Methods of Treating Atopic Dermatitis with Anti-IL-13 Antibodies

Abstract

The present disclosure relates to a method of treating atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-IL-13 antibody, or antigen-binding fragment thereof, thereby treating atopic dermatitis in the subject.

Description

[Technical field]

[0001] The present disclosure relates to the use of anti-IL-13 antibodies to treat atopic dermatitis in a subject in need thereof. [Background technology]

[0002] Atopic dermatitis (AD) is a common, chronic, inflammatory skin disorder that affects a wide range of populations, and its prevalence is increasing worldwide. Although reported prevalence rates of AD vary, affecting 3-10% of the US population and the global population, AD is estimated to affect up to 20% of children and 3% of adults (Sacotte et al., Clin. Dermatol. 36:595-605 (2018)). Consistent with a high disease burden, approximately 40% of affected individuals have moderate to severe disease, causing significant impacts on patients' quality of life (Chiesa et al., J. Invest. Dermatol. 139:583-90 (2019)). AD is associated with increased anxiety, depression, sleep disturbances, reduced productivity, and activity impairment, all of which are roughly equivalent to those observed in psoriasis (Eckert et al., J. Am. Acad. Dermatol. 78:54-61 (2017)). A recent study conducted in the United States focused on the costs and treatment patterns associated with more advanced therapies, such as dupilumab (an anti-IL-4R monoclonal antibody), systemic corticosteroids, systemic immunosuppressants, and phototherapy. The study estimated that nearly two-thirds of patients with moderate to severe AD initiated systemic immunosuppressants, and one-quarter of patients who initiated dupilumab discontinued treatment within six months. These patients represent a significant burden to the health care system, costing approximately $20,000 per patient per year in the United States (Eichenfield et al., Dermatol. Ther. (Heidelb.) 10:791-806 (2020)). Thus, a clear unmet need remains for further advances in treatment options to address the complex medical and social needs of patients with moderate to severe AD.

[0003] Diverse factors, including defective epidermal barrier, dysregulation of innate immune responses, and altered type 2 immunity, are implicated in the pathogenesis of AD, culminating in a complex series of inflammatory responses involving multiple cell types, cytokines, and chemokines. Enhanced penetration of allergens / antigens through impaired skin barriers has been proposed to induce a type 2 T helper (Th2) type environment, based on the crucial association between primary barrier defects and Th2 polarization in patients with AD (Boguniewicz et al., Immunol. Rev. 242:233-46 (2011)). Th2 differentiation of naive CD4+ T cells dominates in AD, leading to increased production of interleukins (ILs), mainly IL-4, IL-5, and IL-13, which in turn leads to increased levels of immunoglobulin E (IgE) (Alexander et al., F1000Res. 8:F1000 Faculty Rev-132 (2019)). Both IL-4 and IL-13 are important cytokines involved in type 2 inflammatory states. However, evidence continues to emerge supporting IL-13 as the primary cytokine involved in AD (Bieber, Allergy 75:54-62 (2020)).

[0004] Until recently, treatments for moderate or severe AD included hydration of the skin and / or topical treatments, such as application of corticosteroids, calcineurin inhibitors, nonsteroidal phosphodiesterase 4 inhibitors, tar, vitamin D, or diluted bleach. The first-line therapy for moderate to severe AD is treatment with topical corticosteroids (TCS). Topical calcineurin inhibitors (TCIs) are commonly used as second-line therapy or as an alternative for patients with TCS intolerance. Although topical therapies remain the mainstay of treatments used in AD, such treatments remain associated with limited efficacy. In addition, long-term application of TCS carries the risk of side effects, such as acne-like rashes, pigmentation disorders, skin atrophy, and the like, as well as the risks associated with systemic absorption (Sidbury et al., J. Am. Acad. Dermatol. 71:327-49 (2014)).

[0005] Moderate or severe AD cases that are not adequately controlled by topical treatments are commonly treated with phototherapy or other systemic treatments (e.g., oral corticosteroids, cyclosporine, methotrexate, mycophenolate, and azathioprine). For most patients, long-term treatment with these agents provides only modest efficacy and has significant safety issues and potential long-term complications, such as organ toxicity (Schneider et al.; Simpson et al., Semin. Cutan. Med. Surg. 36:124-30 (2017)). Summary of the Invention [Problem to be solved by the invention]

[0006] More recently, biological and small molecule therapies have proven to be promising investigational treatments for AD. In particular, the European Medicines Agency and the US Food and Drug Administration recently approved dupilumab, which represents an important treatment advance for AD patients (Ariens et al., Ther. Adv. Chronic Dis. 9:159-70 (2018)). Nevertheless, AD exhibits biological and clinical heterogeneity (Muraro et al., J. Allergy Clin. Immunol. 137:1347-58 (2016); Czarnowicki et al., J. Allergy Clin. Immunol. 143:1-11 (2019)), and even novel therapeutic agents, such as dupilumab, have shown variable efficacy responses in subjects with moderate to severe AD. Results from the Phase III registrational programs for dupilumab (SOLO 1 and SOLO 2) have demonstrated efficacy in treating patients with moderate to severe AD. However, less than half of subjects enrolled in the pivotal trials (38% and 36%, respectively) experienced a decline in Investigators' Global Assessment (IGA) to 1 (almost in remission) or 0 (in remission) after 16 weeks of treatment. These data highlight some of the challenges physicians face when treating patients with moderate to severe disease, as most patients fail to adequately control their disease, even with advanced therapeutic agents such as dupilumab. Thus, there remains a high unmet need for novel targeted therapies to improve patient outcomes, reduce disease burden, and further expand the current treatment paradigms available for AD patients with more advanced disease (Simpson et al. (2017), Simpson et al., N. Eng. J. Med. 375:2335-48 (2016)). [Means for solving the problem]

[0007] One aspect relates to a method of treating atopic dermatitis, the method comprising administering a therapeutically effective amount of an anti-IL-13 antibody or antigen-binding fragment thereof to a subject in need thereof, thereby treating atopic dermatitis in the subject. In some embodiments, the anti-IL-13 antibody comprises an antigen-binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, and the anti-IL-13 antibody comprises at least one of: (a) CDR-H1 comprising residues 31-37 of SEQ ID NO:2; (b) CDR-H2 comprising residues 52-67 of SEQ ID NO:2; (c) CDR-H3 comprising residues 100-112 of SEQ ID NO:2; (d) CDR-L1 comprising residues 24-34 of SEQ ID NO:3; (e) CDR-L2 comprising residues 50-56 of SEQ ID NO:3; or (f) CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, and a CDR-H3 comprising residues 100-112 of SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody comprises a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, a CDR-H3 comprising residues 100-112 of SEQ ID NO:2, a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation. In some embodiments, the anti-IL-13 antibody comprises a L241A mutation.In some embodiments, the anti-IL-13 antibody comprises a L240A mutation and a L241A mutation. In some embodiments, the anti-IL-13 antibody is sendakimab. In some embodiments, the anti-IL-13 antibody is administered subcutaneously. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 100 mg to about 1000 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 200 mg to about 900 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 300 mg to about 800 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 360 mg to about 720 mg. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. In some embodiments, the atopic dermatitis is severe atopic dermatitis. In some embodiments, the atopic dermatitis is moderate to severe atopic dermatitis.

[0008] Another aspect relates to an anti-IL-13 antibody or antigen-binding fragment thereof for use in treating atopic dermatitis. In some embodiments, the anti-IL-13 antibody comprises an antigen-binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, and the anti-IL-13 antibody comprises at least one of: (a) CDR-H1 comprising residues 31-37 of SEQ ID NO:2, (b) CDR-H2 comprising residues 52-67 of SEQ ID NO:2, (c) CDR-H3 comprising residues 100-112 of SEQ ID NO:2, (d) CDR-L1 comprising residues 24-34 of SEQ ID NO:3, (e) CDR-L2 comprising residues 50-56 of SEQ ID NO:3, or (f) CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, and a CDR-H3 comprising residues 100-112 of SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody comprises a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, a CDR-H3 comprising residues 100-112 of SEQ ID NO:2, a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation. In some embodiments, the anti-IL-13 antibody comprises a L241A mutation. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation and a L241A mutation. In some embodiments, the anti-IL-13 antibody is sendakimab.In some embodiments, the anti-IL-13 antibody is administered subcutaneously. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 100 mg to about 1000 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 200 mg to about 900 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 300 mg to about 800 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 360 mg to about 720 mg. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. In some embodiments, the atopic dermatitis is severe atopic dermatitis. In some embodiments, the atopic dermatitis is moderate to severe atopic dermatitis.

[0009] A further aspect relates to the use of an anti-IL-13 antibody or an antigen-binding fragment thereof for the manufacture of a medicament for the treatment of atopic dermatitis. In some embodiments, the anti-IL-13 antibody comprises an antigen-binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, and the anti-IL-13 antibody comprises at least one of: (a) CDR-H1 comprising residues 31-37 of SEQ ID NO:2; (b) CDR-H2 comprising residues 52-67 of SEQ ID NO:2; (c) CDR-H3 comprising residues 100-112 of SEQ ID NO:2; (d) CDR-L1 comprising residues 24-34 of SEQ ID NO:3; (e) CDR-L2 comprising residues 50-56 of SEQ ID NO:3; or (f) CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, and a CDR-H3 comprising residues 100-112 of SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody comprises a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, a CDR-H3 comprising residues 100-112 of SEQ ID NO:2, a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation. In some embodiments, the anti-IL-13 antibody comprises a L241A mutation. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation and a L241A mutation. In some embodiments, the anti-IL-13 antibody is sendakimab.In some embodiments, the anti-IL-13 antibody is formulated for subcutaneous administration. In some embodiments, the anti-IL-13 antibody is formulated for a dosage of about 100 mg to about 1000 mg. In some embodiments, the anti-IL-13 antibody is formulated for a dosage of about 200 mg to about 900 mg. In some embodiments, the anti-IL-13 antibody is formulated for a dosage of about 300 mg to about 800 mg. In some embodiments, the anti-IL-13 antibody is formulated for a dosage of about 360 mg to about 720 mg to a subject. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. In some embodiments, the atopic dermatitis is severe atopic dermatitis. In some embodiments, the atopic dermatitis is moderate to severe atopic dermatitis.

[0010] An additional aspect relates to a method of reducing the incidence of atopic dermatitis by administering a therapeutically effective amount of an anti-IL-13 antibody or antigen-binding fragment thereof to a subject in need thereof, thereby reducing the incidence of atopic dermatitis in the subject. In some embodiments, the anti-IL-13 antibody comprises an antigen-binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, and the anti-IL-13 antibody comprises at least one of: (a) CDR-H1 comprising residues 31-37 of SEQ ID NO:2; (b) CDR-H2 comprising residues 52-67 of SEQ ID NO:2; (c) CDR-H3 comprising residues 100-112 of SEQ ID NO:2; (d) CDR-L1 comprising residues 24-34 of SEQ ID NO:3; (e) CDR-L2 comprising residues 50-56 of SEQ ID NO:3; or (f) CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, and a CDR-H3 comprising residues 100-112 of SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody comprises a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, a CDR-H3 comprising residues 100-112 of SEQ ID NO:2, a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation. In some embodiments, the anti-IL-13 antibody comprises a L241A mutation.In some embodiments, the anti-IL-13 antibody comprises a L240A mutation and a L241A mutation. In some embodiments, the anti-IL-13 antibody is sendakimab. In some embodiments, the anti-IL-13 antibody is administered subcutaneously. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 100 mg to about 1000 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 200 mg to about 900 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 300 mg to about 800 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 360 mg to about 720 mg. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. In some embodiments, the atopic dermatitis is severe atopic dermatitis. In some embodiments, the atopic dermatitis is moderate to severe atopic dermatitis.

[0011] Another aspect relates to a method of treating atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition that blocks the interaction of IL-13 with IL-13Rα1 and IL-13Rα2. In some embodiments, the pharmaceutical composition comprises an anti-IL-13 antibody or antigen-binding fragment thereof, and in some embodiments, the anti-IL-13 antibody comprises an antigen-binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, and the anti-IL-13 antibody comprises at least one of: (a) CDR-H1 comprising residues 31-37 of SEQ ID NO:2; (b) CDR-H2 comprising residues 52-67 of SEQ ID NO:2; (c) CDR-H3 comprising residues 100-112 of SEQ ID NO:2; (d) CDR-L1 comprising residues 24-34 of SEQ ID NO:3; (e) CDR-L2 comprising residues 50-56 of SEQ ID NO:3; or (f) CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, and a CDR-H3 comprising residues 100-112 of SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody comprises a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, a CDR-H3 comprising residues 100-112 of SEQ ID NO:2, a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 3. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation.In some embodiments, the anti-IL-13 antibody comprises a L241A mutation. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation and a L241A mutation. In some embodiments, the anti-IL-13 antibody is sendakimab. In some embodiments, the anti-IL-13 antibody is administered subcutaneously. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 100 mg to about 1000 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 200 mg to about 900 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 300 mg to about 800 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 360 mg to about 720 mg. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. In some embodiments, the atopic dermatitis is severe atopic dermatitis. In some embodiments, the atopic dermatitis is moderate to severe atopic dermatitis.

[0012] A further aspect relates to a method of determining the effectiveness of a treatment for atopic dermatitis in a subject in need thereof, comprising the steps of: (a) administering to the subject a therapeutically effective amount of an anti-IL-13 antibody, or antigen-binding fragment thereof, thereby treating atopic dermatitis in the subject; and (b) determining whether the subject exhibits an increase or decrease in levels of one or more of peripheral blood eosinophils, IgE, lactate dehydrogenase, IL-13, IL-22, TARC, and / or PARC from a baseline level of peripheral blood eosinophils, IgE, lactate dehydrogenase, IL-13, IL-22, TARC, and / or PARC in the subject prior to administration of step (a). In some embodiments, the anti-IL-13 antibody comprises an antigen-binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein the anti-IL-13 antibody comprises at least one of: (a) a CDR-H1 comprising residues 31-37 of SEQ ID NO:2; (b) a CDR-H2 comprising residues 52-67 of SEQ ID NO:2; (c) a CDR-H3 comprising residues 100-112 of SEQ ID NO:2; (d) a CDR-L1 comprising residues 24-34 of SEQ ID NO:3; (e) a CDR-L2 comprising residues 50-56 of SEQ ID NO:3; or (f) a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, and a CDR-H3 comprising residues 100-112 of SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody comprises a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, a CDR-H3 comprising residues 100-112 of SEQ ID NO:2, a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:2.In some embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation. In some embodiments, the anti-IL-13 antibody comprises a L241A mutation. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation and a L241A mutation. In some embodiments, the anti-IL-13 antibody is sendakimab. In some embodiments, the anti-IL-13 antibody is administered subcutaneously. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 100 mg to about 1000 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 200 mg to about 900 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 300 mg to about 800 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 360 mg to about 720 mg. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. In some embodiments, the atopic dermatitis is severe atopic dermatitis. In some embodiments, the atopic dermatitis is moderate to severe atopic dermatitis.

[0013] An additional aspect relates to a method of treating or ameliorating at least one symptom or sign of atopic dermatitis comprising administering a therapeutically effective amount of an anti-IL-13 antibody or antigen-binding fragment thereof to a subject in need thereof, thereby treating or ameliorating at least one symptom in the subject, wherein the at least one symptom is prunus, dry skin, itching, red to brownish-gray patches of skin, small raised bumps that leak fluid and form scabs on them when scratched, thickened skin, cracked skin, scaly skin, rawhide, skin hypersensitivity, or swollen skin. In some embodiments, the anti-IL-13 antibody comprises an antigen-binding domain comprising six CDRs: CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein the anti-IL-13 antibody comprises at least one of: (a) a CDR-H1 comprising residues 31-37 of SEQ ID NO:2; (b) a CDR-H2 comprising residues 52-67 of SEQ ID NO:2; (c) a CDR-H3 comprising residues 100-112 of SEQ ID NO:2; (d) a CDR-L1 comprising residues 24-34 of SEQ ID NO:3; (e) a CDR-L2 comprising residues 50-56 of SEQ ID NO:3; or (f) a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, and a CDR-H3 comprising residues 100-112 of SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody comprises a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a CDR-H1 comprising residues 31-37 of SEQ ID NO:2, a CDR-H2 comprising residues 52-67 of SEQ ID NO:2, a CDR-H3 comprising residues 100-112 of SEQ ID NO:2, a CDR-L1 comprising residues 24-34 of SEQ ID NO:3, a CDR-L2 comprising residues 50-56 of SEQ ID NO:3, and a CDR-L3 comprising residues 89-97 of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:2.In some embodiments, the anti-IL-13 antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:3. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation. In some embodiments, the anti-IL-13 antibody comprises a L241A mutation. In some embodiments, the anti-IL-13 antibody comprises a L240A mutation and a L241A mutation. In some embodiments, the anti-IL-13 antibody is sendakimab. In some embodiments, the anti-IL-13 antibody is administered subcutaneously. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 100 mg to about 1000 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 200 mg to about 900 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 300 mg to about 800 mg. In some embodiments, the anti-IL-13 antibody is administered to the subject at a dosage of about 360 mg to about 720 mg. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. In some embodiments, the atopic dermatitis is severe atopic dermatitis. In some embodiments, the atopic dermatitis is moderate to severe atopic dermatitis.

[0014] Other objects and advantages will become apparent to those skilled in the art from the detailed description which follows. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The applicant has solved the described problem. Sendakimab is a recombinant humanized high affinity neutralizing (immunoglobulin G1 kappa [IgG1κ]) monoclonal antibody (mAb). Sendakimab is highly selective for human IL-13 and was generated by humanization of a rodent anti-human IL-13 mAb, which was identified using hybridoma technology through immunization of mice with human Q110 variant recombinant IL-13. As suggested by literature reports, the crystallizable (Fc) region fragment of sendakimab is mutated at residues L240A and L241A in the heavy chain hinge / CH2 region to reduce effector function (Hezareh et al., J. Virol. 75:12161-68 (2001)). Sendakimab is generated by mammalian cell expression.

[0016] IL-13 is a cytokine expressed by many cell types, including most leukocytes, mast cells, epithelial cells, fibroblasts, and smooth muscle cells (Brightling et al., Clin. Exp. Allergy 40:42-49 (2010)). Sendakimab has high affinity for wild-type IL-13 and the common variant of IL-13, Q110, which is associated with and enhances allergic inflammation in humans (Vladich et al., J. Clin. Invest. 115:747-54 (2005)). Sendakimab binds to an IL-13 epitope composed of residues within helix A and helix D. This binding in turn blocks IL-13 from binding to both IL-13 receptor alpha 1 (IL-13Rα1) and IL-13 receptor alpha 2 (IL-13Rα2) (Ying et al., American Thoracic Society Conference, Abstract 6644 (2010)).

[0017] IL-13, IL-13Rα1, and IL-13Rα2 are overexpressed in AD lesional skin (Tsoi et al., J. Invest. Dermatol. 139:1480-89 (2019); Esaki et al., J. Allergy Clin. Immunol. 135:153-63(2015)). In addition, mechanical scratching, as well as IL-13 itself, also upregulates IL-13 Rα2 expression (Ulzii et al., Int. J. Mol. Sci. 20:3324(2019)). Scratch-induced upregulation of IL-13 Rα2 may attenuate IL-13-mediated epidermal barrier dysfunction and dermal fibrosis.

[0018] Applicants have found that anti-IL-13 antibodies are an effective treatment option for subjects with AD. Novel therapies for AD, such as the use of anti-IL-13 antibodies, offer unique opportunities that may optimize efficacy.

[0019] definition In this disclosure, a number of terms and abbreviations are used. The following definitions are provided:

[0020] As used herein, the terms "about" or "approximately" mean within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or less of a given value or range.

[0021] The term "comprising" is intended to include embodiments encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include embodiments encompassed by the term "consisting of."

[0022] The indefinite articles "a" and "an," as used herein in the specification and claims, should be understood to mean "at least one," unless evidence to the contrary is clearly indicated.

[0023] The phrase "and / or," as used herein in the specification and claims, should be understood to mean "either or both" of the elements so connected, i.e., elements that are conjunctively present in some cases and non-conjunctively present in other cases. Other elements, other than those specifically identified by the phrase "and / or," may optionally be present, whether related or unrelated to the elements specifically identified, unless clearly indicated to the contrary. Thus, as a non-limiting example, a statement such as "A and / or B," when used in conjunction with open-ended language, such as "comprising," may refer in one embodiment to A (optionally including elements other than B) without B, in another embodiment to B (optionally including elements other than A) without A, in yet another embodiment to both A and B (optionally including other elements), etc.

[0024] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating several items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including not only the inclusion of at least one of the several or listed elements, but also two or more and possibly additional unlisted items. Only when used in a term clearly indicating the contrary, such as "only one of" or "exactly one of," or in the claims, "consisting of" refers to the inclusion of exactly one element of the several or listed elements. In general, the term "or" as used herein should be interpreted with the limitation that it represents exclusive alternatives (i.e., "one or the other, but not both") when preceded by the terms of exclusivity "either," "one of," "only one of," or "exactly one of." "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0025] The terms "IL-13" and "IL-13 wild type" as used herein include a cytokine that is primarily secreted by T helper 2 cells. The terms "IL-13" and "IL-13 wild type" include a monomeric protein consisting of a 13 kDa polypeptide. The structure of IL-13 is further described, for example, in Moy et al., J. Mol. Biol. 310:219-30 (2001). The term IL-13 is intended to include recombinant human IL-13 (rhIL-13), which may be prepared by standard recombinant expression methods. Additionally, the term may include orthologs / homologs of IL-13 in other species, such as dog, cat, cow, horse, pig, chicken, etc.

[0026] In some embodiments, IL-13 polypeptide targets of the present disclosure include human IL-13 protein, including variants, fragments, isoforms, and cognate species thereof. The amino acid sequence of human IL-13 is known in the art and is represented by SEQ ID NO: 1 (NCBI Accession No. AF043334.1 (Version 1, updated March 10, 2010); UNIPROT Accession No. P35225 (Version 170, reviewed March 16, 2016)). Human IL-13 wild type sequence (SEQ ID NO:1): MALLLTTVIALTCLGGFASPGPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN

[0027] The term "IL-13 variant" (abbreviated herein as IL-13v) as used herein includes any variant of IL-13. One example of a human IL-13 variant has amino acid residue 130 of SEQ ID NO: 1 changed from arginine to glutamine (R130Q). The sequence of this particular human IL-13 variant is known in the art (NCBI Accession No. AAH96141.2 (Version 2, updated September 23, 2014)).

[0028] The receptor portion of the IL-13 ligand / receptor system comprises a transmembrane receptor multimer that includes the alpha chain of the IL-4 receptor (IL-4Rα) and at least one of the two known IL-13-specific binding chains (Wynn et al., Annu. Rev. Immunol. 21:425-56 (2003)). Action is mediated primarily through the transcription factor signal transducer and activator of transcription 6 (STAT6).

[0029] In particular, the antibodies or antigen-binding fragments thereof specifically bind to an IL-13 polypeptide, thereby reducing or neutralizing binding of the IL-13 ligand to its cognate receptor. At the same time, the IL-13 antibodies or antigen-binding portions thereof may cause inhibition and / or neutralization of the biological activity of the IL-13 ligand / receptor system.

[0030] "Biological activity" as used herein refers to any inherent biological property of a cytokine, including, but not limited to, induction of inflammation by binding to the IL-13 receptor, enhanced secretion of chemokines, increased migration of allergic effector cells, metaplasia, etc. in epithelial tissue surrounding the mucosa of the GI tract.

[0031] The terms "specific binding" or "specifically binding to," as used herein in connection with the interaction of an antibody, protein, or peptide with a second chemical species, mean that the interaction is dependent on the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody does not bind to proteins generally, but rather recognizes and binds to a specific protein structure. If an antibody is specific for epitope "A," then in a reaction involving labeled "A" and an antibody, the presence of a molecule containing epitope A (or free, unlabeled A) will reduce the amount of labeled A that binds to the antibody.

[0032] The term "antibody" as used herein broadly refers to any immunoglobulin (Ig) molecule composed of four polypeptide chains, two heavy (H) and two light (L) chains, or any functional fragment, mutant, variant, or derivative thereof that retains the essential epitope binding properties for an Ig molecule. Such mutant, variant, or derived antibody formats are known in the art. Non-limiting embodiments thereof are discussed herein. In one embodiment, the antibody used in the compositions and methods of the present disclosure is the anti-IL-13 antibody sendakimab.

[0033] In full-length antibodies, each heavy chain is composed of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CHI, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged in the following order from amino-terminus to carboxy-terminus: FRl, CDRl, FR2, CDR2, FR3, CDR3, FR4. The immunoglobulin molecule can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgAl, and IgA2), or subclass of molecule. In some embodiments, the anti-IL-13 antibody has a heavy chain variable region represented by SEQ ID NO:2. In some embodiments, the anti-IL-13 antibody has a light chain variable region represented by SEQ ID NO:3. Heavy chain variable region (SEQ ID NO:2) EVTLRESGPGLVKPTQTLTLTCTLYGFSLSTSDMGVDWIRQPPGKGLEWLAHIWWDDVKRYNPALKSRLTISKDTSKNQVVLKLTSVDPVDTATYYCARTVSSGYIYYAMDYWGQGTLVTVSS Light chain variable region (SEQ ID NO:3) DIQMTQSPSSLSASVGDRVTISCRASQDIRNYLNWYQQKPGKAPKLLIFYTSKLHSGVPSRFSGSGSGTDYTLTISSLQPEDIATYYCQQGNTLPLTFGGGTKVEIK

[0034] The term "antigen-binding portion" of an antibody (or simply "antibody portion"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL-13). It has been shown that the antigen-binding function of an antibody can be performed by multiple fragments of a full-length antibody. Such antibody embodiments may also be in a bispecific, dual specific, or multispecific format that specifically binds to two or more different antigens. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CHI domains; (ii) an F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment, consisting of the VH and CHI domains; (iv) an Fv fragment, consisting of the VL and VH domains of one arm of an antibody; (v) a dAb fragment (Ward et al., Nature 341:544-46 (1989); WO90 / 05144), which contains a single variable domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be linked, using recombinant techniques, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as a single chain Fv (scFv), see, e.g., Bird et al., Science 242:423-26 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-83 (1988)). Such single chain antibodies are also intended to be encompassed by the term "antigen-binding portion" of an antibody. Other forms of single chain antibodies, such as diabodies, are also encompassed.Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, but with a linker that is too short to allow pairing between the two domains on the same chain, thereby allowing pairing of the domains with complementary domains on another chain to create two antigen-binding sites (see, e.g., Holliger et al., Proc. Natl. Acad. Sci. USA 90:6444-48 (1993); Poljak et al., Structure 2:1121-23 (1994)). Such antibody binding moieties are known in the art (Kontermann and Dubel, eds., Antibody Engineering (2001) Springer-Verlag. New York. p. 790 (ISBN 3-540-41354-5)).

[0035] The term "antibody construct" as used herein refers to a polypeptide comprising one or more antigen-binding moieties of the present disclosure linked to a linker polypeptide or immunoglobulin constant domain. A linker polypeptide comprises two or more amino acid residues linked by peptide bonds and is used to link one or more antigen-binding moieties. Such linker polypeptides are well known in the art (see, for example, Holliger et al., Proc. Natl. Acad. Sci. USA 90:6444-48 (1993); Poljak et al., Structure 2: 1121-23 (1994)). An immunoglobulin constant domain refers to a heavy or light chain constant domain. The amino acid sequences of human IgG heavy and light chain constant domains are known in the art and are as set forth in the table below.

[0036] [Table 1]

[0037] Still further, an antibody or an antigen-binding portion thereof may be part of a larger immunoadhesion molecule formed by covalent or non-covalent association of an antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include the use of streptavidin core regions to generate tetrameric scFv molecules (Kipriyanov et al., Human Antibodies and Hybridomas 6:93-101 (1995)), and the use of cysteine ​​residues, marker peptides, and C-terminal polyhistidine tags to generate bivalent and biotinylated scFv molecules (Kipriyanov et al., Mol. Immunol. 31:1047-58 (1994)). Antibody portions, such as Fab and F(ab')2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion of whole antibodies, respectively. In addition, antibodies, antibody portions, and immunoadhesion molecules can be obtained using standard recombinant DNA techniques, such as those described herein.

[0038] An "isolated antibody," as used herein, is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds IL-13 is substantially free of antibodies that specifically bind to antigens other than IL-13). However, an isolated antibody that specifically binds IL-13 may have cross-reactivity with other antigens, such as IL-13 molecules from other species. In addition, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0039] 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 include, for example, within the CDRs, particularly CDR3, 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). 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.

[0040] The term "recombinant human antibody", as used herein, includes all human antibodies that are prepared, expressed, created, or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial human antibody library (Hoogenboom et al., TIB Tech. 15:62-70 (1994); Azzazy et al., Clin. Biochem. 35:425-45 (2002); Gavilondo et al., BioTechniques 29:128-45 (2002); Hoogenboom et al., Immunol. Today 21:371-78 (2000)), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (e.g., Taylor et al., Nucleic Acids Res. 20:6287-95 (1992); Kellermann et al., Curr. Opin. Biotechnol. 13:593-97 (2002); Little et al., Immunol. Today 21:364-70 (2002)), or any other means involving splicing of human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies have been subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, when animals transgenic for human Ig sequences are used) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. One embodiment provides fully human antibodies (which can be generated using techniques well known in the art, such as, but not limited to, using a human Ig phage library, such as the library disclosed in (WO2005 / 007699)) capable of binding to human IL-13.

[0041] The term "chimeric antibody" refers to an antibody that contains heavy and light chain variable region sequences derived from one species and constant region sequences derived from another species, such as an antibody having murine heavy and light chain variable regions linked to human constant regions. See, e.g., Morrison, Science 229:1202-07 (1985); Oi et al., BioTechniques 4:214-21 (1986); Gillies et al., J. Immunol. Methods 125: 91-202 (1989); U.S. Patent Nos. 5,807,715; 4,816,567; and 4,816,397, all of which are incorporated by reference in their entireties. Additionally, "chimeric antibodies" may be produced by techniques known in the art. See Morrison et al., Proc. Natl. Acad. Sci. USA 81:851-55 (1984); Neuberger et al., Nature 312:604-08 (1984); Takeda et al., Nature 314:452-54 (1985).

[0042] In one embodiment, a chimeric antibody for use in the compositions and / or methods of the disclosure is generated by replacing the heavy chain constant region of the mouse monoclonal anti-human IL-13 antibody described in Section 1 with a human IgG1 constant region.

[0043] The term "CDR-grafted antibody" refers to an antibody that comprises heavy and light chain variable region sequences from one species, but in which one or more of the VH and / or VL CDR regions have been replaced with CDR sequences from another species, such as an antibody having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) have been replaced with human CDR sequences.

[0044] The term "humanized antibody" refers to an antibody that contains heavy and light chain variable region sequences derived from a species other than human (e.g., mouse), but in which at least a portion of the VH and / or VL sequences have been altered to be more "human-like", i.e., more similar to human germline variable sequences. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences are introduced into non-human VH and VL sequences, replacing the corresponding non-human CDR sequences. In one embodiment, humanized anti-human IL-13 antibodies and antigen-binding portions are provided. Such antibodies were generated by obtaining mouse anti-IL-13 monoclonal antibodies using conventional hybridoma technology, followed by humanization using in vitro genetic engineering, such as those disclosed in WO2005 / 123126. Human Ig sequences are known in the art. See, for example, Kabat et al., Sequences of Proteins of Immunological Interest, US Dept. Health (1983), which is incorporated by reference in its entirety herein. Such imported sequences can be used to reduce immunogenicity, or to reduce, enhance or modify binding, affinity, association rate, dissociation rate, avidity, specificity, half-life, or any other suitable property, as known in the art.

[0045] Framework residues in the human framework regions may be substituted with corresponding residues from the CDR donor antibody to alter, and in some embodiments improve, antigen binding. Such framework substitutions are identified by methods well known in the art, for example, by modeling the interactions of CDR and framework residues to identify framework residues important for antigen binding, and by sequence comparison to identify rare framework residues in special positions (see, for example, U.S. Pat. No. 5,585,089; Riechmann et al., Nature 332:323-27 (1988), which are incorporated herein by reference in their entirety). Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of such displays allows analysis of the role that the residues are likely to have in the functioning of the candidate immunoglobulin sequence, i.e., for residues that affect the ability of the candidate immunoglobulin to bind to its antigen. In this way, FR residues can be selected and combined from the consensus and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen, is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding.Antibodies can be prepared using a variety of techniques known in the art, for example, Jones et al., Nature 321:522-25 (1986); Verhoeyen et al., Science 239:1534-36 (1988); Sims et al., J. Immunol. 151:2296-2308 (1993); Chothia et al., J. Mol. Biol. 196:901-17 (1987); Carter et al., Proc. Natl. Acad. Sci. USA 89:4285-89 (1992); Presta et al., J. Immunol. 151:2623-32 (1993); Padlan, Mol. Immunol. 28:489-98 (1991); Studnicka et al., Protein Eng. 7:805-14 (1994), Roguska et al., Proc. Natl. Acad. Sci. USA 91:969-73(1994), WO91 / 09967, PCT / US98 / 16280, PCT / US96 / 18978, PCT / US91 / 0 9630, PCT / US91 / 05939, PCT / US94 / 01234, PCT / GB89 / 01334, PCT / GB91 / 01134, PCT / GB92 / 01755, WO90 / 14443, WO90 / 14424, WO90 / 14430, EP229246, EP592,106, EP519,596, EP239,400, U.S. Patent Nos. 5,565,332, 5,723,323, 5,976,862, and 5,824,5 14, 5,817,483, 5,814,476, 5,763,192, 5,723,323, 5,766,886, 5,714,352, 6,204,023, 6,180,370, 5,693,762, 5,530,101, 5,585,089, 5,225,539, and 4,816,567, each of which is incorporated by reference in its entirety, including the references cited therein.

[0046] Other types of libraries can be composed of antibody fragments derived from genetic sources with no apparent bias towards antigen-binding clones. Thus, "naive antibody" or "natural antibody" libraries are derived from natural, unimmunized, rearranged V genes.

[0047] "Synthetic antibody" libraries are constructed entirely by in vitro methods that introduce areas of complete degeneracy or specifically tailored degeneracy into the CDRs of one or more V genes. "Semi-synthetic libraries" combine natural and synthetic diversity and are often created to increase natural diversity while maintaining a desired level of functional diversity. Thus, such libraries can be created, for example, by shuffling natural CDR regions (Soderlind et al., Nat. Biotechnol. 18:852-56 (2000)) or by combining naturally rearranged CDR sequences derived from human B cells with synthetic CDR1 and CDR2 diversity (Hoet et al., Nat. Biotechnol. 23:344-38 (2005)). The present disclosure encompasses the use of naive / natural, synthetic and semi-synthetic antibody libraries or any combination thereof.

[0048] The terms "Kabat numbering," "Kabat definition," and "Kabat labeling" are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues that are more variable (i.e., more hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody or antigen-binding portion thereof (Kabat et al., Ann. NY Acad. Sci. 190:382-91 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242 (1991)). In some embodiments, for the heavy chain variable region of an anti-IL-13 antibody, the hypervariable region spans amino acid positions 31-37 of SEQ ID NO:2 for CDR1, amino acid positions 52-67 of SEQ ID NO:2 for CDR2, and amino acid positions 100-112 of SEQ ID NO:2 for CDR3. In some embodiments, for the light chain variable region of an anti-IL-13 antibody, the hypervariable region spans amino acid positions 24-34 of SEQ ID NO: 3 for CDR1, amino acid positions 50-56 of SEQ ID NO: 3 for CDR2, and amino acid positions 89-97 of SEQ ID NO: 2 for CDR3.

[0049] As used herein, the terms "acceptor" and "acceptor antibody" refer to an antibody or nucleic acid sequence that provides or encodes at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of the amino acid sequences of one or more framework regions. In some embodiments, the term "acceptor" refers to an antibody amino acid or nucleic acid sequence that provides or encodes the constant regions. In yet another embodiment, the term "acceptor" refers to an antibody amino acid or nucleic acid sequence that provides or encodes one or more of the framework regions and constant regions. In particular embodiments, the term "acceptor" refers to a human antibody amino acid or nucleic acid sequence that provides or encodes at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of one or more amino acid sequences of the framework region. In accordance with this embodiment, the acceptor may contain at least 1, at least 2, at least 3, at least 4, at least 5, or at least 10 amino acid residues that do not occur at one or more specific positions in a human antibody. The acceptor framework region and / or the acceptor constant region may be derived or obtained from, for example, germline antibody genes, mature antibody genes, functional antibodies (e.g., antibodies known in the art, antibodies in development, or commercially available antibodies).

[0050] As used herein, the term "CDR" refers to a complementarity determining region within an antibody variable sequence. There are three CDRs in each of the heavy and light chain variable regions (designated CDR1, CDR2, and CDR3 per variable region). The term "CDR set" as used herein refers to a group of three CDRs occurring within a single variable region that has the ability to bind to an antigen. The exact boundaries of these CDRs are defined differently in different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system that can be applied to any variable region of an antibody, but also provides precise residue boundaries that define the three CDRs. These CDRs are sometimes referred to as Kabat CDRs. Chothia and coworkers (Chothia et al., J. Mol. Biol. 196:901-17 (1987); Chothia et al., Nature 342:877-83 (1989)) have described the Kabat CDRs as It has been found that certain portions of the CDRs adopt nearly identical peptide backbone conformations despite significant diversity at the level of amino acid sequence. The portions are designated L1, L2, and L3, or HI, H2, and H3, with "L" and "H" referring to the light and heavy chain regions, respectively. The regions are sometimes referred to as Chothia CDRs (which have boundaries that overlap with the Kabat CDRs). Other boundaries that define CDRs that overlap with the Kabat CDRs have been described by Padlan, FASEB J. 9:133-39 (1995), and MacCallum, J. Mol. Biol. 262:732-45 (1996). Still other CDR boundary definitions, while they may not strictly follow one of the above systems, nevertheless follow the Kabat CDRs. They overlap with the CDRs, but may be shortened or extended in light of prediction or experimental findings that a particular residue or group of residues, or the entire CDR, does not significantly affect antigen binding.Although some embodiments use Kabat or Chothia, the methods used herein may utilize CDRs defined according to any of these systems.

[0051] As used herein, the term "canonical" residues refers to residues in a CDR or framework that define a particular canonical CDR structure, as defined by Chothia et al., J. Mol. Biol. 196:901-07 (1987); Chothia et al., J. Mol. Biol. 227:799-817 (1992), both of which are incorporated herein by reference. According to Chothia et al., a significant portion of the CDRs of many antibodies have nearly identical peptide backbone conformations, despite significant diversity at the amino acid sequence level. Each canonical structure primarily defines a set of peptide backbone rotation angles for a contiguous segment of amino acid residues that form a loop.

[0052] As used herein, the terms "donor" and "donor antibody" refer to an antibody providing one or more CDRs. In some embodiments, a donor antibody is an antibody derived from a species different from the antibody from which the framework regions are obtained or from. In the context of humanized antibodies, the term "donor antibody" refers to a non-human antibody providing one or more CDRs.

[0053] As used herein, the term "framework" or "framework sequence" refers to the remaining sequence of the variable region excluding the CDRs. Since the exact definition of the CDR sequence can be determined by different systems, the meaning of the framework sequence is subject to correspondingly different interpretations. In addition, the six CDRs (CDR-L1, CDR-L2, and CDR-L3 of the light chain and CDR-H1, CDR-H2, and CDR-H3 of the heavy chain) also divide the framework region on the light chain and the heavy chain into four sub-regions (FR1, FR2, FR3, and FR4) on each chain, with CDR1 located between FR1 and FR2, CDR2 located between FR2 and FR3, and CDR3 located between FR3 and FR4. If a particular sub-region is not specified as FR1, FR2, FR3, or FR4, the framework region is otherwise referred to as the combination of FRs in the variable region of a single naturally occurring immunoglobulin chain. As used herein, FR refers to one of the four subregions, and FR(s) refers to two or more of the four subregions that make up a framework region.

[0054] Human heavy and light chain acceptor sequences are known in the art. In one embodiment of the present disclosure, the human heavy and light chain acceptor sequences are selected from the sequences set forth in Tables 3 and 4 disclosed in U.S. Patent No. 7,915,388, the contents of which are incorporated herein by reference.

[0055] As used herein, the term "germline antibody gene" or "gene fragment" refers to an immunoglobulin sequence encoded by a non-lymphoid cell that has not undergone the maturation process that results in gene rearrangement and mutation for expression of a particular immunoglobulin (see, e.g., Shapiro et al., Crit. Rev. Immunol. 22:183-200(2002); Marchalonis et al., Adv. Exp. Med. Biol. 484:13-30(2001)). One advantage provided by various embodiments of the present disclosure stems from the recognition that germline antibody genes are more likely than mature antibody genes to preserve essential amino acid sequence structures characteristic of individuals within a species, and therefore are less likely to be recognized as derived from a foreign source when used therapeutically in that species.

[0056] As used herein, the term "key" residues refers to certain residues in the variable region that have a greater impact on the binding specificity and / or affinity of the antibody, especially in humanized antibodies. Key residues include, but are not limited to, one or more of the following: residues adjacent to the CDRs, potential glycosylation sites (which may be either N- or O-glycosylation sites), rare residues, residues capable of interacting with antigens, residues capable of interacting with CDRs, canonical residues, contact residues between the heavy and light chain variable regions, residues in the Vernier zone, and residues in the overlapping region between the Chothia definition of the variable heavy chain CDR1 and the Kabat definition of the first heavy chain framework.

[0057] As used herein, the term "humanized antibody" refers to an antibody, or a variant, derivative, analog, or fragment thereof, that immunospecifically binds to an antigen of interest and comprises a framework (FR) region having substantially the amino acid sequence of a human antibody and a complementarity determining region (CDR) having substantially the amino acid sequence of a non-human antibody. As used herein, the term "substantially" in the context of a CDR refers to a CDR that has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid sequence of a non-human antibody CDR. A humanized antibody comprises substantially all, at least one, and typically two, of the variable domains (Fab, Fab', F(ab')2, FabC, Fv), in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. In some embodiments, the humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. In some embodiments, the humanized antibody contains both the variable domains of a light chain as well as at least a heavy chain. The antibody may also contain the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. In some embodiments, the humanized antibody contains only a humanized light chain. In some embodiments, the humanized antibody contains only a humanized heavy chain. In particular embodiments, the humanized antibody contains only a humanized variable domain of the light chain and / or a humanized heavy chain.

[0058] The humanized antibody may be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE, and any isotype, including but not limited to IgG1, IgG2, IgG3, and IgG4. A humanized antibody may comprise sequences from more than one class or isotype, and particular constant domains may be selected to optimize desired effector functions using techniques well known in the art.

[0059] The framework and CDR regions of a humanized antibody need not correspond exactly to the parental sequences, for example, the donor antibody CDR or consensus framework may be mutated by substitution, insertion, and / or deletion of at least one amino acid residue such that a certain CDR or framework residue does not correspond to either the donor antibody or the consensus framework. In some embodiments, such mutations, however, are not extensive. Typically, at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% 92%, 93%, 94%, 95% or more of the humanized antibody residues correspond to those of the parental FR and CDR sequences. As used herein, the term "consensus framework" refers to the framework region in the consensus immunoglobulin sequence. As used herein, the term "consensus immunoglobulin sequence" refers to a sequence formed from the most frequently occurring amino acids (or nucleotides) within a family of related immunoglobulin sequences (see, e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987)). Within a family of immunoglobulins, each position within the consensus sequence is occupied by the amino acid that occurs most frequently at that position within the family. If two amino acids occur equally frequently, either can be included in the consensus sequence.

[0060] In some embodiments, the anti-IL-13 antibody is mutated at residues L240A and / or L241A in the heavy chain hinge / CH2 region.

[0061] In some embodiments, the humanized anti-IL-13 antibody is sendakimab. Sendakimab has the sequence of SEQ ID NO:2 (heavy chain variable region) and SEQ ID NO:3 (light chain variable region). Sendakimab is a humanized antibody that binds with significant affinity to helices A and D of interleukin-13 (IL-13) (see U.S. Patent Publication No. 2014 / 0341913). Sendakimab contains mutations at residues L240A and L241A in the heavy chain hinge / CH2 region.

[0062] The term "activity" includes activities such as the binding specificity / affinity of an antibody, e.g., an anti-IL-13 antibody, which binds to an IL-13 antigen, and / or the neutralizing ability of an antibody, e.g., an anti-IL-13 antibody, whose binding to IL-13 inhibits a biological activity of IL-13.

[0063] The term "epitope" includes any polypeptide determinant capable of specific binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitopic determinants include chemically active surface groups of molecules, such as amino acids, sugar side chains, phosphoryl or sulfonyl, and the like, and in certain embodiments may have specific three-dimensional structural characteristics and / or special charge characteristics. An epitope is the region of an antigen to which an antibody binds. In certain embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen within a complex mixture of proteins and / or macromolecules.

[0064] Any known method can be employed to detect antibody-antigen interactions. For example, surface plasmon resonance (SPR) is an optical phenomenon that allows the analysis of biospecific interactions by detecting changes in protein concentration in a biosensor matrix, for example, using the BIACORE system (Pharmacia Biosensor, Piscataway, NJ). See Jonsson et al., Ann. Biol. Clin. 51:19-26(1993); Jonsson et al., Biotechniques 11:620-27(1991); Johnsson et al., J. Mol. Recognit. 8:125-31(1995); and Johnnson et al., Anal. Biochem. 198:268-77(1991).

[0065] Anti-IL-13 antibodies used in the context of the disclosed methods may have pH-dependent binding properties. For example, anti-IL-13 antibodies used in the disclosed methods may exhibit reduced binding to IL-13 at acidic pH compared to neutral pH. Alternatively, anti-IL-13 antibodies of the disclosed disclosure may exhibit enhanced binding to their antigen at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values ​​less than 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 less. 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.

[0066] In certain instances, "reduced binding to IL-13 at acidic pH compared to neutral pH" is expressed in terms of the ratio of the K value of antibody binding to IL-13 at acidic pH to the K value of antibody binding to IL-13 at neutral pH (or vice versa). For example, an antibody or antigen-binding fragment thereof may be considered to exhibit "reduced binding to IL-13 at acidic pH compared to neutral pH" for purposes of this disclosure if the antibody or antigen-binding fragment thereof exhibits an acidic / neutral K ratio of about 3.0 or greater. In certain exemplary embodiments, the acidic / neutral KD ratio for an antibody or antigen-binding fragment of the disclosure can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or more.

[0067] Antibodies with pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for decreased (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. Furthermore, antibodies with pH-dependent properties can be obtained by modifying the antigen-binding domain at the amino acid level. For example, an antibody with decreased antigen-binding properties at acidic pH compared to neutral pH can be obtained by replacing one or more amino acids in the antigen-binding domain (e.g., in the CDR) with histidine residues.

[0068] The above antibodies may be conjugated to other moieties and / or agents to achieve desirable properties, such as physiological stability, increased half-life, increased bioavailability, etc. The term "antibody conjugate" refers to a binding protein, such as an antibody, chemically linked to a second chemical moiety, such as a therapeutic or cytotoxic agent. In other cases, the chemical moiety may be a diagnostic agent, such as a radioligand. The term "agent" is used herein to refer to a chemical substance, a mixture of chemicals, a biological macromolecule, or an extract made from biological material.

[0069] In some embodiments, therapeutic or cytotoxic agents include, but are not limited to, pertussis toxin, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxy anthracinedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin, and analogs or homologs thereof. The terms "control" and "modulate" are used interchangeably and as used herein refer to a change or alteration in the activity of a molecule of interest (e.g., the biological activity of IL-13). Modulation can be an increase or decrease in the magnitude of a particular activity or function of the molecule of interest. Exemplary activities and functions of a molecule include, but are not limited to, binding properties, enzymatic activity, cell receptor activation, and signal transduction.

[0070] Similarly, the term "modulator" as used herein refers to a compound capable of changing or altering an activity or function of a molecule of interest (e.g., the biological activity of IL-13). For example, a modulator can cause an increase or decrease in the magnitude of a particular activity or function of a molecule compared to the magnitude of the activity or function observed in the absence of the modulator. In certain embodiments, a modulator is an inhibitor that decreases the magnitude of at least one activity or function of a molecule. Exemplary inhibitors include, but are not limited to, proteins, peptides, antibodies, peptibodies, carbohydrates, or small organic molecules. Peptibodies are described, for example, in WO01 / 83525.

[0071] The term "agonist" as used herein refers to a modulator that, upon contact with a molecule of interest, causes an increase in the magnitude of a particular activity or function of the molecule compared to the magnitude of the activity or function observed in the absence of the agonist. Specific examples of intended agonists may include, but are not limited to, IL-13 polypeptides, or polypeptides, nucleic acids, carbohydrates, or any other molecules that bind to IL-13.

[0072] The term "antagonist" or "inhibitor" as used herein refers to a modulator that, upon contact with a molecule of interest, causes a decrease in the magnitude of a particular activity or function of the molecule compared to the magnitude of the activity or function observed in the absence of the antagonist. Specific examples of antagonists of interest include those that block or modulate the biological or immunological activity of IL-13 and / or IL-13v. Antagonists and inhibitors of IL-13 and / or IL-13v may include, but are not limited to, proteins, nucleic acids, carbohydrates, or any other molecules that bind to IL-13 or IL-13v.

[0073] The term "inhibiting receptor binding" refers to the ability of a binding protein to block IL-13 from binding to one or more of its receptors. Such inhibition of receptor binding results in a reduction or abolishment of a biological activity mediated by IL-13 binding to its receptor or receptors.

[0074] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an antibody or antigen-binding portion thereof that is sufficient to reduce or ameliorate the severity and / or duration of a disorder or one or more symptoms thereof, prevent the progression of a disorder, cause regression of a disorder, prevent the recurrence, development, manifestation, or progression of one or more symptoms associated with a disorder, detect a disorder, or enhance or improve the prophylactic or therapeutic effects of another therapy (e.g., a prophylactic or therapeutic agent).

[0075] Pharmaceutical Compositions The present disclosure includes methods comprising administering an IL-13 antibody or antigen-binding portion thereof to a subject, the IL-13 antibody or antigen-binding portion thereof being included within a pharmaceutical composition. The pharmaceutical composition may be formulated with suitable carriers, excipients, and other agents that provide suitable transport, delivery, tolerability, and the like. Many suitable formulations may be found in formularies known to any pharmaceutical chemist: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. Such formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, vesicles containing lipids (cationic or anionic) (e.g., LIPOFECTIN™, etc.), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell, J. Pharm. Sci. Technol. 52:238-311 (1998).

[0076] A variety of 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, and receptor-mediated endocytosis (see Wu et al., J. Biol. Chem. 262:4429-32 (1987)). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, such as by infusion or bolus injection, absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can also be administered together with other biologically active agents.

[0077] The pharmaceutical composition can be delivered subcutaneously or intravenously using a standard needle and syringe. In addition, for subcutaneous delivery, a pen delivery device facilitates application in delivering the pharmaceutical composition. Such pen delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge that contains the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is emptied, the empty cartridge can be easily disposed of and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device is therefore reusable. In a disposable pen delivery device, there is no replaceable cartridge. Instead, the disposable pen delivery device will be pre-filled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is depleted of pharmaceutical composition, the entire device is discarded.

[0078] In certain circumstances, the pharmaceutical composition can be delivered by a controlled release system. In one embodiment, a pump can be used. In another embodiment, a polymeric material can be used, see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In yet another embodiment, the controlled release system can be placed in the vicinity of the target of the composition, thus requiring only a fraction of the systemic administration (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, Science 249:1527-33 (1990).

[0079] The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, drip infusions, and the like. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared by dissolving, suspending, or emulsifying the antibody or its salt in a sterile aqueous or oily medium that is customarily used for injections. In the case of an aqueous medium for injection, for example, an isotonic solution containing physiological saline, glucose, and other auxiliary agents, etc. may be present, and may be used in combination with a suitable solubilizing agent, for example, alcohol (e.g., ethanol), polyhydric alcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. In the case of an oily medium, for example, sesame oil, soybean oil, etc. may be employed, and may be used in combination with a solubilizing agent, for example, benzyl benzoate, benzyl alcohol, etc. In some embodiments, the injectable preparation thus prepared is filled into a suitable ampoule.

[0080] The above-mentioned pharmaceutical compositions for oral or parenteral use are prepared in a dosage form with a unit dose suitable for the dose of the active ingredient. Such dosage forms of unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0081] Exemplary pharmaceutical compositions comprising anti-IL-13 antibodies that can be used in the context of the present disclosure are disclosed, for example, in U.S. Patent Application No. 2012 / 0097565, the entire contents of which are expressly incorporated by reference herein.

[0082] The present disclosure provides a pharmaceutical composition comprising one or more of the above IL-13 antibodies and antigen-binding portions thereof and a pharma- ceutically acceptable carrier. In a further related embodiment, the present disclosure provides a diagnostic composition comprising the above IL-13 antibodies and antigen-binding portions thereof and one or more of a plurality of reagents, buffers, and carriers for diagnostic testing. According to this aspect, the pharmaceutical composition may be formulated for intravenous, subcutaneous, intraperitoneal, or intramuscular administration. Still further according to this aspect, the pharmaceutical composition may be formulated for subcutaneous administration as a microneedle patch. The pharmaceutical composition may be formulated for parenteral administration by bolus injection or by gradual perfusion over time. The diagnostic composition may be formulated for in vitro, in vivo, or ex vivo applications.

[0083] Exemplary agents used to formulate the IL-13 antibodies and antigen-binding portions thereof into pharmaceutical and / or diagnostic compositions are provided in U.S. Patent Application No. 2014 / 0341913, which is incorporated herein by reference. In particular, exemplary agents used to formulate the IL-13 antibodies and antigen-binding portions thereof into pharmaceutical compositions for treating AD are provided in U.S. Patent Application No. 2015 / 0017176, which is incorporated herein by reference.

[0084] Usage / Dosage The amount of IL-13 antibody, or antigen-binding portion thereof, administered to a subject according to the methods of the present disclosure is generally a therapeutically effective amount.

[0085] In some embodiments, a therapeutically effective amount is 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, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 81 g, 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 48 0mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg , about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890 The amount of the anti-IL-13 antibody or antigen-binding portion thereof may be about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, or more.

[0086] In some embodiments, the therapeutically effective amount is about 100 mg to about 1100 mg, about 120 mg to about 1100 mg, about 140 mg to about 1100 mg, about 160 mg to about 1100 mg, about 180 mg to about 1100 mg, about 200 mg to about 1100 mg, about 220 mg to about 1100 mg, about 240 mg to about 1100 mg, about 260 mg to about 1100 mg, about 280 mg to about 1100 mg, about 300 mg to about 1100 mg, about 320 mg to about 1100 mg, about 340 mg to about 1100 mg, about 360 mg to about 1100 mg, about 380 mg to about 1100 mg, or about 400 mg. g ~ approx. 1100 mg, approx. 420 mg ~ approx. 1100 mg, approx. 440 mg ~ approx. 1100 mg, approx. 460 mg ~ approx. 1100 mg, approx. 480 mg ~ approx. 00mg, about 580mg to about 1100mg, about 600mg to about 1100mg, about 620mg to about 1100mg, about 640mg to about 1100mg, about 660mg to about 1100mg, about 680mg to about 1100mg, about 700mg to about 1100mg, about 720mg to about 1100mg, Approximately 740mg to approximately 1100mg, approximately 760mg to approximately 1100mg, approximately 780mg to approximately 1100mg, approximately 800mg to approximately 1100mg, approximately 820mg to approximately 1100mg, approximately 840mg to approximately 1100mg, approximately 860mg to approximately 1100mg, approximately 880mg to approximately 1100mg, approximately 900m g ~ approx. 1100 mg, approx. 920 mg ~ approx. 1100 mg, approx. 940 mg ~ approx. 1100 mg, approx. 960 mg ~ approx. 1100 mg, approx. 980 mg ~ approx. 1100 mg, approx. ~1100mg, 1080mg~1100mg, 100mg~1080mg, 120mg~1080mg, 140mg~1080mg, 160mg~1080mg, 180mg~1080mg, 200mg~1080mg, 220mg~10 80mg, about 240mg to about 1080mg, about 260mg to about 1080mg, about 280mg to about 1080mg, about 300mg to about 1080mg, about 320mg to about 1080mg, about 340mg to about 1080mg, about 360mg to about 1080mg, about 380mg to about 1080mg,Approximately 400mg to approximately 1080mg, approximately 420mg to approximately 1080mg, approximately 440mg to approximately 1080mg, approximately 460mg to approximately 1080mg, approximately 480mg to approximately 1080mg, approximately 500mg to approximately 1080mg, approximately 520mg to approximately 1080mg, approximately 540mg to approximately 1080mg, approximately 560 mg ~ approx. 1080 mg, approx. 580 mg ~ approx. 1080 mg, approx. 600 mg ~ approx. 1080 mg, approx. 620 mg ~ approx. 1080 mg, approx. 640 mg ~ approx. 1080mg, about 740mg to about 1080mg, about 760mg to about 1080mg, about 780mg to about 1080mg, about 800mg to about 1080mg, about 820mg to about 1080mg, about 840mg to about 1080mg, about 860mg to about 1080mg, about 880mg to about 1080mg, about 900mg to about 1080mg, about 920mg to about 1080mg, about 940mg to about 1080mg, about 960mg to about 1080mg, about 980mg to about 1080mg, about 1000mg to about 1080mg, about 1020mg to about 1080mg, about 1040mg to about 1080mg , approx. 1060 mg ~ approx. 1080 mg, approx. 100 mg ~ approx. 1060 mg, approx. 120 mg ~ approx. 1060 mg, approx. 140 mg ~ approx. 1060 mg, approx. 160 mg ~ approx. 1060 mg, approx. 40mg to about 1060mg, about 260mg to about 1060mg, about 280mg to about 1060mg, about 300mg to about 1060mg, about 320mg to about 1060mg, about 340mg to about 1060mg, about 360mg to about 1060mg, about 380mg to about 1060mg, about 400mg ~ about 1060mg, about 420mg to about 1060mg, about 440mg to about 1060mg, about 460mg to about 1060mg, about 480mg to about 1060mg, about 500mg to about 1060mg, about 520mg to about 1060mg, about 540mg to about 1060mg, about 560mg to about 1060mg, about 580mg to about 1060mg, about 600mg to about 1060mg, about 620mg to about 1060mg, about 640mg to about 1060mg, about 660mg to about 1060mg, about 680mg to about 1060mg, about 700mg to about 1060mg, about 720mg to about 1060mg,About 740mg to about 1060mg, about 760mg to about 1060mg, about 780mg to about 1060mg, about 800mg to about 1060mg, about 820mg to about 1060mg, about 840mg to about 1060mg, about 860mg to about 1060mg, about 880mg to about 1060mg, about 900mg to about 1060mg, about 920mg to about 1060mg, about 940mg to about 1060mg, about 960mg to about 1060mg, about 980mg to about 1060mg, about 1000mg to about 1060mg, about 1020mg to about 1060mg, about 1040mg to about 1060mg, about 100m g to about 1040mg, about 120mg to about 1040mg, about 140mg to about 1040mg, about 160mg to about 1040mg, about 180mg to about 1040mg, about 200mg to about 1040mg, about 220mg to about 1040mg, about 240mg to about 1040mg, about 260mg to about 1040mg, about 280mg to about 1040mg, about 300mg to about 1040mg, about 320mg to about 1040mg, about 340mg to about 1040mg, about 360mg to about 1040mg, about 380mg to about 1040mg, about 400mg to about 1040mg, about 420mg to about 1040mg , about 440mg to about 1040mg, about 460mg to about 1040mg, about 480mg to about 1040mg, about 500mg to about 1040mg, about 520mg to about 1040mg, about 540mg to about 1040mg, about 560mg to about 1040mg, about 580mg to about 1040mg, about 600mg to about 1040mg, about 620mg to about 1040mg, about 640mg to about 1040mg, about 660mg to about 1040mg, about 680mg to about 1040mg, about 700mg to about 1040mg, about 720mg to about 1040mg, about 740mg to about 1040mg, about 760mg to about 1040mg, about 780mg to about 1040mg, about 800mg to about 1040mg, about 820mg to about 1040mg, about 840mg to about 1040mg, about 860mg to about 1040mg, about 880mg to about 1040mg, about 900mg to about 1040mg, about 920mg to about 1040mg, about 940mg to about 1040mg, about 960mg to about 1040mg, about 980mg to about 1040mg, about 1000mg to about 1040mg, about 1020mg to about 1040mg, about 100mg to about 1020mg, about 120mg to about 1020mg, about 140mg to about 1020mg,Approximately 160mg to approximately 1020mg, approximately 180mg to approximately 1020mg, approximately 200mg to approximately 1020mg, approximately 220mg to approximately 1020mg, approximately 240mg to approximately 1020mg, approximately 260mg to approximately 1020mg, approximately 280mg to approximately 1020mg, approximately 300mg to approximately 1020mg, approximately 32 0mg~about 1020mg, about 340mg~about 1020mg, about 360mg~about 1020mg, about 380mg~about 1020mg, about 400mg~about 1020mg, about 420mg~about 1020mg, about 440mg~about 1020mg, about 460mg~about 1020mg, about 480mg~ about 1020mg, about 500mg to about 1020mg, about 520mg to about 1020mg, about 540mg to about 1020mg, about 560mg to about 1020mg, about 580mg to about 1020mg, about 600mg to about 1020mg, about 620mg to about 1020mg, about 640mg to about 1020mg, about 660mg to about 1020mg, about 680mg to about 1020mg, about 700mg to about 1020mg, about 720mg to about 1020mg, about 740mg to about 1020mg, about 760mg to about 1020mg, about 780mg to about 1020mg, about 800mg to about 1020mg, About 820mg to about 1020mg, about 840mg to about 1020mg, about 860mg to about 1020mg, about 880mg to about 1020mg, about 900mg to about 1020mg, about 920mg to about 1020mg, about 940mg to about 1020mg, about 960mg to about 1020mg, about 980mg to about 1020mg, about 1000mg to about 1020mg, about 100mg to about 1000mg, about 120mg to about 1000mg, about 140mg to about 1000mg, about 160mg to about 1000mg, about 180mg to about 1000mg, about 200mg to about 1000mg, about 220mg to about 1020mg About 1000mg, about 240mg to about 1000mg, about 260mg to about 1000mg, about 280mg to about 1000mg, about 300mg to about 1000mg, about 320mg to about 1000mg, about 340mg to about 1000mg, about 360mg to about 1000mg, about 380mg to about 100 0mg, about 400mg to about 1000mg, about 420mg to about 1000mg, about 440mg to about 1000mg, about 460mg to about 1000mg, about 480mg to about 1000mg, about 500mg to about 1000mg, about 520mg to about 1000mg, about 540mg to about 1000mg,About 560mg~about 1000mg, about 580mg~about 1000mg, about 600mg~about 1000mg, Approximately 620mg to approximately 1000mg, approximately 640mg to approximately 1000mg, approximately 660mg to approximately 1000mg, approximately 680mg to approximately 1000mg, approximately 700mg to approximately 1000mg, approximately 720mg to approximately 1000mg, approximately 740mg to approximately 1000mg, approximately 760mg to approximately 1000mg, approximately 780 mg~1000mg, 800mg~1000mg, 820mg~1000mg, 840mg~1000mg, 860mg~1000mg, 880mg~1000mg, 900mg~1000mg, 920mg~1000mg, 940mg~1 000mg, about 960mg to about 1000mg, about 980mg to about 1000mg, about 100mg to about 980mg, about 120mg to about 980mg, about 140mg to about 980mg, about 160mg to about 980mg, about 180mg to about 980mg, about 200mg to about 980mg, about 220mg to about 980mg, about 240mg to about 980mg, about 260mg to about 980mg, about 280mg to about 980mg, about 300mg to about 980mg, about 320mg to about 980mg, about 340mg to about 980mg, about 360mg to about 980mg, about 380mg to about 980mg, about 400 mg ~ approx. 980 mg, approx. 420 mg ~ approx. 980 mg, approx. 440 mg ~ approx. 980 mg, approx. 460 mg ~ approx. 980 mg, approx. 0 mg to about 980 mg, about 600 mg to about 980 mg, about 620 mg to about 980 mg, about 640 mg to about 980 mg, about 660 mg to about 980 mg, about 680 mg to about 980 mg, about 700 mg to about 980 mg, about 720 mg to about 980 mg, about 740 mg to about 980 mg, about 7 60mg to about 980mg, about 780mg to about 980mg, about 800mg to about 980mg, about 820mg to about 980mg, about 840mg to about 980mg, about 860mg to about 980mg, about 880mg to about 980mg, about 900mg to about 980mg, about 920mg to about 980mg, about 940mg to about 980mg, about 960mg to about 980mg, about 100mg to about 960mg, about 120mg to about 960mg, about 140mg to about 960mg, about 160mg to about 960mg, about 180mg to about 960mg, about 200mg to about 960mg, about 220mg to about 960mg,about 240mg to about 960mg, about 260mg to about 960mg, about 280mg to about 960mg, about 300mg to about 960mg, about 320mg to about 960mg, about 340mg to about 960mg, about 360mg to about 960mg, about 380mg to about 960mg, about 400mg to about 960mg, about 420mg to about 960mg, about 440mg to about 960mg, about 460mg to about 960mg, about 480mg to about 960mg, about 500mg to about 960mg, about 520mg to about 960mg, about 540mg to about 960mg, about 560mg to about 960mg, about 580mg to about 96 0mg, about 600mg to about 960mg, about 620mg to about 960mg, about 640mg to about 960mg, about 660mg to about 960mg, about 680mg to about 960mg, about 700mg to about 960mg, about 720mg to about 960mg, about 740mg to about 960mg, about 760mg to about 960mg, about 780mg to about 960mg, about 800mg to about 960mg, about 820mg to about 960mg, about 840mg to about 960mg, about 860mg to about 960mg, about 880mg to about 960mg, about 900mg to about 960mg, about 920mg to about 960mg, about 940mg to about about 960mg, about 100mg to about 940mg, about 120mg to about 940mg, about 140mg to about 940mg, about 160mg to about 940mg, about 180mg to about 940mg, about 200mg to about 940mg, about 220mg to about 940mg, about 240mg to about 940mg, about 260mg to about 940mg, about 280mg to about 940mg, about 300mg to about 940mg, about 320mg to about 940mg, about 340mg to about 940mg, about 360mg to about 940mg, about 380mg to about 940mg, about 400mg to about 940mg, about 420mg to about 940mg, about 44 0mg to about 940mg, about 460mg to about 940mg, about 480mg to about 940mg, about 500mg to about 940mg, about 520mg to about 940mg, about 540mg to about 940mg, about 560mg to about 940mg, about 580mg to about 940mg, about 600mg to about 940mg, about 620mg to about 940mg, about 640mg to about 940mg, about 660mg to about 940mg, about 680mg to about 940mg, about 700mg to about 940mg, about 720mg to about 940mg, about 740mg to about 940mg, about 760mg to about 940mg, about 780mg to about 940mg,About 800mg to about 940mg, about 820mg to about 940mg, about 840mg to about 940mg, about 860mg to about 940mg, about 880mg to about 940mg, about 900mg to about 940mg, about 920mg to about 940mg, about 100mg to about 920mg, about 120mg to about 920mg, about 140mg to about 920mg, about 160mg to about 920mg, about 180mg to about 920mg, about 200mg to about 920mg, about 220mg to about 920mg, about 240mg to about 920mg, about 260mg to about 920mg, about 280mg to about 920mg, about 300mg to about 92 0mg, about 320mg to about 920mg, about 340mg to about 920mg, about 360mg to about 920mg, about 380mg to about 920mg, about 400mg to about 920mg, about 420mg to about 920mg, about 440mg to about 920mg, about 460mg to about 920mg, about 480mg to about 920mg, about 500mg to about 920mg, about 520mg to about 920mg, about 540mg to about 920mg, about 560mg to about 920mg, about 580mg to about 920mg, about 600mg to about 920mg, about 620mg to about 920mg, about 640mg to about 920mg, about 660mg to about 920mg about 920mg, about 680mg to about 920mg, about 700mg to about 920mg, about 720mg to about 920mg, about 740mg to about 920mg, about 760mg to about 920mg, about 780mg to about 920mg, about 800mg to about 920mg, about 820mg to about 920mg, about 840mg to about 920mg, about 860mg to about 920mg, about 880mg to about 920mg, about 900mg to about 920mg, about 100mg to about 900mg, about 120mg to about 900mg, about 140mg to about 900mg, about 160mg to about 900mg, about 180mg to about 900mg, about 20 0mg to about 900mg, about 220mg to about 900mg, about 240mg to about 900mg, about 260mg to about 900mg, about 280mg to about 900mg, about 300mg to about 900mg, about 320mg to about 900mg, about 340mg to about 900mg, about 360mg to about 900mg, about 380mg to about 900mg, about 400mg to about 900mg, about 420mg to about 900mg, about 440mg to about 900mg, about 460mg to about 900mg, about 480mg to about 900mg, about 500mg to about 900mg, about 520mg to about 900mg, about 540mg to about 900mg,About 560mg to about 900mg, about 580mg to about 900mg, about 600mg to about 900mg, about 620mg to about 900mg, about 640mg to about 900mg, about 660mg to about 900mg, about 680mg to about 900mg, about 700mg to about 900mg, about 720mg to about 900mg, about 740mg to about 900mg, about 760mg to about 900mg, about 780mg to about 900mg, about 800mg to about 900mg, about 820mg to about 900mg, about 840mg to about 900mg, about 860mg to about 900mg, about 880mg to about 900mg, about 100mg to about 88 0mg, about 120mg to about 880mg, about 140mg to about 880mg, about 160mg to about 880mg, about 180mg to about 880mg, about 200mg to about 880mg, about 220mg to about 880mg, about 240mg to about 880mg, about 260mg to about 880mg, about 280mg to about 880mg, about 300mg to about 880mg, about 320mg to about 880mg, about 340mg to about 880mg, about 360mg to about 880mg, about 380mg to about 880mg, about 400mg to about 880mg, about 420mg to about 880mg, about 440mg to about 880mg, about 460mg to about About 880mg, about 480mg to about 880mg, about 500mg to about 880mg, about 520mg to about 880mg, about 540mg to about 880mg, about 560mg to about 880mg, about 580mg to about 880mg, about 600mg to about 880mg, about 620mg to about 880mg, about 640mg to about 880mg, about 660mg to about 880mg, about 680mg to about 880mg, about 700mg to about 880mg, about 720mg to about 880mg, about 740mg to about 880mg, about 760mg to about 880mg, about 780mg to about 880mg, about 800mg to about 880mg, about 82 0mg to about 880mg, about 840mg to about 880mg, about 860mg to about 880mg, about 100mg to about 860mg, about 120mg to about 860mg, about 140mg to about 860mg, about 160mg to about 860mg, about 180mg to about 860mg, about 200mg to about 860mg, about 220mg to about 860mg, about 240mg to about 860mg, about 260mg to about 860mg, about 280mg to about 860mg, about 300mg to about 860mg, about 320mg to about 860mg, about 340mg to about 860mg, about 360mg to about 860mg, about 380mg to about 860mg,Approximately 400mg to approximately 860mg, approximately 420mg to approximately 860mg, approximately 440mg to approximately 860mg, approximately 460mg to approximately 860mg, approximately 480mg to approximately 860mg, approximately 500mg to approximately 860mg, approximately 520mg to approximately 860mg, approximately 540mg to approximately 860mg, approximately 560mg to approximately 860m g, approx. 580 mg ~ approx. 860 mg, approx. 600 mg ~ approx. 860 mg, approx. 620 mg ~ approx. 860 mg, approx. 640 mg ~ approx. 860 mg, approx. 660 mg ~ approx. 860 mg, approx. 0mg, about 760mg to about 860mg, about 780mg to about 860mg, about 800mg to about 860mg, about 820mg to about 860mg, about 840mg to about 860mg, about 100mg to about 840mg, about 120mg to about 840mg, about 140mg to about 840mg, about 160mg to about 840mg, about 180mg to about 840mg, about 200mg to about 840mg, about 220mg to about 840mg, about 240mg to about 840mg, about 260mg to about 840mg, about 280mg to about 840mg, about 300mg to about 840mg, about 320mg to about 840mg, about 340mg to about about 840mg, about 360mg to about 840mg, about 380mg to about 840mg, about 400mg to about 840mg, about 420mg to about 840mg, about 440mg to about 840mg, about 460mg to about 840mg, about 480mg to about 840mg, about 500mg to about 840mg, about 520mg to about 840mg, about 540mg to about 840mg, about 560mg to about 840mg, about 580mg to about 840mg, about 600mg to about 840mg, about 620mg to about 840mg, about 640mg to about 840mg, about 660mg to about 840mg, about 680mg to about 840mg, about 70 0mg to about 840mg, about 720mg to about 840mg, about 740mg to about 840mg, about 760mg to about 840mg, about 780mg to about 840mg, about 800mg to about 840mg, about 820mg to about 840mg, about 100mg to about 820mg, about 120mg to about 820mg, about 140mg to about 820mg, about 160mg to about 820mg, about 180mg to about 820mg, about 200mg to about 820mg, about 220mg to about 820mg, about 240mg to about 820mg, about 260mg to about 820mg, about 280mg to about 820mg, about 300mg to about 820mg,About 320mg to about 820mg, about 340mg to about 820mg, about 360mg to about 820mg, about 380mg to about 820mg, about 400mg to about 820mg, about 420mg to about 820mg, about 440mg to about 820mg, about 460mg to about 820mg, about 480mg to about 820mg, about 500mg to about 820mg, about 520mg to about 820mg, about 540mg to about 820mg, about 560mg to about 820mg, about 580mg to about 820mg, about 600mg to about 820mg, about 620mg to about 820mg, about 640mg to about 820mg, about 660mg to about 820mg 0mg, about 680mg to about 820mg, about 700mg to about 820mg, about 720mg to about 820mg, about 740mg to about 820mg, about 760mg to about 820mg, about 780mg to about 820mg, about 800mg to about 820mg, about 100mg to about 800mg, about 120mg to about 800mg, about 140mg to about 800mg, about 160mg to about 800mg, about 180mg to about 800mg, about 200mg to about 800mg, about 220mg to about 800mg, about 240mg to about 800mg, about 260mg to about 800mg, about 280mg to about 800mg, about 300mg to about 1 About 800 mg, about 320 mg to about 800 mg, about 340 mg to about 800 mg, about 360 mg to about 800 mg, about 380 mg to about 800 mg, about 400 mg to about 800 mg, about 420 mg to about 800 mg, about 440 mg to about 800 mg, about 460 mg to about 800 mg, about 480 mg to about 800 mg, about 500 mg to about 800 mg, about 520 mg to about 800 mg, about 540 mg to about 800 mg, about 560 mg to about 800 mg, about 580 mg to about 800 mg, about 600 mg to about 800 mg, about 620 mg to about 800 mg, about 640 mg to about 800 mg, about 66 0mg to about 800mg, about 680mg to about 800mg, about 700mg to about 800mg, about 720mg to about 800mg, about 740mg to about 800mg, about 760mg to about 800mg, about 780mg to about 800mg, about 100mg to about 780mg, about 120mg to about 780mg, about 140mg to about 780mg, about 160mg to about 780mg, about 180mg to about 780mg, about 200mg to about 780mg, about 220mg to about 780mg, about 240mg to about 780mg, about 260mg to about 780mg, about 280mg to about 780mg, about 300mg to about 780mg,About 320mg to about 780mg, about 340mg to about 780mg, about 360mg to about 780mg, about 380mg to about 780mg, about 400mg to about 780mg, about 420mg to about 780mg, about 440mg to about 780mg, about 460mg to about 780mg, about 480mg to about 780mg, about 500mg to about 780mg, about 520mg to about 780mg, about 540mg to about 780mg, about 560mg to about 780mg, about 580mg to about 780mg, about 600mg to about 780mg, about 620mg to about 780mg, about 640mg to about 780mg, about 660mg to about 78 0mg, about 680mg to about 780mg, about 700mg to about 780mg, about 720mg to about 780mg, about 740mg to about 780mg, about 760mg to about 780mg, about 100mg to about 760mg, about 120mg to about 760mg, about 140mg to about 760mg, about 160mg to about 760mg, about 180mg to about 760mg, about 200mg to about 760mg, about 220mg to about 760mg, about 240mg to about 760mg, about 260mg to about 760mg, about 280mg to about 760mg, about 300mg to about 760mg, about 320mg to about 760mg, about 340mg to about About 760mg, about 360mg to about 760mg, about 380mg to about 760mg, about 400mg to about 760mg, about 420mg to about 760mg, about 440mg to about 760mg, about 460mg to about 760mg, about 480mg to about 760mg, about 500mg to about 760mg, about 520mg to about 760mg, about 540mg to about 760mg, about 560mg to about 760mg, about 580mg to about 760mg, about 600mg to about 760mg, about 620mg to about 760mg, about 640mg to about 760mg, about 660mg to about 760mg, about 680mg to about 760mg, about 70 0mg to about 760mg, about 720mg to about 760mg, about 740mg to about 760mg, about 100mg to about 740mg, about 120mg to about 740mg, about 140mg to about 740mg, about 160mg to about 740mg, about 180mg to about 740mg, about 200mg to about 740mg, about 220mg to about 740mg, about 240mg to about 740mg, about 260mg to about 740mg, about 280mg to about 740mg, about 300mg to about 740mg, about 320mg to about 740mg, about 340mg to about 740mg, about 360mg to about 740mg, about 380mg to about 740mg,About 400mg to about 740mg, about 420mg to about 740mg, about 440mg to about 740mg, about 460mg to about 740mg, about 480mg to about 740mg, about 500mg to about 740mg, about 520mg to about 740mg, about 540mg to about 740mg, about 560mg to about 740mg, about 580mg to about 740mg, about 600mg to about 740mg, about 620mg to about 740mg, about 640mg to about 740mg, about 660mg to about 740mg, about 6 80mg to about 740mg, about 700mg to about 740mg, about 720mg to about 740mg, about 100mg to about 720mg, about 120mg to about 720mg, about 140mg to about 720mg, about 160mg to about 720mg, about 180mg to about 720mg, about 200mg to about 720mg, about 220mg to about 720mg, about 240mg to about 720mg, about 260mg to about 720mg, about 280mg to about 720mg, about 300mg to about 720mg, about 320 mg to about 720 mg, about 340 mg to about 720 mg, about 360 mg to about 720 mg, about 380 mg to about 720 mg, about 400 mg to about 720 mg, about 420 mg to about 720 mg, about 440 mg to about 720 mg, about 460 mg to about 720 mg, about 480 mg to about 720 mg, about 500 mg to about 720 mg, about 520 mg to about 720 mg, about 540 mg to about 720 mg, about 560 mg to about 720 mg, about 580 mg to about 720 mg, about 600 mg to about 720mg, about 620mg to about 720mg, about 640mg to about 720mg, about 660mg to about 720mg, about 680mg to about 720mg, about 700mg to about 720mg, about 100mg to about 700mg, about 120mg to about 700mg, about 140mg to about 700mg, about 160mg to about 700mg, about 180mg to about 700mg, about 200mg to about 700mg, about 220mg to about 700mg, about 240mg to about 700mg, about 260mg to, About 700mg, about 280mg to about 700mg, about 300mg to about 700mg, about 320mg to about 700mg, about 340mg to about 700mg, about 360mg to about 700mg, about 380mg to about 700mg, about 400mg to about 700mg, about 420mg to about 700mg, about 440mg to about 700mg, about 460mg to about 700mg, about 480mg to about 700mg, about 500mg to about 700mg, about 520mg to about 700mg, about 540mg to about 700mg, about 560mg to about 700mg, about 580mg to about 700mg, about 600mg to about 700mg, about 620mg g to about 700 mg, about 640 mg to about 700 mg, about 660 mg to about 700 mg, about 680 mg to about 700 mg, about 100 mg to about 680 mg, about 120 mg to about 680 mg, about 140 mg to about 680 mg, about 160 mg to about 680 mg, about 180 mg to about 680 mg, about 200 mg to about 680 mg, about 220 mg to about 680 mg, about 240 mg to about 680 mg, about 260 mg to about 680 mg, about 280 mg to about 680 mg, about 300 mg to about 680 mg, about 320 mg to about 680 mg, about 340 mg to about 680 mg, about 360 mg to about 680 mg, about 38 0mg to about 680mg, about 400mg to about 680mg, about 420mg to about 680mg, about 440mg to about 680mg, about 460mg to about 680mg, about 480mg to about 680mg, about 500mg to about 680mg, about 520mg to about 680mg, about 540mg to about 680mg, about 560mg to about 680mg, about 580mg to about 680mg, about 600mg to about 680mg, about 620mg to about 680mg, about 640mg to about 680mg, about 660mg to about 680mg, about 100mg to about 660mg, about 120mg to about 660mg, about 140mg to about 660mg, about 160mg to about 660mg, about 180mg to about 660mg, about 200mg to about 660mg, about 220mg to about 660mg, about 240mg to about 660mg, about 260mg to about 660mg, about 280mg to about 660mg, about 300mg to about 660mg, about 320mg to about 660mg, about 340mg to about 660mg, about 360mg to about 660mg, about 380mg to about 660mg, about 400mg to about 660mg, about 420mg to about 660mg, about 440mg to about 660mg, about 460mg to about 660mg, about 480mg to about 660mg, about 500mg to about 660mg,About 520mg to about 660mg, about 540mg to about 660mg, about 560mg to about 660mg, about 580mg to about 660mg, about 600mg to about 660mg, about 620mg to about 660mg, about 640mg to about 660mg, about 100mg to about 640mg, about 120mg to about 640mg, about 140mg to about 640mg, about 160mg to about 640mg, about 180mg to about 640mg, about 200mg to about 640mg, about 220mg to about 640mg, about 240mg to about 640mg, about 260mg to about 640mg, about 280mg to about 640mg, about 300mg to about 64 0mg, about 320mg to about 640mg, about 340mg to about 640mg, about 360mg to about 640mg, about 380mg to about 640mg, about 400mg to about 640mg, about 420mg to about 640mg, about 440mg to about 640mg, about 460mg to about 640mg, about 480mg to about 640mg, about 500mg to about 640mg, about 520mg to about 640mg, about 540mg to about 640mg, about 560mg to about 640mg, about 580mg to about 640mg, about 600mg to about 640mg, about 620mg to about 640mg, about 100mg to about 620mg, about 120mg to about About 620mg, about 140mg to about 620mg, about 160mg to about 620mg, about 180mg to about 620mg, about 200mg to about 620mg, about 220mg to about 620mg, about 240mg to about 620mg, about 260mg to about 620mg, about 280mg to about 620mg, about 300mg to about 620mg, about 320mg to about 620mg, about 340mg to about 620mg, about 360mg to about 620mg, about 380mg to about 620mg, about 400mg to about 620mg, about 420mg to about 620mg, about 440mg to about 620mg, about 460mg to about 620mg, about 48 0mg to about 620mg, about 500mg to about 620mg, about 520mg to about 620mg, about 540mg to about 620mg, about 560mg to about 620mg, about 580mg to about 620mg, about 600mg to about 620mg, about 100mg to about 600mg, about 120mg to about 600mg, about 140mg to about 600mg, about 160mg to about 600mg, about 180mg to about 600mg, about 200mg to about 600mg, about 220mg to about 600mg, about 240mg to about 600mg, about 260mg to about 600mg, about 280mg to about 600mg, about 300mg to about 600mg,About 320mg to about 600mg, about 340mg to about 600mg, about 360mg to about 600mg, about 380mg to about 600mg, about 400mg to about 600mg, about 420mg to about 600mg, about 440mg to about 600mg, about 460mg to about 600mg, about 480mg to about 600mg, about 500mg to about 600mg, about 520mg to about 600mg, about 540mg to about 600mg, about 560mg to about 600mg, about 580mg to about 600mg, about 100mg to about 580mg, about 120mg to about 580mg, about 140mg to about 580mg, about 160mg to about 580mg 0mg, about 180mg to about 580mg, about 200mg to about 580mg, about 220mg to about 580mg, about 240mg to about 580mg, about 260mg to about 580mg, about 280mg to about 580mg, about 300mg to about 580mg, about 320mg to about 580mg, about 340mg to about 580mg, about 360mg to about 580mg, about 380mg to about 580mg, about 400mg to about 580mg, about 420mg to about 580mg, about 440mg to about 580mg, about 460mg to about 580mg, about 480mg to about 580mg, about 500mg to about 580mg, about 520mg to about about 580mg, about 540mg to about 580mg, about 560mg to about 580mg, about 100mg to about 560mg, about 120mg to about 560mg, about 140mg to about 560mg, about 160mg to about 560mg, about 180mg to about 560mg, about 200mg to about 560mg, about 220mg to about 560mg, about 240mg to about 560mg, about 260mg to about 560mg, about 280mg to about 560mg, about 300mg to about 560mg, about 320mg to about 560mg, about 340mg to about 560mg, about 360mg to about 560mg, about 380mg to about 560mg, about 40 0mg to about 560mg, about 420mg to about 560mg, about 440mg to about 560mg, about 460mg to about 560mg, about 480mg to about 560mg, about 500mg to about 560mg, about 520mg to about 560mg, about 540mg to about 560mg, about 100mg to about 540mg, about 120mg to about 540mg, about 140mg to about 540mg, about 160mg to about 540mg, about 180mg to about 540mg, about 200mg to about 540mg, about 220mg to about 540mg, about 240mg to about 540mg, about 260mg to about 540mg, about 280mg to about 540mg,About 300mg to about 540mg, about 320mg to about 540mg, about 340mg to about 540mg, about 360mg to about 540mg, about 380mg to about 540mg, about 400mg to about 540mg, about 420mg to about 540mg, about 440mg to about 540mg, about 460mg to about 540mg, about 480mg to about 540mg, about 500mg to about 540mg, about 520mg to about 540mg, about 100mg to about 520mg, about 120mg to about 520mg, about 140mg to about 520mg, about 160mg to about 520mg, about 180mg to about 520mg, about 200mg to about 52 0mg, about 220mg to about 520mg, about 240mg to about 520mg, about 260mg to about 520mg, about 280mg to about 520mg, about 300mg to about 520mg, about 320mg to about 520mg, about 340mg to about 520mg, about 360mg to about 520mg, about 380mg to about 520mg, about 400mg to about 520mg, about 420mg to about 520mg, about 440mg to about 520mg, about 460mg to about 520mg, about 480mg to about 520mg, about 500mg to about 520mg, about 100mg to about 500mg, about 120mg to about 500mg, about 140mg to about About 500mg, about 160mg to about 500mg, about 180mg to about 500mg, about 200mg to about 500mg, about 220mg to about 500mg, about 240mg to about 500mg, about 260mg to about 500mg, about 280mg to about 500mg, about 300mg to about 500mg, about 320mg to about 500mg, about 340mg to about 500mg, about 360mg to about 500mg, about 380mg to about 500mg, about 400mg to about 500mg, about 420mg to about 500mg, about 440mg to about 500mg, about 460mg to about 500mg, about 480mg to about 500mg, about 10 0mg to about 480mg, about 120mg to about 480mg, about 140mg to about 480mg, about 160mg to about 480mg, about 180mg to about 480mg, about 200mg to about 480mg, about 220mg to about 480mg, about 240mg to about 480mg, about 260mg to about 480mg, about 280mg to about 480mg, about 300mg to about 480mg, about 320mg to about 480mg, about 340mg to about 480mg, about 360mg to about 480mg, about 380mg to about 480mg, about 400mg to about 480mg, about 420mg to about 480mg, about 440mg to about 480mg,About 460mg to about 480mg, about 100mg to about 460mg, about 120mg to about 460mg, about 140mg to about 460mg, about 160mg to about 460mg, about 180mg to about 460mg, about 200mg to about 460mg, about 220mg to about 460mg, about 240mg to about 460mg, about 260mg to about 460mg, about 280mg to about 460mg, about 300mg to about 460mg, about 320mg to about 460mg, about 340mg to about 460mg, about 360mg to about 460mg, about 380mg to about 460mg, about 400mg to about 460mg, about 420mg to about 460mg 0mg, about 440mg to about 460mg, about 100mg to about 440mg, about 120mg to about 440mg, about 140mg to about 440mg, about 160mg to about 440mg, about 180mg to about 440mg, about 200mg to about 440mg, about 220mg to about 440mg, about 240mg to about 440mg, about 260mg to about 440mg, about 280mg to about 440mg, about 300mg to about 440mg, about 320mg to about 440mg, about 340mg to about 440mg, about 360mg to about 440mg, about 380mg to about 440mg, about 400mg to about 440mg, about 420mg to about About 440mg, about 100mg to about 420mg, about 120mg to about 420mg, about 140mg to about 420mg, about 160mg to about 420mg, about 180mg to about 420mg, about 200mg to about 420mg, about 220mg to about 420mg, about 240mg to about 420mg, about 260mg to about 420mg, about 280mg to about 420mg, about 300mg to about 420mg, about 320mg to about 420mg, about 340mg to about 420mg, about 360mg to about 420mg, about 380mg to about 420mg, about 400mg to about 420mg, about 100mg to about 400mg, about 12 0mg to about 400mg, about 140mg to about 400mg, about 160mg to about 400mg, about 180mg to about 400mg, about 200mg to about 400mg, about 220mg to about 400mg, about 240mg to about 400mg, about 260mg to about 400mg, about 280mg to about 400mg, about 300mg to about 400mg, about 320mg to about 400mg, about 340mg to about 400mg, about 360mg to about 400mg, about 380mg to about 400mg, about 100mg to about 380mg, about 120mg to about 380mg, about 140mg to about 380mg, about 160mg to about 380mg,About 180mg to about 380mg, about 200mg to about 380mg, about 220mg to about 380mg, about 240mg to about 380mg, about 260mg to about 380mg, about 280mg to about 380mg, about 300mg to about 380mg, about 320mg to about 380mg, about 340mg to about 380mg, about 360mg to about 380mg, about 100mg to about 360mg, about 120mg to about 360mg, about 140mg to about 360mg, about 160mg to about 360mg, about 180mg to about 360mg, about 200mg to about 360mg, about 220mg to about 360mg, about 240mg to about 36 0mg, about 260mg to about 360mg, about 280mg to about 360mg, about 300mg to about 360mg, about 320mg to about 360mg, about 340mg to about 360mg, about 100mg to about 340mg, about 120mg to about 340mg, about 140mg to about 340mg, about 160mg to about 340mg, about 180mg to about 340mg, about 200mg to about 340mg, about 220mg to about 340mg, about 240mg to about 340mg, about 260mg to about 340mg, about 280mg to about 340mg, about 300mg to about 340mg, about 320mg to about 340mg, about 100mg to about 340mg About 320mg, about 120mg to about 320mg, about 140mg to about 320mg, about 160mg to about 320mg, about 180mg to about 320mg, about 200mg to about 320mg, about 220mg to about 320mg, about 240mg to about 320mg, about 260mg to about 320mg, about 280mg to about 320mg, about 300mg to about 320mg, about 100mg to about 300mg, about 120mg to about 300mg, about 140mg to about 300mg, about 160mg to about 300mg, about 180mg to about 300mg, about 200mg to about 300mg, about 220mg to about 300mg, about 24 0mg to about 300mg, about 260mg to about 300mg, about 280mg to about 300mg, about 100mg to about 280mg, about 120mg to about 280mg, about 140mg to about 280mg, about 160mg to about 280mg, about 180mg to about 280mg, about 200mg to about 280mg, about 220mg to about 280mg, about 240mg to about 280mg, about 260mg to about 280mg, about 100mg to about 260mg, about 120mg to about 260mg, about 140mg to about 260mg, about 160mg to about 260mg, about 180mg to about 260mg, about 200mg to about 260mg,Approximately 220mg to approximately 260mg, approximately 240mg to approximately 260mg, approximately 100mg to approximately 240mg, approximately 120mg to approximately 240mg, approximately 140mg to approximately 240mg, approximately 160mg to approximately 240mg, approximately 180mg to approximately 240mg, approximately 200mg to approximately 240mg , about 220mg to about 240mg, about 100mg to about 220mg, about 120mg to about 220mg, about 140mg to about 220mg, about 160mg to about 220mg, about 180mg to about 220mg, about 200mg to about 220mg, about 100mg to about 200mg , about 120 mg to about 200 mg, about 140 mg to about 200 mg, about 160 mg to about 200 mg, about 180 mg to about 200 mg, about 100 mg to about 180 mg, about 120 mg to about 180 mg, about 140 mg to about 180 mg, about 160 mg to about 180 mg, about 100 mg to about 160 mg, about 120 mg to about 160 mg, about 140 mg to about 160 mg, about 100 mg to about 140 mg, about 120 mg to about 140 mg, or about 100 mg to about 120 mg of an anti-IL-13 antibody or an antigen-binding portion thereof.

[0087] In one embodiment, the composition of the present disclosure is administered once. In another embodiment, the composition is administered weekly. In another embodiment, the composition is administered for 2 weeks. In another embodiment, the composition is administered for 3 weeks. In another embodiment, the composition is administered for 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 2 years, 3 years, 4 years, 5 years, 10 years, duration of the disease, or the lifespan of the subject. In one embodiment, the composition is administered subcutaneously. In another embodiment, the composition is administered intravenously. In one embodiment, the composition is administered once intravenously, followed by weekly subcutaneous administrations.

[0088] The dosage of the pharmaceutical composition may vary depending on the age, sex, health, and weight of the recipient, the type of concurrent treatment, if any, frequency of treatment, and the nature of the desired effect. Formulations used as preclinical and clinical therapeutics or in clinical diagnosis may be prepared by those skilled in the art utilizing accepted principles of diagnosis and treatment. The dosage range of the composition may be broad enough to produce the desired effect. Similarly, the dosage of the diagnostic composition may vary depending on the nature of the diagnostic, e.g., in vitro or in vivo application. Methods for formulating IL-13 antibodies and antigen-binding portions thereof into diagnostic agents, e.g., chelating the antibodies to diagnostic agents selected from radiolabels, colorimetric moieties, fluorescent moieties, chemiluminescent moieties, enzymatic moieties, and immunogenic moieties, are known in the art.

[0089] The compositions and pharmaceutical preparations may be packaged in the form of a kit. The term "kit" as used herein refers to a packaged product containing components with which the anti-IL-13 antibody of the disclosure is administered to treat AD. The kit, in some embodiments, includes a box or container that holds the components of the kit. The box or container is affixed with a label or a Food and Drug Administration approved protocol. The box or container, in some embodiments, holds the components of the disclosure housed in a plastic, polyethylene, polypropylene, ethylene, or propylene container. The container may be a tube or bottle with a cap. The kit may also include instructions for administering the anti-IL-13 antibody.

[0090] Combination therapy The term "combination therapy" as used herein refers to the administration of two or more therapeutic substances, such as an anti-IL-13 antibody and another agent. The other drug may be administered simultaneously with, prior to, or after administration of the anti-IL-13 antibody. In particular, the additional agent is an agent that is useful in the diagnosis and / or treatment of dermatitis disorders.

[0091] The term "combination" in the phrase "combination of a first agent with a second agent" includes, for example, simultaneous administration of a first agent and a second agent, which may be dissolved or mixed in the same pharma- ceutically acceptable carrier, or administration of a first agent followed by a second agent, or administration of a second agent followed by a first agent. The present disclosure thus includes methods of combination therapeutic treatments and combination pharmaceutical compositions.

[0092] The term "concurrent" in the phrase "concurrent therapeutic treatment" includes administration of an agent in the presence of a second agent. Concurrent therapeutic treatment methods include methods in which a first, second, third, or additional agent is administered simultaneously. Concurrent therapeutic treatment methods also include methods in which a first or additional agent is administered in the presence of a second or additional agent, for example, where the second or additional agent has already been previously administered. Concurrent therapeutic treatment methods can be performed stepwise by different subjects. For example, one subject can administer a first agent to a subject, and a second subject can administer a second agent to a subject, and the administering steps can be performed simultaneously or near simultaneously, or separated in time, so long as the first agent (and additional agent) is administered subsequently in the presence of the second agent (and additional agent). The subject and the subject can be the same entity (e.g., a human).

[0093] Atopic dermatitis "Atopic dermatitis", "AD", or "eczema", as used herein, refers to an inflammatory disease characterized by chronic inflammation of the skin. Symptoms of AD include, but are not limited to, pruritus (itchy skin and / or itchy sensation), dry skin, itching that can be severe, especially at night, red to brownish-gray patches of skin (especially on the hands, feet, ankles, wrists, neck, upper chest, eyelids, inner elbows and knees, and in childhood, face, and scalp), small raised bumps that may leak fluid and form crusts on them when scratched, thickened skin, cracked skin, scaly skin, raw skin, skin sensitivity, swollen skin, and interrupted and / or insomnia. AD most frequently begins before age 5 and can persist into adolescence and adulthood. In some patients, AD flares periodically, followed by periods of remission, which may last for several years.

[0094] As used herein, the terms "treat," "treating," and the like refer to improving a symptom, temporarily or permanently removing the cause of a symptom, or preventing or delaying the onset of symptoms of AD. In certain embodiments, the method is useful for reducing the incidence of symptoms or signs associated with AD. Particular embodiments of the present disclosure relate to methods for treating or ameliorating at least one symptom or sign associated with AD.

[0095] In particular, the method is useful for treating or ameliorating at least one symptom or sign of AD. Symptoms or signs associated with AD that are treatable according to this embodiment include, but are not limited to, pruritus, dry skin, itching, red to brownish-gray patches of skin, small raised bumps that may leak liquid and form a crust on top of them if scratched, thickened skin, cracked skin, scaly skin, rawhide, skin hypersensitivity, and swollen skin.

[0096] In embodiments relating to therapy for AD, the disclosed methods include treating a subject with elevated levels of AD-associated markers, such as, but not limited to, peripheral blood eosinophils, immunoglobulin E (IgE), lactate dehydrogenase, IL-13, IL-22, chemokine (CC motif) ligand 17 (CCL17) / thymus activation-regulated chemokine (TARC), and chemokine (CC motif) ligand 18 (CCL18) / pulmonary activation-regulated chemokine (PARC).

[0097] In some embodiments, the subject or patient is an animal, and in some embodiments, a mammal or bird. In some embodiments, the subject is selected from the group consisting of humans, dogs, cats, pigs, cows, buffalo, and horses. In some embodiments, the subject is a human subject.

[0098] In some embodiments, the methods herein can be used to treat AD in children under 3 years old.For example, the methods can be used to treat children under 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.In other embodiments, the methods of the present disclosure can be used to treat children over 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, over 14 years old, or over 15 years old (including all ages in between).

[0099] In related embodiments, the methods herein may be used to treat AD in adult subjects. By "adult" is meant a subject who is at least 16 years of age, including, for example, subjects who are 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, or older (including all ages in between).

[0100] Disclosed herein, in some embodiments, is a method for treating or ameliorating at least one symptom of AD in a subject in need thereof, the method comprising first selecting a subject exhibiting at least one symptom associated with AD, and administering a therapeutically effective amount of an anti-IL-13 antibody, or antigen-binding portion thereof, to the subject.

[0101] Selecting a target In some embodiments, the methods disclosed herein include first selecting a subject having AD. In some embodiments, the methods disclosed herein include first selecting a subject diagnosed with AD. A second step includes administering a composition of the disclosure comprising an anti-IL-13 antibody or antigen-binding portion thereof.

[0102] In the context of this embodiment, the selection step can be used to identify a subset of the population that is more susceptible to eosinophil disorders. In these embodiments, the subject may exhibit a particular trait or condition associated with eosinophil disorders. For example, the subject in need thereof can include a subject suffering from AD.

[0103] In other embodiments, the selection step can be used to identify a subset of the population that is more likely to benefit from therapy with an anti-IL-13 antibody, or antigen-binding portion thereof. An example of such a subset of the population is AD patients who have had an intolerance or inadequate response to treatment with topical agents for at least 4 weeks or who have required at least one systemic therapy to control their AD.

[0104] In therapeutic embodiments further comprising the selection of a susceptible subject population, the method may include the step of introducing one or more reagents and / or tools for detecting disease-specific markers associated with AD. For example, AD-associated markers may include protein markers, such as elevated or decreased IgE, lactate dehydrogenase, IL-13, IL-22, TARC, or PARC, etc. Combinations of the above markers, such as biomarkers and physiological markers, may also be employed.

[0105] Embodiments of the present disclosure relate to the treatment of treatment-naive as well as previously treated subjects, which may include responders, non-responders, refractory or relapsed subjects.

[0106] The term "treatment naive" is intended to include subjects who have never been actively treated for AD. Existing modes of treatment for AD include, for example, topical therapy (e.g., using corticosteroids, hydrocortisone, or antihistamine creams, or wrapping the affected area with topical corticosteroids and wet dressings), or phototherapy (e.g., exposing the skin to controlled amounts of natural sunlight or artificial ultraviolet A (UVA) and narrowband ultraviolet B (UVB) light, alone or in combination with medication). In particular, this embodiment provides a method of treating a subject suffering from AD who has previously received topical therapy.

[0107] Accordingly, embodiments of the present disclosure relate to a method for treating, reducing the incidence of, preventing, or ameliorating at least one symptom or sign of AD in a subject who has previously received a therapy for AD and who is deemed non-responsive to, or who has been refractory or relapsing to, the AD therapy, comprising administering to the subject a therapeutically effective amount of an anti-IL-13 antibody, or antigen-binding portion thereof. The subject, in some embodiments, is a human subject exhibiting at least one symptom or sign associated with AD.

[0108] Determining the effectiveness of treatment According to another aspect of the present disclosure, the method for treating AD is associated with determining the effectiveness of the treatment. In this embodiment, the subject is administered a composition comprising a therapeutically effective amount of an anti-IL-13 antagonist, and changes in AD-related markers are monitored before and / or after the therapy. The therapy is considered effective if at least one AD-related marker (e.g., peripheral blood eosinophils, IgE, lactate dehydrogenase, IL-13, IL-22, TARC, PARC, etc.) is decreased at the time point after administration of the composition compared to the marker level in the subject before administration. In this embodiment, the level of the marker is increased by at least about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%. %, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% or greater decrease in the IL-1 receptor agonist level indicates that the treatment is effective.

[0109] In another embodiment, the subject's global assessment of disease severity is determined.

[0110] In another embodiment, the clinician's global assessment of disease severity is determined. In yet another embodiment, the subject's global assessment of disease severity and the clinician's global assessment of disease severity are determined in combination.

[0111] In another embodiment, the subject's assessment of disease severity is determined both before (baseline) and after (post-treatment) administration of the antibody or antigen-binding portion thereof to the subject, where a decrease in the subject's assessment of disease severity compared to baseline indicates efficacy of the treatment.

[0112] In another embodiment, a clinician assessment of disease severity is performed in a subject both before (baseline) and after administration of the antibody or antigen-binding portion thereof (post-treatment), where a decrease in clinician assessment of disease severity compared to baseline indicates efficacy of treatment.

[0113] In a related embodiment, a composite score (composite score) is determined consisting of the subject's score and the clinician's score before administration of the composition (baseline level) and after administration of the composition (post-treatment level), and a reduction in the post-treatment composite score compared to baseline indicates efficacy of the treatment.

[0114] As will be appreciated by one of skill in the art, an increase or decrease in an AD-associated biomarker can be determined by comparing (i) the level of the biomarker measured in a subject at a defined time point after administration of a composition comprising an anti-IL-13 antibody or antigen-binding portion thereof, to (ii) the level of the biomarker measured in the patient prior to administration of a composition comprising an anti-IL-13 antibody or antigen-binding portion thereof (i.e., a "baseline measurement"). The defined time point at which the biomarker is measured can be, for example, about 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, 35 days, 40 days, 50 days, 55 days, 60 days, 65 days, 70 days, 75 days, 80 days, 85 days, or more after administration of a composition comprising an anti-IL-13 antibody or antigen-binding portion thereof.

[0115] According to certain embodiments of the present disclosure, a subject may exhibit increased or decreased levels of one or more of peripheral blood eosinophils, IgE, lactate dehydrogenase, IL-13, IL-22, TARC, and / or PARC after administration of a composition comprising an anti-IL-13 antibody or antigen-binding portion thereof. For example, at about day 1, 4, 8, 15, 22, 25, 29, 36, 43, 50, 57, 64, 71, or 85 after administration of a first, second, third, or fourth dose of a composition comprising an anti-IL-13 antibody or antigen-binding portion thereof, a subject may, according to the present disclosure, experience a decrease in peripheral blood eosinophils, IgE, lactate dehydrogenase, IL-13, IL-22, TARC, and / or PARC levels from at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17% or more from baseline (wherein "baseline" is defined as the levels of peripheral blood eosinophils, IgE, lactate dehydrogenase, IL-13, IL-22, TARC, and / or PARC in the subject immediately prior to the first dose). ,18%,19%,20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%,36%,37%,38%,39%,40%,41%,42%,43%,44%,45%,46%,47%,48%,49%,50%,51%,52%,53%,54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% or greater increase or decrease in peripheral blood eosinophils, IgE, lactate dehydrogenase, IL-13, IL-22, TARC, and / or PARC.

[0116] The present disclosure also includes methods for determining whether a subject is suitable for therapy with a composition comprising an anti-IL-13 antibody or an antigen-binding portion thereof. For example, if an individual exhibits a level of an AD-associated biomarker indicative of a disease state prior to administration of a composition comprising an anti-IL-13 antibody or an antigen-binding portion thereof, the individual is therefore identified as a suitable patient who would benefit from administration of a composition of the present disclosure (a composition comprising an anti-IL-13 antibody or an antigen-binding portion thereof). In related embodiments, the present disclosure includes methods for treating a suitable subject, where the suitable subject may be more susceptible to AD.

[0117] In other embodiments, diagnostic methods may employ gene expression assays.

[0118] In some embodiments, subjects treated with an anti-IL-13 antibody, or antigen-binding portion thereof, are evaluated at various time points using multiple specific and comprehensive markers. The specific markers can be biomarkers or physiological markers previously described.

[0119] Further, related embodiments of the present disclosure provide methods for monitoring a subject undergoing therapy for AD, comprising determining a parameter before and after therapy. In other embodiments, the parameter is selected from subject global assessment of disease severity, clinician global assessment of disease severity, subject global impression (e.g., based on wellness scoring), histology grade, and disease stage-adjusted score, number and severity of treatment-emergent adverse events (TEAEs) (collectively referred to as "macroscopic assessments").

[0120] In the above embodiments relating to monitoring of AD treatment based on macroscopic assessment, a subject / clinician-assessed disease severity, histology / stage score, or number of TEAEs is at least 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 109%, 108%, 109%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130 A decrease of 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91% 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more indicates that the therapy is effective. Similarly, in the betterment and / or wellness scores, at least 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109 ...9%, 110%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, An increase of 7%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% or more, or at least 1 fold, at least 1.2 fold, at least 1.5 fold, at least 1.8 fold, at least 2.0 fold, at least 2.5 fold, at least 3.0 fold or more indicates that the therapy is efficacious.

[0121] Applicants expressly incorporate the entire contents of all cited references in this disclosure. Furthermore, when an amount, concentration, or other numerical value or parameter is presented as a range or list of upper and lower values, this is understood to specifically disclose all ranges formed from any pair of any upper range or numerical value and any lower range or numerical value, whether or not the ranges are disclosed individually. When a range of numerical values ​​is recited herein, unless otherwise stated, the range is intended to include its endpoints, and all integers and fractions within the range. When a range is defined, it is not intended that the scope of the present disclosure be limited to the specific numerical values ​​recited.

[0122] [Example] This is an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, Phase II study to evaluate the efficacy and safety of sendakimab in adult subjects with moderate-to-severe AD. Subjects enrolled in this study must also be candidates for systemic therapy, defined as those who have had at least 4 weeks of intolerance or inadequate response to treatment with topical agents or who have previously required systemic therapy to control their disease.

[0123] After a screening period of up to 4 weeks, approximately 200 eligible subjects (50 subjects per treatment group) will be randomized (1:1:1:1) to receive sendakimab (720 mg QW, 720 mg Q2W, or 360 mg Q2W) or placebo. Treatment assignment will be stratified by region (Japan vs. the rest of the world); for the rest of the world only, randomization will also be stratified by disease severity based on baseline vIGA-AD score (3 [moderate] or 4 [severe]). Randomization will occur on Day 1 (baseline) through the use of an Interactive Response Technology (IRT) system.

[0124] The overall benefit / risk profile of the sendakimab 720 mg SC QW dose will be explored first in this study. Because this is the first clinical trial to further evaluate the safety and efficacy profile of sendakimab at higher cumulative exposures, additional safety assessments, such as increased frequency of on-site visits, ongoing blinded safety reviews of study data, oversight by an internal Safety Management Team (SMT), and oversight by an external independent Data Monitoring Committee (DMC), as further described in Example 2.6), will be conducted during the study to ensure that subject safety is appropriately monitored.

[0125] Clinical laboratory tests, vital signs, physical examination (including height and weight), pregnancy test, clinical symptom assessment, subject reported outcomes, serum sendakimab concentrations, serum antibodies to sendakimab (to assess immunogenicity), concomitant medications, and AE assessments will be performed. Relevant biomarkers, including but not limited to peripheral blood eosinophils, IgE, lactate dehydrogenase, IL-13, IL-22, CCL17 (TARC), and CCL18 (PARC), will be measured pre- and post-treatment.

[0126] Although concurrent treatment with background therapy to alleviate AD symptoms is prohibited during the treatment and follow-up periods of the study, the use of rescue medication as described in Example 4.4 may be employed for subjects who experience intolerable AD symptoms after randomization.

[0127] The maximum duration for which subjects will participate in this study is approximately 36 weeks.

[0128] Subjects will participate in the Screening Period for up to 4 weeks. Subjects will participate in the Screening Period, which will last up to 4 weeks. During the Treatment Period, subjects will receive a total of 16 IP doses (administered once per week), starting on Day 1 / Week 0 and ending on Week 15. At Week 16, subjects will return for an End of Treatment visit for safety and efficacy assessments. After the Week 16 End of Treatment visit, subjects will enter a 16-week follow-up period and return for two additional visits to evaluate safety, clinical status, PK / PD, and antibodies to sendakimab in serum. The first follow-up visit will be conducted 8 weeks (Week 24) after the End of Treatment visit, and the final follow-up / End of Study visit will be conducted 16 weeks (Week 32) after the End of Treatment visit.

[0129] Blinding should be maintained for personnel involved in the ongoing conduct of the study until after the primary analysis database lock, which is scheduled to begin after all subjects have completed the Week 16 / End of Treatment Visit assessments. Blinded personnel may include, but are not limited to, clinical research physicians, clinical research scientists, clinical trial managers, trial statisticians, data managers, programmers, and clinical research personnel.

[0130] The study will be conducted in compliance with the International Council on Harmonisation (ICH) Technical Requirements for Registration of Pharmaceuticals for Human Use / Good Clinical Practice (GCP) and applicable regulatory requirements.

[0131] 1.1 - Targeted test period The maximum duration of subject participation in this study is approximately 36 weeks.

[0132] Subjects will participate in a screening period of up to 4 weeks. Once randomized, subjects will enter the treatment phase of the study and receive a total of 16 IP doses, starting on Day 1 (baseline) and ending at Week 15.

[0133] At Week 16, subjects return for an End of Treatment visit for safety and efficacy assessments. After the Week 16 End of Treatment visit, subjects enter a 16-week follow-up period and return for two additional visits to evaluate safety, clinical status, PK / PD, and antibodies to sendakimab in serum. The first follow-up visit will occur 8 weeks after the End of Treatment visit (Week 24), and the final follow-up / End of Study visit will occur 16 weeks after the End of Treatment visit (Week 32).

[0134] Ending a trial The end of the trial will be defined as the date of the last subject's final visit to complete post-treatment follow-up, or the date the last data point is received from the last subject requiring primary, secondary, and / or exploratory analyses, whichever is later, as pre-specified in the protocol.

[0135] 1.2 - Study population 1.2.1 - Number of subjects Approximately 200 adult subjects (aged 18-75 years) with moderate to severe AD will be randomized internationally.

[0136] 1.2.2 - Inclusion criteria Subjects must meet the following criteria to be enrolled in the study: Subjects must be aged 18 years or older and 75 years or younger, and weigh 40 kg (88.2 lb) or more when signing the Informed Consent Form (ICF). Subjects in Japan must also be of legal age of consent (20 years or older) when signing the ICF.

[0137] Subjects have chronic AD as defined by Hanifin and Rajka (see Tada, Japan Med. Assoc. J. 45:460-65 (2002)), with AD present for 1 year or more prior to the baseline visit (Day 1).

[0138] Subjects have moderately to severely active and symptomatic AD, defined as meeting all of the following criteria on the day of the baseline visit (Day 1): BSA ≥ 10%, and EASI score ≥ 16, and vIGA-AD ≥ 3, and Pruritus NRS severity score ≥ 4

[0139] Subjects must have a documented history of inadequate response to treatment with topical agents for at least 4 weeks, unless topical treatment is not medically advisable (e.g., due to significant side effects, safety risks, and / or past intolerance) or the subject has required systemic therapy to control their disease.

[0140] An inappropriate response is defined as either or both of the following: Treatment with a daily regimen of medium- to higher-potency TCS (± TCI, as appropriate) administered for at least 4 weeks (28 days) or the maximum duration recommended by the product prescribing information, whichever is shorter, has failed to achieve and / or maintain disease activity equivalent to IGA 0 (remission) to 2 (mild); or Systemic therapy was required to control the disease.

[0141] Subjects must be willing to apply a stable dose of topical emollient (over-the-counter moisturizer) twice daily for at least 7 days prior to the baseline visit and to continue application throughout the study. See Example 4.3 for additional requirements related to application of topical emollients throughout the study.

[0142] Subjects must undertake to avoid prolonged exposure to the sun and not use tanning beds, sunlamps, or other sources of ultraviolet light for the duration of the study.

[0143] Subjects currently taking concomitant medications for any reason other than AD, such as inhaled corticosteroids, leukotriene receptor blockers (e.g., montelukast), or mast cell stabilizers for asthma (e.g., sodium cromoglycate), must be on a stable regimen (defined as no new medications initiated, no changes in medication, or no discontinuation of medication within 7 days or 5 half-lives, whichever is longer, prior to Day 1 of the study and throughout the treatment period).

[0144] Female subjects of childbearing potential must agree to use highly effective contraceptive methods. Highly effective contraceptive methods, either alone or in combination, when used consistently and correctly, provide an annual Pearl Index failure rate of less than 1%. A female of childbearing potential (FCBP) is a woman who: 1) has had menarche at some point; 2) has never had a hysterectomy or bilateral oophorectomy; or 3) has not been in a post-menopausal state for at least 24 consecutive months (amenorrhea after cancer therapy does not preclude fertility) (i.e., has had menses at any time within the preceding 24 consecutive months); and As verified by the investigator, two negative pregnancy tests must be obtained prior to the start of study therapy. Women of childbearing potential must agree to continuous pregnancy testing throughout the course of the study and until the final follow-up visit. This is indicative of true abstinence from heterosexual intercourse. * This rule applies even if the practice is

[0145] True abstinence from heterosexual intercourse without interruption throughout the study and for 5 months after the last dose of IP * (which must be reviewed monthly and the source documented) or agree to use highly effective contraception and be able to comply.

[0146] Acceptable methods of birth control in this study were: Combined hormonal (estrogen and progestogen-containing) contraceptive methods (which may be oral, intravaginal, or transdermal). Note: Intravaginal and transdermal combined hormonal contraceptive methods have not been approved by the health authorities of Japan and therefore are not acceptable contraceptive methods for subjects enrolled in this region. b. Progestogen-only hormonal contraception associated with the inhibition of ovulation (which may be oral, injectable, or implantable). Note: Progestogen-only hormonal contraception has not been approved by the health authorities of Japan and is therefore not an acceptable method of contraception for subjects enrolled in this region. c. Placement of an intrauterine device (IUD) d. Placement of an intrauterine hormone-releasing system (IUS) e. Bilateral tubal obstruction f. Partner's vasectomy g. Abstinence

[0147] Subjects are willing to receive weekly SC injections throughout the study. Subjects must understand and willingly sign the ICF before any study-related assessments / procedures are performed. Subjects are willing and able to comply with the study visit schedule and other protocol requirements.

[0148] * True abstinence is acceptable if it is the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptom-temperature, post-ovulation methods), withdrawal (coital abortion), and lactational amenorrhea are not acceptable methods of contraception.

[0149] 1.2.3 - Exclusion criteria A subject will be removed from registration if any of the following are present: Evidence of active and / or coexisting inflammatory skin conditions (e.g., seborrheic dermatitis, psoriasis, acute allergic contact dermatitis, etc.) that would interfere with investigator- or subject-performed assessments of AD. Evidence of acute AD flare-up between screening and baseline / randomization (e.g., a 2-fold increase in EASI score between screening and baseline). Use of topical treatments that may affect the assessment of AD (e.g., corticosteroids, calcineurin inhibitors, tar, antibiotic creams, topical antihistamines) within 7 days of the Day 1 visit. Received narrowband UVB (NB-UVB) phototherapy or broadband phototherapy within 4 weeks prior to the baseline visit. Evidence of immunosuppression. Subjects were receiving or had received within 4 weeks prior to the baseline visit any systemic immunosuppressive or immunomodulatory medication (e.g., azathioprine, cyclosporine, systemic corticosteroids, IFN-γ, Janus kinase inhibitors, methotrexate, mycophenolate mofetil, etc.). Treatment with immunomodulatory biologics includes: Dupilumab within 3 months of the Baseline visit. b. Cell-depleting biologics, including rituximab, within 6 months prior to the baseline visit. c. Other immunomodulatory biologics within 5 half-lives (if known) or 16 weeks, whichever is longer, prior to the Baseline visit. d. Concurrent treatment with another IP (including through participation in an interventional trial for COVID-19). Prospective subjects must not have received an IP within 5 drug half-lives prior to participating in a concurrent IP trial or signing the ICF for this study. Additionally, for subjects who received an investigational COVID-19 vaccine as part of a clinical trial prior to the initial screening visit, enrollment must be delayed until the biological effects of the vaccine have stabilized, as determined by a joint effort between the investigator and the clinical trial physician. e. Receipt of a live attenuated vaccine within 1 month prior to the initial screening visit or anticipated need for vaccination with a live attenuated vaccine during the study. Any administration of a live attenuated vaccine is prohibited during the study until the final follow-up visit. f. Previously received sendakimab treatment (formerly known as RPC4046 and ABT-308). g. Hepatic dysfunction or persistent elevation of aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST / SGOT) or alanine aminotransferase / serum glutamic pyruvic transaminase (ALT / SGPT) ≥2x the upper limit of normal (ULN) or total bilirubin ≥1.5x the ULN. Subjects with clinically insignificant elevations in total bilirubin associated with Gilbert's syndrome may be enrolled. h. Active chronic or acute skin infection requiring treatment with a systemic antibiotic, antiviral, anthelmintic, antiprotozoal, or antifungal agent within 2 weeks prior to Day 1, or a superficial skin infection within 1 week prior to Day 1. i. Active or suspected parasitic / helminthic infection. Subjects with suspected infection may be enrolled if active infection is excluded by clinical and / or laboratory assessment prior to randomization. j. Treated infections (including, but not limited to, hepatitis B or C, human immunodeficiency virus [HIV], or tuberculosis that require testing to rule out during the screening period as defined by standard medical guidelines and outlined in Example 3.1) k. History of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 4 weeks prior to screening. Symptoms must have fully resolved and there are no sequelae that would place the participant at higher risk of receiving study treatment based on the investigator's assessment in consultation with the clinical trial physician. See Example 3.1.3 for additional guidance related to SARS-CoV-2 testing during screening. l. Pregnant or breastfeeding. History of idiopathic anaphylaxis or major immunological reaction (e.g., anaphylactic reaction, anaphylactoid reaction, or serum sickness) to immunoglobulin G (IgG)-containing drugs. Known hypersensitivity to any component in the investigational product (IP) is also excluded. History of cancer or lymphoproliferative disease within 5 years of screening, except for successfully treated nonmetastatic cutaneous squamous or basal cell carcinoma or adequately treated in situ cervical carcinoma. o. History of alcohol or drug abuse within 5 years prior to beginning screening. p. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the Study. q. Any condition, including the presence of abnormal test results, that places the subject at unacceptable risk if he or she participates in the study. r. Any other condition that impairs the ability to interpret the data obtained from this study.

[0150] Example 2 - Procedure Study assessments and procedures are described herein. The day the first dose IP is administered is defined as Day 1 (Baseline / Pre-dose).

[0151] It is recommended that study visits be scheduled in the morning. Whenever possible, the order of assessments should be kept consistent and should occur at approximately the same time of day throughout the study.

[0152] 2.1 - Screening Period A screening evaluation will be performed on all subjects to determine study eligibility. This evaluation must be completed within 28 days (4 weeks) prior to receiving the first dose of IP unless otherwise noted below. Under no circumstances will waivers of the protocol be permitted during the conduct of this study.

[0153] Screening procedures will be performed on all subjects to determine their eligibility for the study. All screening procedures must be completed within 4 weeks prior to receiving the first dose of IP.

[0154] An electronic patient-reported outcomes (ePRO) instrument on a handheld device will be distributed to subjects at the screening visit. After completing the training module, subjects will complete the Pruritus NRS daily for at least the final week (7 days) during the screening period (prior to Day 1). However, values ​​to assess inclusion criteria will be assessed on Day 1 (baseline / pre-dose).

[0155] Safety laboratory analyses and all assessments are performed. Screening laboratory values ​​must demonstrate subject eligibility. However, if necessary, analytes may be repeated (and analyzed by a central laboratory) within the screening window.

[0156] Prior to performing any study-related procedures, written, signed and dated informed consent from the subject must be obtained by the principal investigator or his / her designee. A copy of the signed informed consent must be given to the subject for the subject's records.

[0157] At screening, after obtaining informed consent / assent, the following assessments will be performed: Evaluation of inclusion / exclusion criteria Demographics and baseline characteristics Medical history including atopic conditions (documentation of AD history, other atopic conditions, and previous medical treatment for AD and other atopic conditions), and details of any prior therapies or procedures to treat AD or other atopic conditions. Prior and concomitant therapies (including all procedures occurring within 28 days prior to screening). ● Assessment of adverse events will begin once the subject signs the informed consent / assent form. Every effort must be made to remain vigilant for possible AEs or serious AEs (SAEs) throughout the course of the study. Once the subject has consented, AEs / SAEs will be recorded at each study visit. See Example 6 for definition, monitoring, and reporting of AEs / SAEs. Hematology, chemistry, coagulation panel, and urinalysis (central laboratory). The following safety laboratory tests will be performed to evaluate the safety profile of sendakimab: o Hematology: Red blood cell (RBC) count, total and differential white blood cell (WBC) percentages (basophils, eosinophils, lymphocytes, monocytes, and neutrophils), platelet count, hemoglobin (hgb), hematocrit (hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Blood Chemistry: Chemistry indices included at all required time points are sodium, potassium, chloride, calcium, magnesium, phosphate, blood urea nitrogen, glucose (random, not requiring fasting), albumin, alkaline phosphatase, creatinine, creatine phosphokinase (CPK), ALT / SGPT, AST / SGOT, gamma glutamyl transferase (GGT), amylase, total bilirubin, direct bilirubin, and C-reactive protein (CRP). In addition, a fasting lipid panel (total cholesterol, triglycerides, high density lipoprotein, and low density lipoprotein) and fasting glucose (in lieu of random glucose) will be performed only on Day 1 and Week 6 / EOT / ET. o Coagulation: Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR). Urine analysis: white blood cells, specific gravity, bilirubin, blood, glucose, ketones, pH, protein, and urobilinogen. • Testing (central laboratory) for Hepatitis B virus (HBV), Hepatitis C virus (HCV), and HIV will be performed at the time of screening only. HBV: A Hepatitis B surface antigen (HBsAg) screening test and a Hepatitis B core antibody (HBcAb) test will be performed. Subjects who test positive for HBsAg will be excluded from the study. For subjects who test positive only for HBcAb, an HBV deoxyribonucleic acid (DNA) test must be performed. If the HBV DNA test is positive, the subject will be excluded from the study. If the HBV DNA test is negative (no antiviral therapy) and ALT and AST are below the ULN, the subject is eligible for the study. HCV: HCV antibody (anti-HCV IgG) testing will be performed. Subjects who test positive for HCV antibody and have a positive confirmatory test (HCV ribonucleic acid [RNA]) will be excluded from the study. Subjects with evidence of recovery from HCV infection (e.g., HCV antibody-positive subjects who are negative for HCV RNA) and who have not received anti-HCV therapy for at least 12 weeks will be eligible for participation. HIV: HIV antibody testing will be performed. Subjects who test positive for HIV (enzyme-linked immunosorbent assay [ELISA] test result, confirmed by Western blot) will be excluded from the study. Testing for tuberculosis (TB) will be performed at screening only. Active TB must be ruled out per local medical practice. TB must be assessed using a TB skin test, QuantiFERON Gold test, or other interferon gamma release assay (IGRA) (e.g., T-SPOT). Subjects with latent TB must have documentation of completion of preventive treatment per local standard of care. Subjects with indeterminate test results using any of the IGRA tests must be discussed for eligibility by the sponsor's medical monitor or his / her designee, as appropriate. Subjects with latent TB who are only partially treated or currently receiving preventive treatment are not eligible for randomization. ● Serum pregnancy test (FCBP only). Serum testing for the β-subunit of human chorionic gonadotropin (β-hCG) must be performed at screening in women of childbearing potential. Urine (or serum) β-hCG will be performed on Day 1 and at multiple time points thereafter. If the urine test is positive, the subject will not be dosed and confirmation with a serum pregnancy test should be performed. At screening and each subsequent study visit, the investigator will counsel FCBP subjects on pregnancy prevention for the duration of the study. ●Physical Examination: A complete physical examination (including evaluation of the heart, lungs, head and neck, abdomen, neurological assessment, and extremities) will be performed. Height and weight Vital signs: heart rate, blood pressure (systolic and diastolic), respiratory rate, and temperature will be assessed at each visit. Once the subject is at rest in a seated position, blood pressure and heart rate will be assessed. Validated automated devices may be used if available. ● Electrocardiogram (ECG): At the screening visit only, a unipolar 12-lead ECG will be performed while the subject is at rest and may be repeated to confirm any abnormal findings. ●AD Disease Activity Assessment: 〇vIGA-AD 〇EASI 〇BSA 〇Pruritis NRS

[0158] 2.1.1 - Additional Information Regarding Safety Laboratory Assessments Analysis of samples will be performed by a central laboratory. Details regarding sample collection, sample transport, reporting of results, laboratory reference ranges, and abnormal value alerts will be provided to the facilities in a Test Laboratory Manual prior to facility opening. Results of the analysis will be made available to each facility by the central laboratory.

[0159] Additional and repeated laboratory safety tests may be performed locally at the discretion of the investigator. Since local laboratory data are not collected in the electronic case report form (eCRF), samples should also be sent to a central laboratory, when feasible. In addition, when safety laboratory samples are collected to further evaluate AEs, it is recommended that serum samples to evaluate ADAs and PK also be collected and sent to a central laboratory, when feasible. If retesting is required during the screening period, laboratory samples required to confirm study eligibility (e.g., liver function tests, serology panels, etc.) are required to be performed by the central laboratory. Retesting of specific laboratory parameters to confirm eligibility is permitted once during the screening period. If the subject still does not meet the eligibility criteria after retesting, the subject should fail the screen.

[0160] 2.1.2 - Screening failure and rescreening of potential subjects A screen failure is defined as a subject who provides informed consent / assent but fails to meet the inclusion and / or exclusion criteria. Subjects who fail to meet the inclusion / exclusion criteria initially may be rescreened according to the investigator's assessment. Subjects who are rescreened will be required to re-consent and perform all required screening visit procedures. Subjects may be rescreened one additional time for this study without prior consultation with the medical monitor.

[0161] 2.1.3 - Rescreening of subjects who develop COVID-19 during the screening period Molecular testing for asymptomatic COVID-19 infection is not required for this study. However, where local requirements or institutional practices are more stringent, screening for asymptomatic COVID-19 may be performed locally to ensure compliance with current local guidance. In addition, some subjects may develop suspected or confirmed symptomatic COVID-19 infection, or subjects may be found to have asymptomatic COVID-19 infection during the screening period. In such cases, subjects may be considered eligible for the study after meeting all inclusion / exclusion criteria related to active infection and after meeting the following criteria: At least 10 days (20 days in the case of severe / critical illness) have passed since the first appearance of symptoms or a positive test result, and At least 24 hours have passed since the last fever without the use of fever-reducing medication, and Symptoms (e.g., cough and shortness of breath) have resolved and, in the opinion of the investigator, there are no signs of COVID-19 sequelae that would place the subject at higher risk of receiving study treatment; and • Follow-up negative molecular test for COVID-19 per facility, local, or regional guidelines.

[0162] 2.2 - Treatment duration On Day 1, prior to randomization, baseline assessments (including laboratory assessments and possible skin biopsy) will be completed prior to administration of study drug. The Investigator will review all available information to confirm subject eligibility. Screening tests will be used to determine eligibility for randomization, with the exception of pregnancy tests which must be confirmed by a Day 1 test result. A urine (or serum) pregnancy test must be performed on all females of childbearing potential on Day 1 and the results must be reviewed prior to randomization. A negative pregnancy test result must be obtained prior to randomization. If the urine pregnancy test result is positive but is thought to be a false positive, the site must perform a serum pregnancy test in an on-site laboratory to confirm pregnancy status. A baseline laboratory test will be performed on Day 1 for comparison with the follow-up test. However, the results of this test will not be available prior to randomization on Day 1. Baseline vIGA-AD, EASI, BSA, and subject-reported pruritus NRS performed on Day 1 will be used to assess subject eligibility; providing stratified data points for vIGA-AD score for randomization.

[0163] After eligibility is confirmed and baseline assessments are completed, eligible subjects will be randomized to treatment on Day 1. Subsequent visits, assessments, and procedures will be conducted. Assessment of inclusion / exclusion criteria to confirm eligibility (Day 1 only) Combination therapy Assessment of AEs / SAEs. In addition, starting from Day 1, any malfunctions or failures of the device (i.e., prefilled syringes) should be captured and any device-related AEs should also be collected. Hematology, chemistry, fasting lipid panel, and urine analysis ●Urine pregnancy test (FCBP only) Perform a physical examination (including a full physical exam (including evaluation of the heart, lungs, head and neck, abdomen, neurological assessment, and extremities) or an abbreviated (intermediate / short) physical exam (including areas with previously noted abnormalities and / or relevant to any new complaints from the subject). Weight Vital signs Antibodies against sendakimab in serum PK assessment of sendakimab in serum ● Whole blood and serum biomarker assessment SARS-CoV-2 serological assessment ● If applicable based on government and local regulations, a Pharmacogenetic Assessment will be collected once on Day 1 (Note, samples may be obtained at any subsequent visit). Possible skin biopsy AD Disease Activity and Efficacy Assessment: 〇vIGA-AD 〇EASI 〇BSA 〇SCORAD 〇Pruritis NRS 〇PROMIS Sleep Disorders SF 〇DLQI 〇HADS IP administration

[0164] See Example 2.5 for a detailed description of efficacy assessments and outcome measures performed throughout the study.

[0165] 2.2.1 - Termination or early termination of treatment An EOT / ET visit will be conducted for subjects who complete the treatment phase of the study (Week 16) or who discontinue early from the study for any reason (i.e., before Week 16). For subjects who discontinue early from the study, every attempt should be made to complete the assessments detailed in the ET visit, which will be conducted as close as possible to the time of study discontinuation. If study discontinuation occurs during a regularly scheduled visit, the ET visit and all corresponding ET visit procedures should be conducted. In addition, such subjects should return for a follow-up visit.

[0166] 2.3 - Follow-up period All subjects will be followed for 16 weeks after the EOT / ET visit for AE reporting, as described in Example 6.1, and any SAEs suspected to be related to IP will be disclosed to the investigator at any time thereafter. Subjects will return for the first (24 weeks) and final (32 weeks) follow-up visits 8 and 16 weeks after the end of the EOT / ET visit, respectively. For subjects who discontinue the study early, the 16-week follow-up period should be based on the date of the last study visit (e.g., ET visit) performed during the treatment phase of the study, and therefore may be performed earlier than 24 and 32 weeks.

[0167] 2.4 - Effectiveness Assessment The following efficacy assessments will be performed by the investigator: Investigator's Global Assessment for Atopic Dermatitis (validated), Eczema Area and Severity Index, Body Surface Area (BSA)%, and SCORing Atopic Dermatitis Index. Clinical efficacy assessments for atopic dermatitis will be performed by experienced and qualified medical professionals with experience in conducting AD clinical trials.

[0168] All efficacy assessors must receive and document protocol-specific and applicable efficacy assessment scale training prior to performing any assessment. To ensure consistency and reduce variability, whenever possible, the same assessor must perform all dermatological clinical assessments for any individual subject throughout the study. In rare cases where a designated assessor is unable to perform an assessment, only qualified, protocol-trained assessors with supporting experience will be permitted. Every effort should be made to ensure that the same assessor performs assessments for a given subject at all study visits.

[0169] 2.4.1 - Validated Investigator Global Assessment The vIGA-AD is a validated 5-point assessment designed to assess the global severity of the major acute clinical signs of AD, including erythema, induration / papulation, and weeping / crusting (but lichenification is excluded). At scheduled visits as defined in Example 1, ratings of remission (0), near remission (1), mild (2), moderate (3), and severe (4) are assessed. The vIGA-AD must be performed prior to the EASI assessment. The IGA is a static assessment that is performed regardless of scores obtained at previous visits.

[0170] 2.4.2 - Eczema area / severity index The EASI is a composite scoring system assessed by the investigator based on the percentage of each of the four body regions (head and neck, upper limbs, lower limbs, and trunk) affected by AD and the intensity of each of the four cardinal signs of AD (e.g., erythema, induration / papulation, excoriation, and lichenification) on a 4-point scale of 0 (absent), 1 (mild), 2 (moderate), and 3 (severe). Evaluation of the four cardinal clinical signs is performed separately for the four body regions: head and neck, upper limbs, trunk (including axillae and groin), and lower limbs (including buttocks). Overall EASI scores range from 0 to 72, with higher scores indicating more severe disease.

[0171] 2.4.3 -Body surface area Body Surface Area Involvement is calculated from the sum of the number of hand prints of skin affected by atopic dermatitis within a body region. The number of hand prints of skin affected by atopic dermatitis within a body region can be used to determine the percent of body area involved in AD. When measured, one hand print unit refers to the size of each individual subject's hand with the fingers placed in a closed position. BSA is calculated by the Investigator or qualified designee using the 1% hand print rule, where the area represented by the palm with all five fingers pressed together is approximately 1% of the subject's BSA.

[0172] 2.4.4 -SCORing Atopic Dermatitis Index SCORAD is a validated scoring index for atopic dermatitis that combines subjective symptoms (0-20) based on extent (0-100), severity (0-18), and pruritus and insomnia (respectively scored (0-10)). Subjects rate the subjective symptoms (pruritus and insomnia) portion of the assessment.

[0173] 2.5 - Subject-Reported Efficacy Assessments and Outcome Measures Subject-reported efficacy assessments and outcome measures relevant to AD include assessment of the following: Pruritus Numeric Rating Scale PROMIS Sleep Disorders Short Form 8a Patient-centered eczema scale Dermatology Quality of Life Index Hospital Anxiety and Depression Scale

[0174] 2.5.1 - Pruritus Numeric Rating Scale Pruritus is assessed by subjects using a single-item developed and validated Pruritus NRS, a patient-reported outcome (PRO) of pruritus severity. Clinical response is represented by change from baseline in peak Pruritus NRS score (2 points to 4 points or more). Pruritus intensity is rated using a validated 11-point NR, ranging from 0 ("no pruritus") to 10 ("worst pruritus imaginable"), based on the most recent 24 hours. Subjects enter their pruritus intensity daily (e.g., study visit / investigational drug administration days) through week 4 and weekly thereafter through the week 16 visit in an electronic diary.

[0175] 2.5.2 - PROMIS Sleep Disorders Short Form The PROMIS Sleep Disorders Short Form 8a is a subjective questionnaire consisting of 8 questions designed to capture the subject's perception of sleep quality, sleep depth, and sleep-related restoration during the previous week. The questionnaire is scored by [sum of items × 8) divided by the number of items answered]. The higher the total score, the more severe the symptoms. A total score of less than 24 suggests no to slight sleep disturbance, 24-28 suggests mild disturbance, 29-38 suggests moderate disturbance, and >38 suggests severe sleep disturbance.

[0176] Subjects will complete the questionnaire on-site during their study visit.

[0177] 2.5.3 - Patient-centered eczema scale The POEM is a validated tool used to monitor atopic eczema severity. It is a seven-item questionnaire completed by subjects to assess the severity of their eczema over the previous week. Each of the seven questions has equal weighting, and responses are scored from 0 to 4, with a total score ranging from 0 to 28: to date, there has been general agreement in two published studies that the minimally important change (MIC) of the POEM is 3 points (Howell, 2018).

[0178] Subjects will complete the questionnaire on-site during their study visit.

[0179] 2.5.4 - Dermatology Quality of Life Index The DLQI is completed by subjects at the study visit. The DLQI is a self-administered, easy-to-use, dermatology-specific quality of life (QOL) questionnaire consisting of 10 questions relating to the subject's perception during the previous week of the impact of their skin disease on several different aspects of their QOL. Questions are scored from 0 to 3, resulting in a possible total score ranging from 0 (meaning no impact of the skin disease on quality of life) to 30 (meaning maximal impact on quality of life).

[0180] 2.5.5 - Hospital Anxiety and Depression Scale (HADS) The HADS is a subject-completed questionnaire that assesses anxiety and depression in non-psychiatric populations. The HADS has two subscales (depression and anxiety), each containing seven questions. Responses are based on the relative frequency of symptoms during the previous week, using a 4-point scale ranging from 0 (never) to 3 (very often). The HADS is completed by subjects at study visits.

[0181] 2.6 - Safety assessment The safety parameters evaluated in this study are outlined in Example 1 and are similar to those used in previous or ongoing clinical trials of sendakimab. Careful safety monitoring of clinical and laboratory findings by both the sponsor's medical monitor and the investigators was implemented in this protocol. Because this is the first clinical trial to further explore the safety and efficacy profile of sendakimab at higher cumulative exposures, additional risk minimization measures, such as frequency of on-site visits, ongoing blinded safety review of study data, internal safety management team (SMT) oversight, and external independent data monitoring committee (DMC) oversight, will be implemented throughout this Phase II study to ensure that subject safety is appropriately monitored. Additional safety monitoring measures for this study are summarized below.

[0182] 2.6.1 - On-site visit frequency All subjects will return to the site weekly for the first 3 weeks for routine safety monitoring, IP dosing, and a 30-minute observation period after IP dosing. Subjects may have the option to return to the clinic weekly throughout the entire 16-week treatment period, or, beginning in week 3, subjects may have the option to return to the clinic every other week for IP dosing and receive injections at home by a home health visitor during the alternate weeks.

[0183] Subjects using the home health nurse option will be required to return to the site at least every 2 weeks (e.g., at Week 4 [Visit 5 / 29], Week 6 [Visit 7 / 43], Week 8 [Visit 9 / 57, Week 10 [Visit 11 / 71], Week 12 [Visit 13 / 85], Week 14 [Visit 15 / 99], and Week 16 [Visit 17 / 113]) to ensure that additional safety assessments can be performed, such as collection of safety laboratory samples by the investigator and site staff, and on-site assessments. Subjects using the home health service option for any visit will still be contacted (within 24 hours) by site staff to assess any changes in concomitant therapy use, evaluate for adverse events, and ensure there is continuity in the safety monitoring performed by the investigator and site staff.

[0184] 2.6.2 - Blinded Safety Data Review From the start of the study (defined as the randomization of the first subject), blinded safety reviews will be performed on an ongoing basis by internal study team / blinded data review team members. In addition, safety data will be periodically evaluated by the SMT, and certain members of the SMT may also participate in ongoing study data review related activities. The expected frequency of these planned reviews is outlined below: A preliminary interim blinded safety review involving the internal study team and SMT will also be conducted after the first 8 subjects have been treated with IP for at least 4 weeks. A similar review will be initiated after the first 8 Japanese subjects have been treated for at least 4 weeks. The purpose of this preliminary interim review is to review the data in a blinded, centralized manner to evaluate any potential clinically significant safety findings early in the conduct of the study. From the start of the study (defined as the randomization of the first subject), ongoing blinded safety reviews will be performed approximately monthly by internal study team / data review team members. More frequent reviews may be performed ad-hoc if necessary.

[0185] 2.6.3 - Internal Safety Management Team In addition to ongoing safety monitoring performed by the investigators and study personnel, cumulative and interim blinded AEs, AESIs, SAEs; discontinuations due to AEs; and abnormal laboratory findings are reviewed internally by the sponsor's Safety Management Team (SMT). The SMT is comprised of lead representatives from multiple sponsor divisions involved in the sendakimab development program. Scope, execution, process, and quantity controls are defined by the sponsor's Standard Operating Procedures (SOPs).

[0186] Subject or study level safety assessments and any subsequent trial conduct related recommendations and / or actions (provided by the SMT) will be derived solely from blinded data. The DMC will be informed of any relevant subject or study level decisions made by the SMT.

[0187] 2.6.4 - Safety monitoring by the Data Monitoring Committee A DMC and SMT, independent of the study team, are provided to provide an additional level of safety oversight. The DMC acts in an advisory capacity and makes recommendations to the study team and SMT based on its independent assessment of safety data. Members of the internal study team / data review team or SMT may also meet ad hoc with the DMC throughout the study to discuss relevant safety findings that may arise during the study or conduct of the study (e.g., AESIs, SAEs, findings related to subject discontinuation, etc.).

[0188] 2.7 - Anti-drug antibody assessment Serum samples to assess circulating levels of antibodies to sendakimab will be obtained pre-dose, at the EOT / ET visits, and at various follow-up visits.

[0189] Details of the procedures to be followed for sample collection, processing, storage, transport and testing will be documented in the attached Testing Laboratory Manual.

[0190] Serum antibodies to sendakimab will be monitored to assess the impact of immunogenicity on the safety, PK, and efficacy of sendakimab. The impact of immunogenicity will be assessed by combining the results of PK, pharmacodynamic, and immunogenicity data. Samples will be archived for additional analysis, if necessary.

[0191] Further analysis on samples positive for ADA may be performed if warranted, including evaluation of neutralizing antibodies. Samples will be stored for up to 5 years after completion of the study.

[0192] 2.8 - Pharmacokinetics Serum samples to assess sendakimab concentrations will be obtained at study visits, pre-dose at EOT / ET visits, and at various time points at follow-up visits.

[0193] Details of the procedures to be followed for sample collection, processing, storage, transport and testing will be documented in a separate Testing Laboratory Manual.

[0194] 2.9 – Biomarkers, Pharmacodynamics, and Pharmacogenomics 2.9.1 – Whole Blood and Serum Biomarker Assessment Blood samples will be obtained pre-dose at the EOT / ET visit and at various time points at follow-up visits to assess levels of various biomarkers in whole blood and serum (including but not limited to peripheral blood eosinophils, IgE, lactate dehydrogenase, IL-13, IL-22, CCL17 (TARC), and CCL18 (PARC)) and for possible assessment of SARS-CoV-2 serological status. Serum will be collected for SARS-CoV-2 serology (total anti-SARS-CoV-2 or IgG) measurement according to national and local regulations. Of note, serum will be collected for SARS-CoV-2 serology at Day 1 (baseline), at the EOT / ET visit, and approximately 4 weeks after documented or suspected SARS-CoV-2 infection, if applicable.

[0195] Pharmacogenomic samples are collected at one time point only, scheduled for day 1 (see Example 1), for biomarker assessment, including but not limited to IL-13 single nucleotide polymorphism (SNP) characterization. Pharmacogenomic samples are collected from subjects if necessary government and local approvals are obtained. If necessary, pharmacogenomic samples can be collected at any subsequent time points during the study.

[0196] These samples will be transported to a central laboratory for analysis. Details of the procedures to be followed for sample collection, processing, storage and transport will be documented in the attached Testing Laboratory Manual.

[0197] 2.9.2 - Tissue Biomarker Assessment Skin punch biopsies are optional but are crucial to fully understand the response to these therapies in AD patients. With a view to future studies, having as many skin samples as possible will also allow for a better understanding of which tissue measures may have promising blood / serum surrogate properties and what can only be accurately assessed from a biopsy. Skin punch biopsies from the same AD lesion site are taken at baseline, EOT / ET, and final follow-up visits. For comparison, an adjacent non-lesional skin biopsy is taken at baseline to provide a reference point. Samples are frozen, formalinized, or sent for an equivalent process as appropriate (e.g., isolation processing for RNA extraction) for eventual use of the material for experimental purposes. Details of the biopsy procedure are provided in the study laboratory manual.

[0198] Example 3 - Description of Trial Treatment 3.1 - Description of investigational product The active ingredient of sendakimab is a recombinant humanized IgG1 monoclonal antibody targeting human IL-13. The investigational products (sendakimab and placebo solutions for injection) will be stored at 2°C to 8°C. IP should not be frozen. Labeling will be in accordance with GCP and any other local regulatory requirements. During the study, IP will be dispensed into prefilled syringes (PFS) provided by the sponsor.

[0199] Sendakimab injection (or placebo) will be provided as a sterile liquid in the PFS at a concentration of 180 mg / mL (or placebo), 2.0 mL fills will be utilized in the study, and the IP will be packaged in cartons (2 PFS per carton).

[0200] Additional instructions relating to the handling, preparation, dispensing, and administration of the IP are provided in the attached Test Pharmacy Manual.

[0201] 3.2 -Treatment Dosing Schedule Two injections of 2 mL volume will be administered SC once weekly with PFS consisting of 180 mg / ml sendakimab (active IP) or matching placebo. To maintain blinding, all subjects, regardless of their treatment assignment, will receive two injections of active IP, placebo, or a combination of both. Subjects will be randomized 1:1:1:1 to one of the following treatment arms: Sendakimab 720 mg SC once weekly for 16 weeks. Administered weekly via 2 injections of active IP. Sendakimab 720 mg SC every other week for 16 weeks. Starting at the baseline visit, 2 injections of active IP will be administered, alternated by 2 injections of placebo. Sendakimab 360 mg SC every other week for 16 weeks. Starting at the baseline visit, one injection of active IP and one injection of matching placebo will be administered, with two injections of placebo administered each week in alternating weeks to maintain blinding. Matching placebo SC, once weekly for 16 weeks. Administered via two injections of placebo each week.

[0202] The first 3 doses of IP should be administered in the clinic. During the first 3 dosing visits, subjects should remain in the clinic for at least 30 minutes for further observation. At the investigator's discretion, the number of injections administered in the clinic and the post-injection observation period may be increased / extended as necessary to comply with local requirements.

[0203] Thereafter, administration of two SC injections of IP will continue weekly until the Week 15 visit. Beginning in Week 3 (Visit 4 / 22), subjects will return to the clinic every other week for IP administration and have the option to receive injections at home by a licensed home health care provider during the alternate week. Subjects using home health care services will be required to return to the facility at least every 2 weeks (e.g., Week 4 [Visit 5 / 29], Week 6 [Visit 7 / 43], Week 8 [Visit 9 / 57], Week 10 [Visit 11 / 71], Week 12 [Visit 13 / 85], Week 14 [Visit 15 / 99], and Week 16 [Visit 17 / 113]) for scheduled laboratory collections and additional safety and efficacy assessments during the treatment phase of the study. Additionally, during weeks when IP is not administered in-clinic, subjects will be contacted (within 24 hours) by site personnel to assess any changes in concomitant therapy use and to evaluate adverse events.

[0204] Subjects for whom a home health care provider's services are not available locally, or who choose not to use the services, will be required to return to the clinic each week to receive all of their IP injections.

[0205] The two SC doses should be administered on the abdomen or other suitable alternate sites, including the thigh or back of the upper arm (alternating injection sites each time) to differentiate between locations, avoiding any blood vessels, thickened or sensitive skin, scars, fibrous tissue, stretch marks, wounds, redness, birthmarks, or other skin imperfections.

[0206] 3.2.1 - Administration by visiting healthcare providers Beginning in week 3, subjects will return to the clinic every other week for IP dosing and may have the option of having injections administered at home by a home health visitor the alternate week. Subjects utilizing the home health visitor option will be required to return to the site at least every 2 weeks (e.g., Week 4 [Visit 5 / 29], Week 6 [Visit 7 / 43], Week 8 [Visit 9 / 57], Week 10 [Visit 11 / 71], Week 12 [Visit 13 / 85], Week 14 [Visit 15 / 99], and Week 16 [Visit 17 / 113]) for scheduled laboratory collection and additional safety and efficacy assessments during the treatment phase of the study. Home health care providers will be trained and will be able to monitor for injection site reactions upon administration. Within 24 hours of the home health care provider's visit, site personnel will be contacted to assess any changes in concomitant medications and / or adverse events. Subjects for whom home health visitor services are not available in their area or who choose not to use the home health visitor service option will be required to return to the clinic each week for their injections.

[0207] 3.2.2 - No administration If a subject is unable to receive their dose on the normally scheduled day: Subjects can receive dosing within ±3 days of their usual dosing date and continue dosing on their usual date the following week. If you are unable to receive your dose within ±3 days of your usual dosing date, you should wait until your next dose on your usual dosing date the following week.

[0208] Any dose failures will be noted in the study records, and after three or more consecutive dose failures, subjects will be required to permanently discontinue IP.

[0209] 3.2.3 - Overdose An overdose is any administration of IP given to or taken by a subject that exceeds the dose described in the protocol. No information on overdoses exists for sendakimab. Any overdoses must be reported promptly to the medical monitor, regardless of whether there is an associated AE (see Example 6.1). Any IP administration given more frequently than the minimum of 3 calendar days of dose administration allowed by the visit window further described in Example 3.2.2 should be reported as an overdose.

[0210] 3.2.4 - Dose adjustment There are no provisions for dose adjustment in this study. Subjects who cannot tolerate the assigned dose of IP, as determined by the investigator, will permanently discontinue IP.

[0211] 3.2.5 - Guidelines for Temporary Interruptions Subjects should be discontinued (temporarily discontinued IP) if any of the following events occur: ● The subject has any AE, intercurrent medical condition, or is undergoing major surgery that, as determined by the investigator, would pose undue risk to the subject if continued with study treatment. ●Subject experiences single or multiple significant laboratory abnormalities. If practical, laboratory testing should be repeated within 48-72 hours of first observation of the abnormalities for confirmation. - The subject experiences an infection requiring parenteral treatment with an antibiotic, antifungal, antiviral, anthelmintic, or antiprotozoal agent. For infections requiring oral antibiotic, antifungal, antiviral, anthelmintic, or antiprotozoal treatment for longer than 2 weeks, interruption of IP is not necessary; however, the investigator should determine whether interruption of administration is in the subject's best interest. In the case of localized and recurrent infections, the investigator should determine the appropriate action associated with interrupting the IP. Depending on the severity of the infection, the investigator should communicate with the medical monitor to determine whether additional actions, such as discontinuing the IP, are in the best interest of the subject. If a subject develops suspected or confirmed symptomatic COVID-19 infection, or if a subject is found to have asymptomatic COVID-19 infection during the treatment period, IP should be temporarily suspended until the following conditions are met: For symptomatic subjects: At least 10 days (20 days in the case of severe / critical illness) have passed since the first onset of symptoms or a positive test result, and At least 24 hours have passed since the last fever without the use of fever-reducing medication, and Symptoms (e.g., cough and shortness of breath) have resolved, and - the subject has no known sequelae of COVID-19 that, in the opinion of the investigator, would place the subject at higher risk from undergoing the study treatment; and · A follow-up negative molecular test for COVID-19 per institutional, local, or regional guidelines and / or requirements. For asymptomatic subjects: · At least seven days have passed since your positive test result (based on the date of collection, not the date the test result became available). · A follow-up negative molecular test for COVID-19 per institutional, local, or regional guidelines and / or requirements.

[0212] The decision to discontinue administration of IP remains the responsibility of the treating physician. However, before discontinuing administration, the investigator may contact the medical monitor. Once laboratory abnormalities have stabilized or the condition has resolved, IP administration may be resumed at the investigator's discretion, preferably at the next scheduled visit. The medical monitor may also be consulted to discuss the timing and appropriateness of reintroducing IP. After three or more consecutive dose failures, the subject must permanently discontinue IP, as defined in Example 3.2.6.

[0213] 3.2.6 - Discontinuation Criteria If, after initiating IP, a subject experiences any of the events listed below, the subject should be permanently discontinued (discontinued treatment). • In the judgment of the investigator or sponsor, the SAE is suspected to be related to the IP and continuing with investigational treatment would expose the subject to unreasonable risk. You experience any of the following significant laboratory abnormalities suspected to be associated with IP. For confirmation, laboratory tests should be repeated within 48-72 hours of first observation of the abnormality or whenever practical before permanently discontinuing IP: 〇Neutrophil count≦0.5×103 / μL 〇Platelet count ≦50×103 / μL ALT and / or AST >3xULN and total bilirubin >2xULN or INR >1.5, except for confirmed Gilbert syndrome and therapeutic anticoagulation ALT and / or AST >5×ULN for more than 2 weeks 〇ALT or AST>8×ULN ● Experience a severe or serious (based on the Investigator's assessment) opportunistic infection (suggesting the subject is immunocompromised). - diagnosed as a malignant tumor, except for in situ carcinoma of the cervix, or squamous or basal cell carcinoma of the skin, if such can be safely treated by local excision; Experiencing an anaphylactic reaction or other severe systemic reaction (e.g., hypersensitivity, allergic, or autoimmune) suspected by the investigator or sponsor to be associated with IP. ●Experience two separate occurrences of severe injection site reactions (ISR) lasting longer than 24 hours. Severe ISR is defined as ISR manifested as symptoms causing severe discomfort / pain, requiring medical / surgical attention / intervention, interfering with activities of daily living (ADLs) including the inability to perform usual social and functional activities (e.g., absent from work and / or bed rest), and / or requiring pharmacotherapy. ●I'm pregnant. Use of prohibited systemic immunosuppressants or immunomodulators. • Use of systemic salvage therapy. ●Failure to administer three or more consecutive doses.

[0214] Such subjects will be encouraged to remain in the study and will complete all required study assessments while remaining in the treatment and follow-up periods of the study (except for dosing via IP). To prevent missing data, site staff will ensure that attempts are made to contact subjects who do not maintain contact with the investigator by phone or email. Any subjects who discontinue early from the study will be asked to complete the ET visit, as well as the first and final follow-up visits.

[0215] 3.3 - Packaging and labelling Labeling for IP will include the sponsor's name, address, and telephone number, protocol number, name of IP, dosage form, and strength (if applicable), amount of IP per container, lot number, expiration date (if applicable), drug identification / kit number, administration instructions, storage conditions, and any required precautions and / or regulatory notices as appropriate. Labeling may contain additional information as required in accordance with local regulations.

[0216] Sendakimab and placebo solutions differ slightly in physical appearance and, when provided in vials, have slight color differences in the IPs that preclude complete blinding; therefore, for PFS, label covers on the active and placebo syringes are used (applied during packaging / labeling) to maintain blinding.

[0217] 3.4 - Quantity management and disposal of investigational drugs The applicant (or its designee), together with the investigator and relevant site personnel, will review the procedures for the return, disposal, and / or destruction of the IP, including the site's and the applicant's (or its designee's) responsibilities.

[0218] All supplies of IP and placebo will be quantity controlled in accordance with GCP. There will be an individual IP quantity control record for each subject, and the investigator should maintain accurate records related to IP supplies received during the study. Such records should include the quantity of clinical drug supplies and the dates they were received, distributed, and administered to the subject by the investigational site or by the home health care service, or returned by designated investigational site staff or by the home health care service, and returned to the sponsor. In the event of an error or damage in the shipment of clinical drug supplies, the investigator should promptly contact the IP supplier and the study monitor. A copy of the IP quantity control record will be provided by each investigator and will be placed in the trial master file after database lock. The study monitor will periodically check the supplies of IP held by the investigator or pharmacist to verify quantity control of all IP used.

[0219] Applicant will provide IP only to identified subjects in this study, following the procedures outlined in the study protocol. After study completion, the study monitor will ensure that all unused IP and, if necessary, all drug containers can be destroyed on-site, provided proper documentation is provided. If on-site destruction is not possible, all unused drug and, if necessary, containers will be returned to the sponsor or its designee. The study monitor will perform final quantity control, packaging, sealing, and preparing for shipment. The clinical research organization (CRO) will verify that a final report of drug quantity control is generated and maintained in the investigator trial master file.

[0220] 3.5 - Study Drug Adherence The applicant will ensure that IP is used only according to the protocol, that subjects are properly briefed on how to administer their IP, and that each subject will fully comply with their designated dosing regimen. Non-compliance will be defined as less than 80% or more than 120% of IP administered during the entire study period. Records of IP used and intervals between visits will be maintained during the study. Drug quantity controls will be kept by field monitors during site visits and at the end of the study. IP should be dispensed by the investigator or by qualified individuals under the applicant's supervision. Up-to-date treatment inventory / dispensation records must be maintained.

[0221] Example 4 - Concomitant medications and procedures All treatments (including prescription and over the counter (OTC) medications, herbal and dietary supplements, dietary modifications, and procedures) used by the subject within 4 weeks (28 days) prior to the initial screening visit or at any time during the study will be considered prior or concomitant treatments and must be documented in the appropriate section of the eCRF. In addition, the history of prior treatments for AD will be documented.

[0222] All concomitant procedures, including blood and blood products, used from 28 days prior to the initial screening visit through the final safety follow-up visit or final study visit must be reported on the eCRF.

[0223] 4.1 - Permitted Concomitant Medications and Procedures The following concomitant medications are permitted during the study: Oral antihistamines are permitted, however, dose and regimen should remain stable for at least 2 weeks prior to Day 1 (Baseline) through the EOT / ET visit at Week 16. Subjects should also refrain from taking them within 24 hours prior to the study visit. ●Subjects may be using inhaled corticosteroids, leukotriene receptor blockers (e.g., montelukast), or mast cell stabilizers (e.g., sodium cromoglycate) for indications other than AD, such as asthma, provided they have been on a stable dose / regimen for at least 4 weeks prior to the first screening visit and will remain on a stable regimen throughout the treatment period of the study. If one of these medications has been recently discontinued, it must have been discontinued for at least 4 weeks prior to the first screening visit. ● Medically necessary dose adjustments (e.g., to treat unanticipated exacerbations) are permitted. However, changes should be consistent with local treatment guidelines. In addition, medical monitors should be consulted to discuss the potential impact of medication changes. • Ophthalmic corticosteroids are tolerated for subjects receiving stable doses to treat allergic conjunctivitis.

[0224] Except where prohibited, subjects may receive any other medications necessary to treat coexisting medical conditions or adverse events if deemed necessary by the Investigator. After Day 1, the addition of concomitant medications or any changes in dosage should be limited to those deemed medically necessary.

[0225] 4.2 - Prohibited Concomitant Medications and Procedures The administration of medications or therapies for other medical conditions known to affect AD (e.g., systemic corticosteroids, mycophenolate mofetil, interferon gamma (IFN-y), Janus kinase inhibitors, biologic therapies, TCS (unless administered for the purpose of salvage therapy), TCIs, cyclosporine, azathioprine, methotrexate, phototherapy, etc.) is not permitted during the study.

[0226] Additional details relating to concomitant medications and procedures that are prohibited throughout the duration of the study are first identified in the Exclusion Criteria (Example 5.3) and are summarized below. Topical treatments that may affect the assessment of AD (e.g., corticosteroids, calcineurin inhibitors, tar, antibiotic creams, topical antihistamines) within 7 days of the Day 1 visit and throughout the study period. Treatment with systemic antibiotics, antivirals, anthelmintics, antiprotozoals, or antifungals within 2 weeks prior to Day 1. However, their use is permitted during the study if treating an infection-related adverse event. Narrowband UVB (NB-UVB) or broadband phototherapy administered within 4 weeks prior to the baseline visit and throughout the duration of the study. Systemic immunosuppressant or immunomodulatory medications (e.g., azathioprine, cyclosporine, systemic corticosteroids, IFN-γ, Janus kinase inhibitors, methotrexate, mycophenolate mofetil, etc.) administered within 4 weeks prior to the baseline visit and throughout the study period. Treatment with immunomodulatory biologics throughout the study period, including: Dupilumab within 3 months of the baseline visit. - Cell-depleting biologics, including rituximab, within 6 months prior to the baseline visit. - Other immunomodulatory biologics within 5 half-lives (if known) or 16 weeks, whichever is longer, prior to the Baseline visit. With the exception of oral antihistamines, any additional medications and / or procedures that may affect AD are also prohibited throughout the study. Due to the potential effect of UV exposure on AD, subjects must also avoid prolonged exposure to the sun and must not use tanning beds, sunlamps, or other sources of UV light during the study. Concurrent treatment with another IP, including through participation in an interventional trial for COVID-19, is prohibited throughout the duration of the study. Prospective subjects must not have participated in a concurrent IP study or received an IP within 5 drug half-lives prior to signing the ICF / consent for the study. Additionally, for subjects who received an investigational COVID-19 vaccine as part of a clinical trial prior to the initial screening visit, enrollment must be delayed until the biological effects of the vaccine have stabilized, as determined by a joint decision between the investigator and the clinical trial investigator. Live attenuated vaccines are prohibited within 1 month prior to the first screening visit and throughout the duration of the study.

[0227] Except where prohibited, subjects may receive any other medications necessary to treat coexisting medical conditions or adverse events if deemed necessary by the Investigator. After Day 1, the addition of concomitant medications or any changes in dosage should be limited to those deemed medically necessary.

[0228] 4.3 - Required Concomitant Medications and Procedures Non-medicated topical emollients should be applied twice daily for at least 7 days prior to the Baseline / Day 1 visit, and application (at the same frequency twice daily) should continue throughout the study. On the day of the study visit, subjects should not moisturize or apply emollients prior to the visit. The last application of emollient should be applied the evening before the scheduled study visit. Non-medicated emollients are permitted after the visit is completed, and the same type of emollient should be used throughout the study period.

[0229] 4.4 - Rescue medicine If a subject develops intolerable AD symptoms that require rescue therapy, exceptions related to prohibited medications, such as the use of TCS, will be permitted. The use of rescue therapy should be withheld throughout the treatment phase of the trial and reserved only for severe symptoms associated with AD flare-ups. In such cases, subjects may continue to participate in the study while continuing to use concurrent rescue therapy. However, depending on the type of rescue medication administered, discontinuation of IP may be required. Subjects requiring rescue therapy should consider adding TCS before considering systemic treatment. Any subjects requiring TCS rescue therapy treatment are encouraged to continue treatment with IP and continue TCS for as short a period as possible (e.g., <7 days) while maintaining the study visit schedule. Any subject who requires systemic rescue therapy to treat their AD during the treatment phase of the study will be encouraged to discontinue IP and continue participating in the study without IP administration. Subjects who decline further participation in the study should proceed to the Early Termination Visit and Follow-Up Visit Assessment. Subjects who require systemic rescue therapy during the follow-up period of the study should continue to attend study visits as scheduled. All instances of rescue therapy administration occurring during study participation will be appropriately captured in source documents within the eCRF.

[0230] The impact of rescue therapy will also be assessed by defining these endpoints as missing for subjects who begin rescue therapy before week 16 and analyzing according to the methods described in Example 5.

[0231] Example 5: Statistical Considerations 5.1 - Overview This is a phase II, multicenter, international, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of sendakimab in adult subjects with moderate-to-severe AD. Subjects will be randomized to receive the investigational drug for 16 weeks, and randomization will be stratified by region (Japan vs. Rest of the World (RoW)) and, within the RoW region only, by disease severity based on baseline v-IGA-AD score (3 [moderate] or 4 [severe]). An independent DMC will be used to periodically review safety data during the course of the study.

[0232] 5.2 - Definition of the study population The following analysis populations will be used in the statistical analysis: Modified intent-to-treat (mITT) population All randomized participants who had received at least one IP dose of study medication.

[0233] The mITT population will be used as the primary population for all efficacy parameters. Subjects who leave the trial early for any reason and subjects who are not assessed for any reason will still be included in the mITT population. Subjects will be included in the treatment group to which they were randomized. Subjects randomized with a misreported strata will be classified according to their original (misreported) strata.

[0234] Safety Group The safety population consists of all subjects who received at least one dose of IP. This population will be used in all safety data summaries. Subjects randomized to placebo and receiving any dose of sendakimab will be summarized within the sendakimab group. Subjects randomized to sendakimab and receiving only placebo will be summarized within the placebo group, otherwise within the sendakimab group.

[0235] Pharmacokinetics Group All subjects who received at least one dose of active drug and had at least one measurable concentration.

[0236] Biomarkers All participants receiving any study treatment and with any available biomarker measurements.

[0237] 5.3 - Sample size and power considerations Approximately 200 subjects will be randomized in this Phase II dose-ranging study. Randomization will be even across the four treatment arms (approximately 50 subjects per arm): placebo, 300 mg Q2W, 720 mg Q2W, and 720 mg QW. For the primary endpoint of percent change from baseline in EASI score at Week 16, a sample size of 45 subjects per arm will provide approximately 90% power to detect a 35% treatment difference (mean difference) compared to placebo, assuming a 10% dropout rate. In calculating this power, superiority of a particular treatment arm over placebo is met if the lower limit of the (two-sided) 95% confidence interval (z-score) for the treatment difference is greater than zero (after adjusting for multiplicity).

[0238] The sample size calculation is based on the following consideration of the mean percent change from baseline in EASI score at week 16 compared to placebo. Notably, a recent Phase IIb study of dupilumab reported that a mean of 18.1% was observed for placebo, while the corresponding treatment differences were 50.1% (standard error [SE=6.7%]) and 55.7% (SE=6.7%) for the 300 mg Q2W and 300 mg QW doses, respectively (Thaci, 2016). This study evaluating sendakimab is designed to detect a (true) treatment difference of 35% compared to placebo. Applicant assumes that the (true) mean for placebo is 20%, with a common standard deviation (SD) of 50%, and the corresponding means for treatment differences for the active arms are 25% (300 mg Q2W), 30% (720 mg Q2W), and 35% (720 mg QW). Applicants specifically note that a common SD of 50% was assumed for the percent change from baseline in EASI score at week 16, which was also assumed in the dupilumab Phase IIb trial design (Thaci et al., Lancet 387:40-52 (2016)). Based on this assumption, with a sample size of 45 subjects per group, and an overall type I error of α=0.05 (2-sided), the study is estimated to provide approximately 90% power to detect superiority over placebo for at least one dose when using a hierarchical testing approach (in the following order: 720 mg QW vs placebo, 720 mg Q2W vs placebo, and 300 mg Q2W vs placebo).

[0239] In addition, the study provides greater than 90% power to detect superiority over placebo for at least one dose for the key secondary endpoint IGA response at week 16 (0-remission, 1-almost remission), assuming true rates of 2% (placebo), 15% (300 mg Q2W), 25% (720 mg Q2W), and 25% (720 mg QW). Applicants specifically note that in Phase II dupilumab trials, rates of 30% and 33% were reported for the 300 mg Q2W and 300 mg QW doses, respectively (Thaci et al., (2016)). For the IGA response endpoint, the hierarchical testing approach used for the primary endpoint was utilized to maintain an overall type I error α=0.05 (two-sided). However, multiplicity adjustments were not performed comprehensively across endpoints (e.g., for both the primary and key secondary endpoints simultaneously).

[0240] 5.4 - Background and demographic characteristics A summary of demographics, baseline characteristics, medical history, prior medications, and protocol deviations will be presented by treatment group for the mITT population. Concomitant medications will be presented by treatment group for the safety population. A separate listing will also be provided, including concurrent medical procedures for the safety population.

[0241] 5.5 - Treatment of Subjects Subject disposition will be summarized by treatment group with numbers and percentages for all enrolled subjects. The summary will include the numbers and percentages of subjects in the following categories: Those who were randomized, those who received (at least one dose of the study treatment), those who permanently discontinued IP, those who withdrew from the study, those who discontinued IP but remained in study follow-up, and those who completed the study. ●Main reasons for canceling exams

[0242] 5.6 - Effectiveness Analysis 5.6.1 -Percentage change from baseline in EASI score at Week 16 The primary efficacy endpoint, percent change from baseline in EASI score at week 16, will be analyzed based on the modified intent-to-treat (mITT) population using an analysis of covariance (ANCOVA) model with treatment group indicator as the primary effect adjusting for baseline EASI score, and stratification factors of vIGA-AD score (3 [moderate] or 4 [severe]) and region (Japan vs RoW) as covariates. Adjusted mean percent change from baseline in EASI score at week 16 and corresponding differences from placebo (based on least squares means) will be estimated for each active treatment group, along with 95% Wald confidence intervals (CIs) and p-values.

[0243] Missing EASI scores at week 16 (e.g., due to dropout or other missing assessments) will be addressed using a multiple imputation (MI) approach based on the missing at random (MAR) hypothesis (Berglund, SAS Institute, Paper 2018-2015), which Applicants will hereafter refer to as the MI approach.

[0244] To adjust for multiplicity, a standard hierarchical approach will be utilized by performing comparisons at the two-sided 0.05 α-level (based on the adjusted p-values ​​above) in the following order: 720 mg QW vs placebo, 720 mg Q2W vs placebo, and 360 mg Q2W vs placebo, respectively.

[0245] To support the primary analysis, sensitivity analyses are performed by utilizing alternative missing data approaches as well as by assessing the impact of salvage therapy. In the first sensitivity analysis, the MI approach is replaced by LOCF (last observation carried forward) imputation if the EASI score is missing at week 16. The impact of salvage therapy is evaluated by defining EASI scores after the start of salvage therapy (before week 16) as missing. In the second sensitivity analysis, the MI approach is applied while adding missingness (another degree) due to salvage. In the third sensitivity analysis, the first and second sensitivity analyses are combined by replacing the MI approach in the second sensitivity analysis with LOCF.

[0246] 5.6.2 - Subgroup analysis of the primary endpoint To assess whether the treatment effect is consistent across the various groups, subgroup analyses will be performed for the primary endpoint at week 16. Treatment differences and two-sided 95% CIs are provided for each subgroup listed below. Subgroup forest plots of treatment differences are also provided. 1. Non-elderly adults (under 65 years old) and elderly adults (over 65 years old) 2. vIGA-AD baseline scores (4 and 3) 3. Gender (female and male) 4. Region (Japan and the rest of the world) 5. Race (white and non-white) 6. Previous experience with systemic immunosuppressants

[0247] If there are not enough subjects within each subgroup and treatment category (e.g., less than 8% of the mITT population based on observed cases), the corresponding subgroup analysis will not be performed; instead, summary statistics will be provided.

[0248] 5.6.3 -Analytical methods For the first key secondary endpoint, the proportion of subjects with both a vIGA-AD score of 0 (remission) or 1 (almost remission) and a ≥2-point reduction in v-IGA-AD score from baseline at week 16 will be analyzed based on the mITT population using a stratified CMH test at a two-sided 5% significance level. The randomization stratification levels are: (1) Japan region, (2) RoW region and vIGA-AD score of 3, and (3) RoW region and vIGA-AD score of 4. Estimates of the observed differences in proportions between each treatment group and placebo and associated 95% confidence intervals are provided along with p-values. Missing endpoint values ​​(e.g., due to dropout from the study or other missing assessments) will be imputed as non-responders. Subjects who start salvage therapy (before week 16) will be defined as missing, sensitivity analyses will be performed based on that, and treated as non-responders.

[0249] The second key secondary endpoint will be the proportion of subjects achieving a 75% improvement from baseline in EASI (EASI-75) at week 16, analyzed as above.

[0250] The hierarchical testing approach used for the primary endpoint will be utilized to adjust for multiplicity across the three active doses for each of these key secondary endpoints, except that multiplicity adjustments will not be performed simultaneously across the primary endpoint and the two key secondary endpoints.

[0251] The following endpoints will be analyzed as key secondary endpoints (except p-values ​​will not be provided): The secondary endpoint was the proportion of subjects who achieved a change of 4 or more from baseline in the pruritus NRS at week 16. The secondary endpoint was the proportion of subjects achieving a 90% improvement from baseline in EASI (EASI-90) at week 16.

[0252] The following endpoints will be analyzed similarly to the primary endpoint (except p-values ​​will not be provided): The secondary endpoint was the percentage change from baseline in the pruritus NRS at week 16. Secondary endpoint: Percentage change from baseline in SCORAD score at 16 weeks The secondary endpoint was the mean percent change from baseline in AD-related body surface area (BSA) at week 16.

[0253] For the secondary endpoint of time to achieve at least a 4-point improvement in severity of the Pruritus NRS scale within the first 16 weeks of treatment, the distribution of time to first event of 4-point improvement will be compared based on Kaplan-Meier (KM) and log-rank approaches. For separate comparisons by treatment group against placebo, it will be based on a stratified log-rank test with associated p-values ​​provided. The stratification levels are: (1) Japan region, (2) RoW region and IGA score 3, and (3) RoW region and vIGA-AD score 4. KM estimates of the cumulative proportion of subjects achieving a 4-point improvement by a given time point will be provided by treatment group and the difference from placebo and associated 95% confidence intervals. These will be reported at various time points (e.g., days 1-28, followed by weekly assessments).

[0254] 5.7 - Safety Analysis All analyses of safety data will be performed over the entire 32-week study period using the safety population by treatment. Safety evaluations will include AEs leading to discontinuation of study treatment, SAEs, AEs, and AEs leading to study discontinuation, changes from baseline in laboratory values ​​and vital signs, and the incidence and type of laboratory, vital sign, and physical examination abnormalities. Individual data listings will also be provided.

[0255] Adverse events will be monitored during the trial and data will be summarized by worst severity grade. Adverse events will be summarized by MedDRA system organ class and preferred term, with emphasis on treatment-emergent AEs: study drug-related adverse events, adverse events leading to death or treatment discontinuation, events rated as moderate or severe, IP-related events, and serious adverse events, and events of interest.

[0256] Laboratory assessments will be performed by a central laboratory. All summaries will be based on standard International System of Units (SI) provided by the central laboratory. Each subject's hematology, blood chemistry, and urinalysis values ​​will be flagged as "low," "normal," or "high" compared to the central laboratory's normal ranges.

[0257] Summary statistics of actual values ​​and changes from baseline in vital signs will be provided for each visit.

[0258] 5.8 -Other Topics 5.8.1 - Analysis of Exploratory Endpoints Exploratory efficacy endpoints will be summarized using descriptive statistics by treatment group. For continuous endpoints, number of subjects (n), mean, SD, SE, median, minimum and maximum will be presented. Binary endpoints will be summarized by number and percentage (%).

[0259] 5.8.2 - Pharmacokinetics, Pharmacodynamics, and Exposure Response Serum trough concentrations of sendakimab (Ctrof) will be summarized by treatment and visit using descriptive statistics. Additional analyses may be performed as appropriate (e.g., by ADA status).

[0260] Population PK analyses will be performed using non-linear mixed-effects modeling to characterize the population PK of sendakimab and identify important covariate effects (e.g., immunogenicity, intrinsic and extrinsic factors). Data from other studies may be included, if applicable. Exposure-response and pharmacodynamic relationships will be performed for efficacy, safety, and biomarker endpoints. Details regarding the studies and methodology will be outlined in the attached PK analysis plan, and results will be published separately from the clinical study report as a standalone report.

[0261] 5.8.3 - Data Monitoring Committee Additional safety monitoring will be performed by an external, independent Data Monitoring Committee (DMC) that meets to include physicians and statisticians experienced in treating subjects with type 2 inflammatory diseases, none of whom are otherwise involved in the conduct of the trial and have no identified conflicts of interest.

[0262] During the study, the DMC will periodically review selected data (as defined in the DMC Charter) to assess benefit-risk and to determine whether to continue the study. An independent third party will prepare reports consisting of aggregate data summaries and individual subject data listings for the DMC members at each scheduled meeting, as appropriate. The DMC's operational details will also be described in the DMC Charter, including a blinding plan to ensure that all personnel involved in the conduct of the study remain blinded to the results of the data review. The DMC will act in an advisory capacity and make recommendations based on its independent assessment of the safety data. Unblinded safety data may be reviewed by the DMC on a regular or ad-hoc basis, as necessary, to further enhance the ongoing risk / benefit assessment of the IP.

[0263] Example 6: Adverse Events 6.1 - Monitoring, recording, and reporting of adverse events An AE is any adverse, unintended, or untoward medical occurrence that may appear in or worsen a subject during the course of a study. An AE may be any concurrent disturbance in the health of a subject, regardless of etiology, including a new intercurrent illness, a worsening of a intercurrent illness, an injury, or a laboratory test value (as defined by the criteria in Example 6.3). Any deterioration (i.e., any clinically significant adverse change in the frequency or intensity of a pre-existing condition) should be considered an AE. Diagnostic or pathological events should be recorded on the AE page of the CRF, not individual signs or symptoms of the diagnostic or pathological event.

[0264] Abuse, discontinuation, hypersensitivity, or toxicity of the investigational drug should be reported as an AE. Accidental or intentional overdose, whether or not associated with an AE, should be reported on the Overdose CRF (see Example 3.2 for the definition of an overdose). Any sequelae of an accidental or intentional overdose of investigational drug that meet the definition of an adverse event should be reported on the CRF as an AE. If the sequelae of an overdose meet the seriousness criteria, they should be labeled as serious on the CRF. The overdose itself should not be reported as an AE.

[0265] In case of overdose, subjects should be monitored appropriately and symptomatic measures should be taken as necessary. There is no known specific antidote for sendakimab overdose. The actual treatment should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

[0266] All subjects will be monitored for AEs during the study. Assessment may include monitoring of any or all of the following parameters: the subject's clinical symptoms, laboratory, pathological, radiological, or surgical findings, physical examination findings, or findings from other tests and / or procedures.

[0267] The investigator will record all AEs from the time the subject signs the informed consent until 16 weeks after the last dose of IP or the last follow-up visit, whichever is longer, and any SAEs suspected to be related to IP and disclosed to the investigator thereafter. All adverse events (serious / non-serious) will be recorded on the CRF and subject source documents. See Example 6.5 for instructions on how to report SAEs to the drug safety department.

[0268] 6.2 - Evaluation of Adverse Events Qualified investigators will assess all adverse events for the following:

[0269] 6.2.1 - Severity An SAE is any AE occurring at any dose that: Brings death, life-threatening (i.e., in the investigator's opinion, the subject is at imminent risk of death due to the AE); Requiring inpatient hospitalization or an extension of an existing hospital stay (hospitalization is defined as inpatient admission regardless of the length of stay), Causes persistent or significant disability / incapacity (substantial impairment of the subject's ability to carry out normal life functions); - Congenital anomalies / birth defects, •Constitutes a significant medical event.

[0270] A significant medical event is defined as an occurrence that is not immediately life-threatening or likely to result in death, hospitalization, or disability, but that may compromise the subject or require medical or surgical intervention to prevent one of the other outcomes listed above. Medical and scientific judgment should be used in determining whether such an AE should be considered serious.

[0271] Events that are not considered SAEs are hospitalizations due to: ● Planned procedures (already planned before starting procedures in the study) must be documented in the source documents and CRF. Hospitalization or prolonged hospitalization due to complications remains a reportable SAE. Elective treatment or procedures for a pre-existing condition unrelated to the indication being studied and without progression from baseline. Urgent outpatient treatment or observation not resulting in hospitalization, unless other severity criteria described above are met.

[0272] For each AE, the investigator will provide information on severity, start and stop dates, relationship to the IP, actions taken with respect to the IP, and outcome.

[0273] 6.2.2 - Severity / Intensity For each AE, the investigator must rate the severity / intensity of the event. The following rating scale should be used to rate the severity / intensity: Mild Asymptomatic or mildly symptomatic, with only clinical or diagnostic observations Intervention is not applicable Minimal or no impact on activities of daily living (ADL) Minimal or no intervention / therapy may be required. moderate The condition causes moderate discomfort. Local or non-invasive interventions are indicated - More than minimal and interfering with ADL, but able to carry out daily social and functional activities ●Medication may be required. Severe (can be non-severe or severe) Symptoms that cause severe discomfort / pain Symptoms requiring medical / surgical attention / intervention Impairment of ADLs, including inability to perform daily social and functional activities (e.g., absenteeism and / or bed rest) ●Medical therapy is required.

[0274] The term "severe" is often used to describe the intensity of a particular event (such as mild, moderate, or severe myocardial infarction). However, the event itself may have a relatively minor medical significance (e.g., a severe headache, etc.). This criterion is not the same as "serious," which is based on subject / event outcome or behavioral criteria associated with the event posing a threat to the life or function of the subject.

[0275] Severity (not severity) serves as a guide for defining regulatory obligations.

[0276] 6.2.3 – Causation Applicant will determine the relationship between administration of IP and the occurrence of AEs as unsuspected or suspected according to the following definitions: Unsuspected: A causal relationship between the adverse event and IP administration is unlikely or only marginally likely, or other medications, therapeutic interventions, or underlying conditions provide a sufficient explanation for the observed event. Suspect: There is a reasonable possibility that administration of the IP caused the adverse event. "Reasonable possibility" means that there is evidence suggesting a causal relationship between the IP and the adverse event.

[0277] Causality should be assessed and presented for each AE based on the currently available information. Causality should be reassessed and presented as additional information becomes available.

[0278] 6.2.4 - Duration For each AE, Applicant will provide a record of the start and stop dates of the event.

[0279] 6.2.5 - Actions to be taken Applicants will report any actions taken with respect to the IP as a result of each AE (e.g., discontinuation, interruption, or dose reduction of the IP, as appropriate), as appropriate, and any concomitant and / or additional measures taken for the event.

[0280] 6.2.6 - Outcome Applicants will report the event outcome for each AE.

[0281] All SAEs that do not resolve when the subject discontinues participation in the study must be followed until recovery (return to baseline), recovery with sequelae, or death (attributed to the SAE).

[0282] 6.3 - Abnormal Laboratory Values An abnormal laboratory value is considered an AE if the abnormality: ●Causing the test to be cancelled; requires treatment, modification / interruption of IP administration, or any other therapeutic intervention; or • Abnormalities judged to be of significant clinical importance, e.g., suggesting a new disease process and / or organ toxicity, or which are an exacerbation or worsening of an existing condition.

[0283] Only laboratory abnormalities that meet the severity criteria, regardless of severity grade, need to be documented as serious adverse events.

[0284] If the laboratory abnormality is a component of a diagnosis or pathology event, then only the diagnosis or pathology event should be recorded as an AE. If the abnormality was not part of a diagnosis or pathology event, then the laboratory abnormality should be recorded as an AE. When possible, laboratory abnormalities should be recorded as medical terms rather than simply as abnormal laboratory results (e.g., recording thrombocytopenia rather than decreased platelets).

[0285] 6.4 - Pregnancy All pregnancies or suspected pregnancies occurring in either a female subject of childbearing potential or the childbearing partner of a male subject are events that must be reported immediately.

[0286] 6.5 - Women of childbearing potential Pregnancy and suspected pregnancy (including an increase in β-hCG or a positive pregnancy test in a female subject of childbearing potential, regardless of disease status) occurring during administration of IP to a subject or at or within 5 months thereafter will be considered a promptly reportable event. The investigational product will be discontinued immediately. Pregnancy, suspected pregnancy, or a positive pregnancy test must be reported promptly to the applicant's Drug Safety Office by email, telephone, or fax using the First Pregnancy Reporting Form or an approved equivalent form, or by other appropriate method.

[0287] The female subject may be referred to an obstetrician-gynecologist or another suitable health care professional for further evaluation.

[0288] Applicant shall follow female subjects until the completion of pregnancy and shall promptly notify Applicant's Drug Safety Office of the outcome of the pregnancy (normal or abnormal outcome) using the Pregnancy Follow-Up Report Form or an approved equivalent.

[0289] If the pregnancy outcome is abnormal (e.g., spontaneous abortion), applicant will report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, the abnormal outcome must be reported as an SAE to applicant's drug safety office within 24 hours of applicant becoming aware of the event.

[0290] All neonatal deaths occurring within 28 days of birth should be reported as SAEs, regardless of causality. In addition, any child deaths after 28 days that the investigator suspects to be related to in utero exposure to IP should also be reported as SAEs.

[0291] 6.5 - Reporting of Serious Adverse Events Any AE that meets any of the serious criteria must be reported as an SAE within 24 hours of the investigator becoming aware of the event. This instruction pertains to the initial SAE report as well as any follow-up reports.

[0292] This requirement applies to all SAEs (whether or not related to IP) occurring during the study period (from the time the subject signs the informed consent until 16 weeks after the last dose of IP or the last follow-up visit, whichever is longer) or any SAE suspected to be related to IP that is disclosed to the investigator at any time thereafter. Serious adverse events occurring prior to treatment (after signing the ICF) should be recorded on the CRF but do not need to be reported to the applicant's drug safety unit.

[0293] If required by local law, the applicant is responsible for notifying the Institutional Review Board / Ethics Committee (IRB / EC) of an SAE and for providing it with all relevant initial and additional information about the event. The applicant will keep copies of all SAE information on file, including correspondence between the applicant and the IRB / EC.

[0294] SAEs will be recorded in the CRF and the data will be transmitted electronically to Applicant's Drug Safety Unit. If electronic transmission is not available, a paper SAE reporting form will be generated and sent directly to Applicant's Drug Safety Unit, ensuring that the event is also recorded on the CRF.

[0295] 6.6 - Adverse events of special interest Although the risk for serious infections is expected to be low in this Phase II study, adverse events of special interest (AESIs) have been identified to provide further safety monitoring guidance to investigators. AESIs fall into several categories based on safety observations from clinical trials of dupilumab, lebrikizumab, and other sendakimab, as well as the potential pharmacological effects of the IL-4 receptor antagonist and anti-IL-13 antibody. The applicant will identify AEs that meet the following criteria as adverse events of special interest (AESIs). All AESIs must be reported within 24 hours of the applicant becoming aware of the event. AESIs include: Anaphylactic reaction Systemic or severe hypersensitivity reactions Severe injection site reactions (ISR) lasting longer than 24 hours Severe ISR is defined as ISR when it is manifested by symptoms that cause severe discomfort / pain, require medical / surgical attention / intervention, interfere with activities of daily living (ADL), including the inability to perform daily social and functional activities (e.g., absent from work and / or bed rest), and / or requires pharmacotherapy. Malignant tumors other than in situ carcinoma of the cervix or nonmetastatic squamous cell or basal cell carcinoma of the skin Helminth or parasitic infection Opportunistic infections Any severe infection or infection requiring treatment with a parenteral antibiotic, antiviral or antifungal agent, or an infection requiring treatment with an oral antibiotic, antiviral or antifungal agent for more than two weeks.

[0296] 6.7 - Expedited reporting of adverse events For regulatory reporting purposes, the applicant's Drug Safety Unit will determine the predictability of events suspected to be related to sendakimab based on the Investigator Brochure.

[0297] [Example 7] - Discontinued 7.1 - Discontinuation of treatment The following events are considered sufficient reason for a subject to permanently discontinue IP: Adverse events Doctor's decision Lack of effectiveness ● Deviation from protocol Withdrawal by the subject ●Death Untraceable IP non-compliance ●Other (specified in eCRF)

[0298] Subjects who permanently discontinue IP will be encouraged to continue in the study without IP administration to complete all required remaining study assessments, including efficacy evaluations. Subjects who decline further participation in the study should complete the Early Termination Visit and Follow-Up Visit assessments.

[0299] The reason for discontinuing treatment should be recorded on the CRF and in the source documents.

[0300] The decision for a subject to discontinue treatment remains the responsibility of the Treating Investigator and may not be delayed or denied by the Sponsor, however, prior to discontinuing a subject, the Investigator may contact the Medical Monitor and submit applicable supporting documentation for review and discussion.

[0301] 7.2 - Cancellation of the exam The following events are considered sufficient reason for a subject to discontinue the study: ● Screening failure Adverse events Doctor's decision Withdrawal by the subject ●Death Untraceable ●Other (specified in eCRF)

[0302] Reasons for study discontinuation should be recorded in the eCRF and source documents. Follow-up of subjects who discontinue from the study early is of special importance, and every attempt should be made to collect all or selected definitive data on discontinued subjects.

Claims

1. A pharmaceutical composition for treating atopic dermatitis, comprising an anti-IL-13 antibody or an antigen-binding fragment thereof, wherein the anti-IL-13 antibody or the antigen-binding fragment thereof has six CDRs: (a) CDR-H1 comprising residues 31 to 37 of SEQ ID NO:2; (b) CDR-H2 comprising residues 52 to 67 of SEQ ID NO:2; (c) a CDR-H3 comprising residues 100 to 112 of SEQ ID NO:2; (d) CDR-L1 comprising residues 24 to 34 of SEQ ID NO:3; (e) a CDR-L2 comprising residues 50 to 56 of SEQ ID NO:3; or (f) CDR-L3 comprising residues 89 to 97 of SEQ ID NO:3 A pharmaceutical composition comprising an antigen-binding domain comprising:

2. The pharmaceutical composition of claim 1, wherein the anti-IL-13 antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:

3.

3. The pharmaceutical composition of claim 1 or 2, wherein the anti-IL-13 antibody or antigen-binding fragment thereof comprises an L240A mutation.

4. The pharmaceutical composition of claim 1 or 2, wherein the anti-IL-13 antibody or antigen-binding fragment thereof comprises an L241A mutation.

5. The pharmaceutical composition of claim 1 or 2, wherein the anti-IL-13 antibody or antigen-binding fragment thereof comprises an L240A mutation and an L241A mutation.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the anti-IL-13 antibody or antigen-binding fragment thereof is sendakimab.

7. The pharmaceutical composition of claim 1 , wherein the anti-IL-13 antibody or antigen-binding fragment thereof is formulated for subcutaneous administration.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the anti-IL-13 antibody or antigen-binding fragment thereof is formulated for a dosage of about 100 mg to about 1000 mg.

9. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the anti-IL-13 antibody or antigen-binding fragment thereof is formulated for a dosage of about 200 mg to about 900 mg.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the anti-IL-13 antibody or antigen-binding fragment thereof is formulated for dosage to a subject of about 300 mg to about 800 mg.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein the anti-IL-13 antibody or antigen-binding fragment thereof is formulated for dosage to a subject of about 360 mg to about 720 mg.

12. 12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the atopic dermatitis is moderate atopic dermatitis.

13. 12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the atopic dermatitis is severe atopic dermatitis.

14. The pharmaceutical composition according to any one of claims 1 to 11, wherein the atopic dermatitis is moderate to severe atopic dermatitis.