g., TCS).

[0138] For example, when administered "before" a pharmaceutical composition comprising an IL-4R antagonist, an additional therapeutic agent can be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition comprising an IL-4R antagonist. When administered "after" a pharmaceutical composition comprising an IL-4R antagonist, an additional therapeutic agent can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition comprising an IL-4R antagonist. Administration "concurrently with" or with a pharmaceutical composition comprising an IL-4R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than about 10 minutes of (before, after, or simultaneously with) administration of the pharmaceutical composition comprising the IL-4R antagonist, or is administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the IL-4R antagonist.

[0139] In some embodiments, the additional therapeutic agent is TCS. In some embodiments, the TCS is a medium-potency TCS. In some embodiments, the TCS is a low-potency TCS. In some embodiments, the additional therapeutic agent is a TCI. In some embodiments, the additional therapeutic agent is crisaborole. [Example]

[0140] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the present disclosure, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weights are average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric.

[0141] Example 1: Clinical study evaluating the efficacy and safety of dupilumab in adult and adolescent patients with moderate to severe atopic hand and / or foot dermatitis. Study design and objectives This was a global, multicenter, randomized, double-blind, parallel-group, placebo-controlled Phase 3 study (NCT04417894) investigating the efficacy and safety of dupilumab monotherapy in adult and adolescent patients with moderate to severe atopic hand and / or foot dermatitis. The study consisted of three periods: a screening period (at least 4 weeks and up to 8 weeks), a randomized treatment period (16 weeks), and a post-treatment follow-up period (12 weeks).

[0142] Dupilumab is a fully human anti-IL-4R antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10, an HCVR / LCVR amino acid sequence pair comprising SEQ ID NOs: 1 / 2, and heavy and light chain CDR sequences comprising SEQ ID NOs: 3 to 8.

[0143] This study was conducted in accordance with the provisions of the Declaration of Helsinki, the guidelines of the International Conference on Harmonization Good Clinical Practices, 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 were performed. For adolescent patients, a parent or legal guardian provided informed consent, and the patient provided assent.

[0144] Patient population The study population consisted of patients with chronic, moderate-to-severe atopic hand and / or foot dermatitis who were inadequately responsive to, or for whom, moderate-to-high-potency TCS was inadvisable. Only patients who met the diagnostic criteria for AD were included in the study. Patients with a confirmed diagnosis of irritant or allergic contact dermatitis as the primary cause of their hand and / or foot dermatitis were excluded from the study. Patients were stratified by age (adults vs. adolescents), baseline disease severity (HF-IGA score 3 vs. 4), and geographic region (US vs. Japan vs. EU) and randomized in a 1:1 ratio to receive subcutaneous dupilumab or placebo every 2 weeks (q2w) for 16 weeks.

[0145] Inclusion criteriaTo be eligible for inclusion in this study, patients had to meet the following criteria: (1) male or female, age ≥12 years at the screening visit; (2) patients with chronic hand and / or foot dermatitis diagnosed at least 3 years prior to the screening visit for patients ≥18 years old and at least 1 year prior to the screening visit for patients ≥12 to <18 years old; (3) patients with involvement of at least two anatomical regions at screening and baseline. These two anatomical regions could be both hands, one hand and one foot, or both feet. (4) Patients had to have an IGA Hand and Foot score of 3 or 4 (moderate to severe disease) at screening and baseline. Note: Investigators should assign a single IGA score based on the overall impression of disease severity in the hands and feet. Patients must have overall moderate to severe disease in the hands / feet and involvement of at least two anatomical regions to be eligible. (5) Patients with a documented recent history of inadequate response of atopic hand and / or foot dermatitis to topical medications (within 6 months prior to the screening visit) or for whom topical treatment of atopic hand and / or foot dermatitis is medically inadvisable (e.g., intolerance due to significant side effects or safety risks). In cases of insufficient documentation, potential patients may be offered a course of treatment involving a daily regimen of a medium- or higher-potency TCS (±TCI, if appropriate) for at least 28 days during the screening period or for the maximum duration recommended by the product's prescribing information, whichever is shorter. Patients who demonstrate an inadequate response during this period are eligible for inclusion in the study after an appropriate washout, as defined above. (6) Patients must meet the Hanifin and Rajka criteria for diagnosis (Hanifin, 1980).(7) baseline Hand and Foot Peak Pruritus NRS score for maximum itch intensity ≥ 4, (8) at least 11 (out of 14 total) applications of topical emollient (moisturizer) during the 7 consecutive days (not including the day of randomization) immediately preceding the baseline visit, (9) willingness and ability to comply with clinic visits and study-related procedures, (10) providing informed consent / assent signed by the study patient or legally acceptable representative, and (12) patients must adhere to skin protection measures throughout the entire duration of the screening period (minimum 4 weeks but lasting up to 8 weeks), including avoidance of known irritants identified as causing exacerbations of hand and / or foot AD.

[0146] Note on inclusion criteria (5): An inadequate response is defined as failure to achieve and maintain remission or a state of low disease activity according to the attending physician's clinical judgment despite treatment with a daily regimen of a medium- to higher-potency TCS (± topical calcineurin inhibitor [TCI], if appropriate) applied for at least 28 days or for the maximum duration recommended by the product's prescribing information (e.g., 14 days for extra-potent TCS), whichever is shorter. Important side effects or safety risks from the treatment of atopic hand and / or foot dermatitis outweigh the potential treatment benefits and include treatment intolerance, hypersensitivity reactions, significant skin atrophy of the hands and feet, and systemic effects, as assessed by the investigator or the patient's physician. Acceptable documentation includes contemporaneous chart notes recording topical medication prescriptions and treatment outcomes, or investigator documentation based on communication with the patient's physician.

[0147] Note on inclusion criteria (6): A diagnosis of AD requires the presence of at least three of four major criteria: (a) pruritus, (b) dermatitis affecting the flexural surfaces in adults, (c) chronic or recurrent dermatitis, and (d) a personal or family history of cutaneous or respiratory atopy. In patients without AD lesions on body sites other than the hands and feet at screening, study investigators should inquire about any previous history of the presence of AD lesions in a typical age-specific distribution pattern, e.g., on the flexural surfaces (cutaneous atopy). A history of respiratory atopic disease (e.g., asthma, allergic rhinitis) should also be elicited. Patients must also meet three of 23 minor criteria. Mild criteria include: features of the so-called "atopic facies": facial pallor or erythema, hypopigmented macules, infraorbital darkening, infraorbital folds or wrinkles, cheilitis, recurrent conjunctivitis, anterior neck wrinkles; triggers of atopic dermatitis: food, 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, palmar hyperfibrosis, keratosis pilaris (plugged hair follicles of the proximal extremities), hand and / or foot dermatitis, nipple eczema, leukoderma, and perifollicular accentuation.

[0148] Exclusion criteriaThe following were the exclusion criteria for this study: (1) Patients with a positive patch test reaction (score ≥ 1 according to the International Contact Dermatitis Research Group (ICDRG) grading scale) to one or more allergens, either in (a) the baseline patch test series, or (b) the extended baseline or supplemental patch test allergens if such additional testing was performed by the investigator, or (c) a personal product if testing with such products was performed by the investigator, that, in the investigator's opinion, is considered clinically relevant as a current cause of hand and / or foot dermatitis. [Note: Patients with a documented diagnosis of allergic contact dermatitis of the hands and / or feet and a positive patch test reaction at screening will also be excluded from the study, regardless of whether there is a history of current skin exposure (current relevance) to products containing this allergen. Patients with a positive reaction that is interpreted as an irritant based on morphology, timing (e.g., positive on day 2, followed by a tapering pattern) will remain eligible for the study as long as they meet the other eligibility criteria for the study. (2) Patients with a documented diagnosis of protein contact dermatitis of the hands and / or feet. These are patients with occupational or non-occupational contact with proteins, such as food, latex, etc., with a positive prick test and contact urticaria or dermatitis lesions on the hands / feet. (3) Patients for whom patch testing cannot be performed for any reason (including, but not limited to, patient refusal to have patch testing, inability to discontinue systemic immunosuppressants / topical AD medications for the required washout period before patch testing, lack of clean skin (without lesions) on the upper back and / or upper arms to apply the patch test, etc.). (4) Patients with documented exposure to irritants in an occupational or non-occupational (household / recreational) setting that, according to the investigator's judgment, is considered the primary cause of their current hand and / or foot dermatitis. (5) Past treatment with dupilumab.(6) Patients who have used any of the following treatments within 4 weeks prior to the baseline visit: (a) systemic corticosteroids, (b) immunosuppressants / immunomodulatory drugs (e.g., alitretinoin, cyclosporine, mycophenolate mofetil, IFN-γ, Janus kinase inhibitors, azathioprine, or methotrexate), (c) phototherapy (including topical psoralen and UVA [PUVA] or narrow-band ultraviolet B [UVB] on the hands and / or feet). (7) Treatment with biologics other than dupilumab, including: (a) any cytodepleting agents, including but not limited to rituximab, within 6 months prior to the baseline visit or until lymphocyte counts and CD19+ lymphocyte counts return to normal, whichever is longer; (b) other biologics, within 5 half-lives (if known) or 16 weeks prior to the baseline visit, whichever is longer. (8) Treatment with TCS or TCI or crisaborole or topical JAK inhibitors on the hands and feet within 2 weeks prior to the baseline visit. (9) Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, prior to the baseline visit. (10) Treatment with a live (attenuated) vaccine within 4 weeks prior to the baseline visit. (11) Planned or expected use of any prohibited medications and procedures during study treatment. (12) Known or suspected immunodeficiency, including a history of invasive opportunistic infection (e.g., tuberculosis [TB], histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis) despite resolution of infection, or otherwise recurrent infections with an unusual frequency as determined by the investigator. (13) Known history of human immunodeficiency virus (HIV) infection or HIV seropositivity. (14) A current diagnosis of hepatitis B virus infection at the time of screening, as evidenced by (a) a positive hepatitis B surface antigen (HBsAg) or (b) a positive total hepatitis B core antibody (HBcAb). (15) A current diagnosis of hepatitis C virus infection at the time of screening, as evidenced by (a) a positive HCV Ab and (b) a positive HCV RNA.(16) Currently undergoing treatment for liver disease, including but not limited to acute or chronic hepatitis, cirrhosis, liver failure, or having evidence of liver disease as indicated by persistent (confirmed by repeat testing ≥ 2 weeks apart) elevated transaminases (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) greater than 3 times the upper limit of normal (ULN) during the screening period. (17) Presence of any one or more of the following abnormalities in laboratory test results at screening: (a) Platelets ≤ 100 x 10. 3 / μL, (b) Neutrophils <1.5 × 10 3 / μL. (18) Diagnosed with active parasitic infection. (19) Presence of skin complications on the hands and / or feet that may interfere with study evaluation. This includes, but is not limited to, palmoplantar psoriasis, palmoplantar keratosis, lichen planus, pityriasis rubra pilaris, herpes simplex, erythema multiforme, tinea manus / pedis, scabies, and granuloma annulare. (20) History of malignancy within 5 years prior to the baseline visit, excluding fully treated cervical intraepithelial neoplasia, and fully treated and resolved non-metastatic squamous cell carcinoma or basal cell carcinoma of the skin. (21) Severe complications that, in the investigator's judgment, may adversely affect the patient's participation in this study. Examples include, but are not limited to, patients with a short life expectancy, patients with poorly controlled diabetes (HbA1c ≥ 9%), patients with a cardiovascular condition (e.g., stage III or IV heart failure according to the New York Heart Association classification), severe renal conditions (e.g., patients on dialysis), neurological conditions (e.g., demyelinating diseases), active major autoimmune diseases (e.g., eosinophilic granulomatosis with polyangiitis (EGPA), lupus, inflammatory bowel disease, rheumatoid arthritis, etc.), other severe endocrinological, gastrointestinal, hepatobiliary, metabolic, pulmonary, or lymphatic diseases. (22) Any other medical or psychological condition (including relevant laboratory test abnormalities at screening) that, in the investigator's opinion, may suggest a new and / or poorly understood disease, may pose an unreasonable risk to the study patient as a result of his / her participation in this clinical trial, may make the patient's participation unreliable, or may interfere with study evaluations. (23) A history of alcohol or drug abuse within 2 years prior to the screening visit. (24) A patient who is institutionalized pursuant to an order issued by a judicial or administrative authority. (25) The patient is a member of the clinical trial team or his / her close relative. (26) Pregnant or lactating women, or those planning to become pregnant or lactate during the patient's participation in this study. (27) Women of childbearing potential (WOCBP) who are not willing to practice highly effective contraception before the start of the first dose / first treatment, during the study, and for at least 12 weeks after the last dose.

[0149] Test treatment The study drug treatments were as follows: Dupilumab, subcutaneous administration Q2W -In adults: Dupilumab 300 mg, regardless of weight, after a 600 mg loading dose on day 1. In adolescents: Body weight ≥ 60 kg, dupilumab 300 mg after a 600 mg loading dose on day 1; body weight < 60 kg, dupilumab 200 mg after a 400 mg loading dose on day 1. Matched placebo, subcutaneously administered Q2W

[0150] It was recommended that the SC injection site of the study drug be alternated between different quadrants of the abdomen (avoiding the navel and lumbar region), upper thigh, and upper arm so that the same site was not injected for two consecutive injections.

[0151] Background treatment: All patients were required to apply moisturizer to their hands and feet at least twice daily during the screening period. Patients were encouraged to continue using moisturizers throughout the study (all 28 weeks, if applicable). All types of moisturizers were permitted; however, patients could not begin treatment with prescription moisturizers or moisturizers containing additives during the screening period or during the study. Patients could continue using a stable dose of such moisturizers if they had been started before the screening visit. It was recommended that moisturizers used be free of additives, fragrances, perfumes, and other potentially sensitizing agents. Furthermore, it was recommended that moisturizers be free of compounds with known anti-itch effects (e.g., pramoxine, lidocaine, prilocaine, capsaicin, etc.).

[0152] Rescue treatment:Rescue treatment for worsening hand and / or foot AD could be provided to study patients at the discretion of the investigator in this study. The use of rescue treatment was permitted only after 14 days of study. Investigators were required to perform an IGA for hand and foot assessment before initiating rescue treatment and to initiate rescue treatment only in patients with an IGA hand and foot score of ≥3. When possible, investigators were encouraged to first consider rescue with topical treatment (e.g., high- or ultra-high-potency TCS, TCI, crisaborole, or topical JAK inhibitors) and to titrate to systemic medications only for patients who did not adequately respond after at least 7 days of topical treatment. Rescue treatment for topical treatment could be used in accordance with the prescribing information and local guidelines. Patients were allowed to continue study treatment if rescue consisted of topical medications.

[0153] Investigators could also use systemic corticosteroids or nonsteroidal systemic immunosuppressive drugs (e.g., alitretinoin, cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, JAK inhibitors) for rescue in patients with worsening AD of the hands and feet. Patients could continue study treatment if rescue consisted of these systemic treatments, based on the investigator's discretion. All patients were required to complete scheduled study visits and assessments of whether they would complete study treatment and whether they would receive rescue treatment for AD. Investigators should make every attempt to conduct efficacy and safety assessments (e.g., disease severity scores, safety laboratory tests) immediately prior to administering any rescue treatment.

[0154] Outcomes assessed The primary endpoint for the study was the proportion of patients achieving an IGA (hands and feet) score of 0 or 1 at 16 weeks.

[0155] The key secondary endpoint was the proportion of patients with a weekly mean improvement (decrease) of ≥ 4 in the daily Hands and Feet Peak Pruritus NRS from baseline to week 16.

[0156] Other secondary efficacy endpoints included: percent change in modified Total Lesion Symptom Score (mTLSS) for hand / foot lesions from baseline to week 16; proportion of patients with improvement (decrease) in weekly mean daily Hands and Foot Peak Pruritus NRS ≥ 3 from baseline to week 16; percent change from baseline to week 16 in weekly mean daily Hands and Foot Peak Pruritus NRS; percent change from baseline to week 16 in weekly mean daily Hands and Foot Peak Pain NRS; percent change from baseline to week 16 in weekly mean daily Sleep NRS; change from baseline to week 16 in percent AD-affected area of ​​hands and feet; percent change from baseline to week 4 in weekly mean daily Hands and Foot Peak Pruritus NRS. percent, percentage of patients with weekly average improvement (decrease) in daily Hand and Foot Peak Pruritus NRS ≥ 4 from baseline to week 4; for patients with hand dermatitis, percent change from baseline to week 16 in Hand Eczema Severity Index (HECSI) score; for patients with hand dermatitis, percentage of patients with HECSI-75 at week 16; for patients with hand dermatitis, percentage of patients with HECSI-50 at week 16; for patients with hand dermatitis, percentage of patients with HECSI-90 at week 16; for patients with hand dermatitis, change from baseline to week 16 in Hand Eczema Quality of Life Questionnaire (QOLHEQ); change from baseline to week 16 in Work Productivity and Impairment (WPAI) and Classroom Impairment Questionnaire (CIQ).

[0157] Secondary safety endpoints included the incidence of treatment-emergent adverse events (TEAEs) through 16 weeks.

[0158] Secondary clinical pharmacology and immunogenicity endpoints included trough concentrations of functional dupilumab in serum at various time points, the incidence of treatment-emergent anti-drug antibodies (ADAs) and their titers over time.

[0159] Procedures for assessing efficacy (e.g., using IGA for hands and feet, mTLSS, daily Hands and Feet Peak Pruritus NRS, daily Hands and Feet Peak Pain NRS, or other methods of assessment) are described below or in WO2021 / 026205, which is incorporated herein by reference.

[0160] Modified Total Lesion Signs Score for Hands and Feet The modified Total Lesion Sign Score (mTLSS) was adapted for hands and feet and has been previously used in registration studies in hand dermatitis (Ruzicka, et al., Br J Dermatol, 2008, 158:808-817). Investigators use this scale to assess the severity of disease signs on the hands and feet; this assessment is limited to the hands and feet and is not affected by the severity of AD lesions on other parts of the body. mTLSS scores are assessed at screening, baseline, and on designated days during and / or after treatment.

[0161] The mTLSS is assessed by assigning a score on a scale of 0 to 3 (0 = absent, 1 = mild, 2 = moderate, 3 = severe) to each of six features (erythema, scaling / peeling, lichenification, vesiculation / erosion, edema, fissures) based on the morphological description of severity provided in Table 1 below. Separate scores are assigned for the hands and for the feet. 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. [Table 1]

[0162] Investigator's overall assessment of the hands and feetThe IGA for hands and feet is an adaptation of the physician's global assessment tool previously used in registration trials for hand dermatitis (Ruzicka, et al., Br J Dermatol 2008, 158:808-17). Investigators use this scale to assess the severity of disease signs on the hands and feet; this assessment is limited to the hands and feet and is not influenced by the severity of AD lesions on other parts of the body. IGA scores are assessed at screening, baseline, and on specified days during and / or after treatment, based on the scoring algorithm shown in Table 2 below. IGA assessment should be based on the investigator's overall impression of disease severity in the hands and feet, according to the investigator's clinical judgment at the time of assessment. Not all signs need to be present for a patient to be assigned to an IGA category. [Table 2]

[0163] Hand and Foot Pruritus Numerical Rating Scale: The Pruritus NRS is a patient-reported assessment tool for rating the intensity of pruritus (itch) on their hands and feet during a 24-hour recall period. It is an 11-point scale (0-10), where 0 indicates no itch, while 10 indicates the worst itch possible. Patients complete the rating scale daily at specified time points throughout the study. The Pruritus NRS score is calculated as the average of the past 7 days, with a minimum of 4 daily scores.

[0164] Hand and Foot Cutaneous Pain Numerical Rating Scale Hand and foot cutaneous pain is measured using the Cutaneous Pain NRS, an 11-point scale (0-10) where 0 indicates no pain and 10 indicates the worst pain possible. Patients complete the rating scale daily at specified time points throughout the study.

[0165] Sleep Numerical Rating ScaleSleep quality is measured using the Sleep Quality NRS, an 11-point scale (0-10) where 0 indicates the worst possible sleep, while 10 indicates the best sleep. Patients are asked to select the number that best describes their sleep quality during the previous night. Patients complete the rating scale daily at specified time points throughout the study.

[0166] Dermatology Quality of Life Indicators: This questionnaire is based on general AD, not just AD of the hands and / or feet. For adults, the DLQI is a validated 10-item questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on quality of life (Badia, et al., Br J Dermatol, 1999, 141:698-702). The format involves simple responses (0 to 3, where 0 = "not at all," 1 = "a little," 2 = "quite a bit," and 3 = "extremely") to 10 questions to assess quality of life over the past week, with an overall scoring system from 0 to 30, with higher scores indicating poorer quality of life. The DLQI is assessed at specified time points during the study.

[0167] For adolescents, the CDLQI is a validated questionnaire designed to measure the impact of skin diseases in children (Lewis-Jones, et al., Br J Dermatol, 1995, 132:942-949). The purpose of the questionnaire is to measure the extent to which a patient's skin problems have affected them over a recall period of the past week. To complete the questionnaire, patients are required to provide answers to 10 questions (questions focus on the impact of the disease on domains such as symptoms associated with the disease, emotions, leisure time, school or holidays, personal relationships, sleep, and side effects of treatment for skin diseases. The tool has a 7-day recall period. Nine of the 10 questions are scored from 0 to 3 (where 0 = "not at all" or question not answered, 1 = "a little", 2 = "quite a bit", and 3 = "very much"). Question 7 has an additional possible answer (hindered school), which is assigned a score of 3. The CDLQI for the patient 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 quality of life. The CDLQI is assessed at specified time points throughout the study.

[0168] Hospital Anxiety and Depression Scale This questionnaire is based on general AD, not just AD of the hands and / or feet. The HADS is a tool for screening anxiety and depression in non-psychiatric populations, and repeated administration also provides information about 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 each for anxiety and depressive symptoms, with possible scores ranging from 0 to 21 for each subscale. The following cutoff scores are recommended for both subscales: 7-8 for possible presence, 10-11 for probable presence, and 14-15 for severe anxiety or depression. The questionnaire is administered to patients at specific time points during the study.

[0169] Patient-oriented eczema measurements: The POEM is a validated seven-item questionnaire used 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 uses a scoring system of 0 to 28 to answer seven items (dryness, itching, scaling, cracking, poor sleep, bleeding, and weeping) based on the frequency of these disease symptoms during the past week (i.e., 0 = none, 1 = 1-2 days, 2 = 3-4 days, 3 = 5-6 days, and 4 = all days), with the total score reflecting disease-related morbidity. The POEM questionnaire is assessed at specified time points throughout the study.

[0170] Hand eczema severity index The HECSI is similar to the scoring systems for AD (EASI) and plaque psoriasis (PASI) in incorporating both the extent and intensity of disease. Each hand is divided into five regions: fingertips, fingers (excluding tips), palm, back of hand, and wrist. For each of these regions, the intensity of six clinical signs: erythema, induration / papules, vesicles, fissures, scaling, and edema is graded on the following scale: 0, no skin changes; 1, mild disease; 2, moderate disease; and 3, severe disease. For each location (both hands combined), the affected area is given a score of 0 to 4 (0, 0%, 1, 1-25%, 2, 26-50%, 3, 51-75%, and 4, 76-100%) for the severity of clinical symptoms. Finally, the score given for severity at each location is multiplied by the sum of the intensities of each clinical feature to calculate a sum called the HECSI score, ranging from 0 to a maximum severity score of 360. The HECSI has been previously validated in patients with hand dermatitis (Held, et al., Br J Dermatol, 2005, 152:302-307).

[0171] Quality of Life Questionnaire in Hand EczemaThe QoLHEQ is a disease-specific tool for assessing health-related quality of life (HRBMS) in patients with hand eczema (HE) (Ofenloch, et al., Br J Dermatol, 2014, 171:304-312). The QoLHEQ consists of 30 items assessing four domains of HRQOL: (a) symptoms, (b) emotions, (c) function, and (d) treatment / prevention. The SPHEQ total score ranges from 0 to 127 points. The QoLHEQ will be assessed at specified time points during the study.

[0172] result A total of 133 patients were enrolled in approximately 1:1 randomization to receive dupilumab (n=67) (300 mg for adults, 200 mg for adolescents, or 300 mg based on weight) or placebo (n=66) every two weeks. Of these patients, a higher percentage of patients in the dupilumab group completed treatment compared with placebo (94.0% for dupilumab vs. 81.5% for placebo, 88.0% of total patients).

[0173] Baseline demographic and disease characteristics are summarized in Tables 3 and 4. Baseline demographics were generally balanced across treatment groups, with a slight bias toward 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 substantial chronic disease, with the majority having disease in both the hands and feet. The study population had high baseline disease severity as reflected by signs, symptoms, and quality of life measures. Approximately two-thirds of patients had disease localized to the hands and feet or had mild disease (EASI<16). A significant number of patients had previous use of systemic immunosuppressants, reflecting the high patient burden imposed by disease on the hands and feet. [Table 3] [Table 4-1] [Table 4-2]

[0174] As shown in Table 5, there was a high incidence of atopic complications in the patient population, highlighting the common type 2 pathophysiology underlying these disorders. [Table 5]

[0175] Effectiveness Treatment with dupilumab met all pre-specified efficacy endpoints with highly significant p-values. See Table 6. The primary endpoint assessed the proportion of patients with clear or nearly clear skin on their hands and feet at week 16 (measured by an Investigator Global Assessment (IGA) of hands and feet with a score of 0 or 1). At week 16, 40.3% of dupilumab-treated patients achieved an IGA of 0 / 1 for hands and feet, compared with only 16.7% of placebo-treated patients. Statistically significant improvement in the primary endpoint was evident at week 4 and sustained through week 16.

[0176] The key secondary endpoint measured the proportion of patients with improvement in itch from baseline (measured by a ≥4-point reduction on the Peak-Pruritis Numerical Rating Scale [PP-NRS] on a 0-10 scale) at week 16. The onset of improvement in hand and foot pruritus was rapid with dupilumab treatment (by week 1) and sustained through week 16. At week 16, 52.2% of dupilumab-treated patients achieved a ≥4-point reduction on the PP-NRS compared with only 13.6% of placebo-treated patients.

[0177] To evaluate the effect of dupilumab treatment on individual signs of atopic hand and / or foot dermatitis, the proportion of patients reporting absent, mild, moderate, or severe erythema, scaling / peeling, lichenification, vesiculation / erosion, edema, and fissures on the hands and feet as assessed by the mTLSS was analyzed. Of 133 patients enrolled, more than 65% (n=67) of dupilumab-treated patients achieved absent or mild scores by week 16 for each of the assessed signs / symptoms. The proportion of patients with absent or mild hand scores increased from baseline to week 16 for erythema (9% vs. 71.6%), scaling / peeling (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 fissures (23.9% vs. 83.5%). The proportion of patients with absent or mild foot scores increased from baseline to week 16 for erythema (56.7% vs. 80.6%), scaling / peeling (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 fissures (77.6% vs. 86.6%). [Table 6]

[0178] Use of rescue medications Rescue medication use was seven times higher in placebo-treated patients compared to dupilumab-treated patients (14 / 66 (21.2%) for placebo vs. 2 / 67 (3.0%) for dupilumab at week 16). See Table 7 below. No patients in the dupilumab-treated group required rescue with systemic medications. [Table 7]

[0179] safety Dupilumab was well tolerated and demonstrated an acceptable safety profile, with no new safety concerns identified. See Table 8. Over the 16-week treatment period, the overall rate of treatment-emergent adverse events (TEAEs) was 65.7% for dupilumab and 74.2% for placebo. There was a low incidence of serious adverse events (SAEs) and AEs leading to permanent treatment discontinuation. A higher incidence of conjunctivitis and a lower incidence of COVID-19 infection were seen in the dupilumab-treated group. [Table 8]

[0180] overview This phase 3 trial evaluated the efficacy and safety of dupilumab in 133 adolescents and adults with moderate to severe atopic dermatitis of the hands and feet who had an inadequate response or intolerance to topical corticosteroids. Patients with irritant contact dermatitis were excluded from the study. Atopic and allergic complications were present in 73% and 64% of dupilumab- and placebo-treated patients, respectively.

[0181] Patients received dupilumab (n=67) every two weeks (300 mg for adults, 200 mg for adolescents, or 300 mg based on weight) or placebo (n=66). At week 16, more than twice as many dupilumab-treated patients achieved clear or almost clear skin (40% compared with 17% for placebo (p=0.0030)). For the key secondary endpoint, 52% of dupilumab-treated patients experienced a clinically meaningful reduction in itch compared with 14% for placebo (p<0.0001). Dupilumab-treated patients had a mean improvement of 73% in disease severity from baseline compared with 38% for placebo (p<0.0001). Dupilumab-treated patients also showed significant improvements in measures of skin pain, sleep, and health-related quality of life compared with placebo-treated patients. Dupilumab rapidly improved disease signs and symptoms, significantly reducing pruritus as early as one week and improving pain and health-related quality of life within two weeks. Furthermore, required use of rescue medication was significantly lower in dupilumab-treated patients compared with placebo (3% vs. 21%).

[0182] The trial demonstrated safety results similar to the known safety profile of dupilumab in atopic dermatitis. Over the 16-week treatment period, the overall rate of adverse events (AEs) was 66% for dupilumab and 74% for placebo. AEs more commonly observed with dupilumab (≥5%) included conjunctivitis (6% dupilumab, 2% placebo) and herpes virus infection (6% dupilumab, 3% placebo).

[0183] The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to be within the scope of the appended claims. [Table 9-1] [Table 9-2] Table 9-3 Table 9-4 Table 9-5 Table 9-6 Table 9-7 Table 9-8 Table 9-9 Table 9-10 Table 9-11 Table 9-12 Table 9-13

Claims

1. 1. A method for treating atopic dermatitis (AD) of the hands and / or feet, said method comprising: Selecting a subject with moderate to severe atopic dermatitis of the hands and / or feet, wherein the subject has a baseline Investigator Global Assessment (IGA) score of ≥ 3, the subject has a history of poor response of atopic hand and / or foot dermatitis to topical medications, or the subject is a subject for whom topical treatment of atopic hand and / or foot dermatitis is medically inadvisable; and administering to the subject one or more doses of an interleukin-4 receptor (IL-4R) antagonist, wherein the IL-4R antagonist is an anti-IL-4R antibody, or 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. 10. The method of claim 1, wherein the subject has a baseline Hand and Foot IGA score of 4.

3. 10. The method of claim 1, wherein the subject is inadequately responsive to treatment with medium or higher potency topical corticosteroids (TCS).

4. 10. The method of claim 1, wherein the subject has a baseline Hands and Feet Peak Pruritus Numerical Rating Score (NRS) of ≧4.

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

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

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

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

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

10. The method of any one of claims 1 to 9, wherein the subject does not have atopic dermatitis lesions on any part of the body 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 of 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. 13. The method of any one of claims 1 to 12, wherein the subject has a modified Total Lesion Signs Score for Hands and Feet (mTLSS) > 16.

14. 14. The method of any one of claims 1 to 13, wherein the subject has a baseline hand and foot area of ​​atopic dermatitis involvement of at least 24%.

15. 15. The method of any one of claims 1 to 14, wherein the subject has an atopic dermatitis body surface area involvement (BSA) score < 10% and / or an Eczema Area and Severity Index (EASI) score < 21.

16. The object is (a) have a baseline whole body IGA score of ≦2, and / or (b) having a baseline whole body EASI score <16.

17. 1. A method for treating atopic dermatitis (AD) of the hands and / or feet, said method comprising: selecting a subject with moderate to severe AD of the hands and / or feet, wherein the subject is selected based on having an mTLSS for the hands and feet > 16; and administering to the subject one or more doses of an IL-4R antagonist, 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. 18. The method of claim 17, wherein the subject is further selected based on having a baseline hand and foot IGA score of ≥ 3 and / or a baseline hand and foot area of ​​atopic dermatitis involvement of at least 24%.

19. 19. The method of claim 17 or 18, wherein the subject has a history of poor response of AD of the hands and / or feet to topical medications or is a subject for whom topical treatment of AD of the hands and / or feet is medically inadvisable.

20. 20. The method of any one of claims 17 to 19, wherein the subject does not have atopic dermatitis lesions on any part of the body 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 object is (a) baseline BSA score <10%; (b) a baseline whole body IGA score of ≦2, and / or (c) having a baseline whole body EASI score <16.

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

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

25. 25. The method of any one of claims 17 to 24, wherein the subject is further selected based on not having allergic contact dermatitis and / or not having irritant contact dermatitis.

26. 26. The method of any one of claims 1 to 25, wherein the subject has chronic dry cracked hands and / or feet AD.

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

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

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

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

32. 31. The method of any one of claims 1 to 30, wherein the IL-4R antagonist is administered subcutaneously as an initial dose of 300 mg, followed by one or more subsequent doses of 300 mg.

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

34. 31. The method of any one of claims 1 to 30, wherein the IL-4R antagonist is administered subcutaneously as an initial dose of 200 mg, followed by one or more subsequent doses of 200 mg.

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

36. 31. The method of 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 the IL-4R antagonist is administered subcutaneously as an initial dose of 600 mg, followed by one or more subsequent doses of 300 mg Q2W.

37. 31. The method of 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 the IL-4R antagonist is administered subcutaneously as an initial dose of 400 mg, followed by one or more subsequent doses of 200 mg Q2W.

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

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

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

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

42. 42. The method of claim 41, wherein the topical AD medication is a topical corticosteroid (TCS).

43. 43. The method of any one of claims 1 to 42, wherein treatment with the IL-4R antagonist results in the subject achieving an IGA Hand and Foot score of 0 or 1 by 16 weeks after administration of a first dose of the IL-4R antagonist.

44. The treatment with the IL-4R antagonist comprises: a ≧4 point reduction in the Hands and Feet Peak Pruritus NRS compared to the subject's baseline Hands and Feet Peak Pruritus NRS score by 16 weeks after administration of the first dose of the IL-4R antagonist; a reduction in the mTLSS for Hands and Feet score of at least 50% compared to the baseline mTLSS for Hands and Feet score for the subject by 16 weeks after administration of the first dose of the IL-4R antagonist; a reduction in Hands and Feet Peak Pruritus NRS score of at least 50% compared to the baseline Hands and Feet Peak Pruritus NRS score for said subject by 16 weeks after administration of the first dose of said IL-4R antagonist; a ≧4 point reduction in Hands and Feet Peak Pain NRS compared to the subject's baseline Hands and Feet Peak Pain NRS score by 16 weeks after administration of the first dose of the IL-4R antagonist; a reduction in Hand Eczema Severity Index (HECSI) score of at least 50%, relative to the subject's baseline HECSI score, by 16 weeks after administration of the first dose of the IL-4R antagonist; Achievement of HECSI-75 by 16 weeks after administration of the first dose of the IL-4R antagonist; a reduction of at least 15% in the percent surface area of ​​hands and feet involved with AD compared to the subject's baseline percent surface area of ​​hands and feet involved with AD by 16 weeks after administration of the first dose of the IL-4R antagonist; and 44. The method of any one of claims 1-43, wherein the method results in an improvement selected from the group consisting of: at least a 40% reduction in the Quality of Life Questionnaire for Hand Eczema (QoLHEQ) score by 16 weeks after administration of the first dose of the IL-4R antagonist, compared to the subject's baseline QoLHEQ score.

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

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

49. 49. The method of any one of claims 1 to 48, wherein the IL-4R antagonist is contained in a container selected from the group consisting of a glass vial, a syringe, a pre-filled syringe, a pen delivery device, and an auto-injector.

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

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

52. 50. The method of claim 49, wherein the IL-4R antagonist is contained in an autoinjector.

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

Images