Use of IL-18 antagonists for treating and / or preventing atopic dermatitis or related conditions

Abstract

The present invention relates to the treatment and / or prevention of atopic dermatitis or related conditions. More specifically, the present invention relates to the administration of an IL-18 antagonist, such as an anti-IL-18 antibody or a fragment thereof, to treat or prevent atopic dermatitis or related conditions in a subject in need thereof.

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on October 21, 2020, is named PAT058945_Sequence_Listing_ST25.txt and is 220 kilobytes in size.

[0002] The present invention relates to the treatment and / or prevention of atopic dermatitis or related conditions. More specifically, the present invention relates to the administration of an IL-18 antagonist, such as an anti-IL-18 antibody or a fragment thereof, to treat or prevent atopic dermatitis in a subject in need thereof. [Background technology]

[0003] Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease characterized by symptoms including intense pruritus (e.g., severe itching) and scaling, dry eczema lesions. Severe disease can be extremely disabling, resulting in significant psychological problems, significant insomnia, and impaired quality of life, resulting in high socioeconomic costs. The pathophysiology of AD is influenced by complex interactions between immunoglobulin E (IgE)-mediated sensitization, the immune system, and environmental factors. Primary skin defects can be immunological disorders that cause IgE-mediated sensitization through epithelial barrier dysfunction as a result of both genetic mutations and local inflammation. AD often develops in childhood before the age of 5 and can persist into adulthood.

[0004] Typical treatments for AD include topical lotions and moisturizers, topical corticosteroid ointments, creams or injections.However, most treatment options only provide temporary and incomplete symptom relief.In addition, many patients with moderate to severe AD become resistant to topical corticosteroid or calcineurin inhibitor treatment.Therefore, there is a need in the art for new targeted therapies for treating and / or preventing AD.

[0005] Interleukin-18 (IL-18) is a pro-inflammatory cytokine associated with the induction of Th1 responses, enhanced activation of type I macrophages, and cytotoxicity of NK / CD8+ T cells (Okamura et al. (1995) Nature; 378:88-91; Yoshimoto et al. (1998) J Immunol; 161(7):3400-7; Arend et al. (2008) Immunol Rev.; 223:20-38). IL-18 was originally described in 1989 as interferon-gamma-inducing factor (IGIF). IL-18 is related to the IL-1 family and is structurally related to IL-1β (Okamura et al. (1995) Nature; 378:88-91). IL-18 is produced primarily by macrophages and T cells as a precursor protein (pro-IL-18) and is secreted as an active protein after cleavage by caspase 1 (Dinarello CA et al (1999) J Allergy Clin Immunol;103:11-24). In addition to macrophages and T cells, pro-IL-18 is produced by a wide variety of other cells, including keratinocytes, intestinal epithelial cells, and osteoblasts.

[0006] In normal physiology, IL-18, in synergy with IL-12, is involved in the induction of cell-mediated immunity after infection with microbial products such as lipopolysaccharide (LPS) (Sareneva T et al. (2000) J Immunol;165(4):1933-8). After stimulation by IL-18, natural killer (NK) cells and T cells release interferon gamma (IFN-γ), a cytokine that plays an important role in activating macrophages and other cells. IL-18 also possesses various functions in addition to its ability to induce IFN-γ. These biological properties include activation of NF-κB, expression of Fas ligand, induction of both CC and CXC chemokines, and increased production of transforming human immunodeficiency virus (HIV). IL-18 plays an important role in Th1-type immune responses due to its ability to induce IFN-γ production in T cells and macrophages, and is involved in both innate and adaptive immunity. IL-18 is a pleiotropic cytokine involved in the activation and survival of T cells, NK cells, mast cells, basophils, and macrophages, and has the property of promoting Th2 responses depending on the surrounding cytokine environment (Kaplanski (2018) Immunol Rev 281;138-153; Nakanishi (2018) Front Immunol 9;763).

[0007] Apart from its physiological role, IL-18 has been shown to mediate a variety of autoimmune, e.g., Crohn's disease, psoriasis, rheumatoid arthritis, multiple sclerosis and cardiovascular diseases (Braddock et al. (2004) Expert Opin Biol Ther;4(6):847-860), as well as inflammatory diseases. IL-18 expression has been demonstrated to be upregulated in several autoimmune diseases, such as chronic obstructive pulmonary disease (COPD) (Imaoka et al. (2008) Eur Respir; J31:287-297), idiopathic pulmonary fibrosis (IPF) (Kitasato et al. (2004) Am J Resp Cell Mol Biol; 31:619-625), macrophage activation syndrome (MAS) (Dinarello and Kaplanski (2005) Expert Rev Clin Immunol; 1(4); 619-632), adult-onset Still's disease (AOSD) (Arlet JB et al. (2006) Ann Rheum Dis 65(12):1596-601), and systemic juvenile idiopathic arthritis (SJIA) (Akashi et al. (1994) Br J Haematol; 87(2):243-50). Serum IL-18 levels are elevated in patients with AD and have been shown to correlate with disease severity (Thijs et al. (2015) Clin Exp Allergy 45:698-701, Zedan et al. (2015) J Clin Diagn Res 9:WC01-05, Gohar et al. (2017) Egypt J Immunol 24;9-22). IL-18 has also been shown to be overexpressed in the epidermis of pediatric AD participants and to be associated with AD disease activity (McAleer et al. (2019) Br J Dermatol 180:586-596, Hulshof et al. (2019) Br J Dermatol 180;621-630).

[0008] In preclinical models, such as K14 / IL-18 transgenic mice that overexpress IL-18 in skin keratinocytes, IL-18 contributes to the development of AD-like inflammatory lesions independently of IgE / STAT6 (Konishi et al. (2002) Proc Natl Acad Sci USA 99;11340-11345). Similarly, keratinocyte-specific Casp1 transgenic mice (K14Casp1Tg), which express high levels of mature IL-18, develop AD-like itchy skin lesions with age (Tsutsui et al. (2011) Curr Probl Dermatol 41:93-103; Yamanaka et al. (2000) J Immunol 165;997-1003), and blocking IL-18 prevented Staphylococcus aureus-induced AD-like disease in mice (Terada et al. (2006) Proc Natl Acad Sci USA 103;8816-8821). In vivo administration of IL-18 induces Th2 differentiation in mice in a CD4+ T cell, IL-4, and STAT6-dependent manner, leading to increased IgE production (Yoshimoto et al. (2000) Nat Immunol 1:132-137; Hoshino et al. (2000) Eur J Immunol 30;1998-2006).

[0009] An IL-18 antagonizing antibody has been disclosed (e.g., in WO 2014 / 037899) and is a fully human, Fc-silenced (IgG1-LALA) high-affinity monoclonal antibody that selectively binds to IL-18 and inhibits IL-18 activity.

[0010] The present invention relates to the use of IL-18 antagonists, such as anti-IL-18 antibodies or fragments thereof, in the treatment and / or prevention of atopic dermatitis or related conditions. Summary of the Invention

[0011] The present invention relates to the discovery that IL-18 antagonists, such as anti-IL-18 antibodies or fragments thereof, can be used to treat and / or prevent atopic dermatitis (AD) or related symptoms. According to the present invention, AD is identified using IL-18 antagonists, such as anti-IL-18 antibodies or fragments thereof, as an indicator. Recent publications have linked IL-18 levels to AD disease activity (Thijs et al. (2015) Clin Exp Allergy 45:698-701, Zedan et al. (2015) J Clin Diagn Res 9:WC01-05, Gohar et al. (2017) Egypt J Immunol 24:9-22; McAleer et al. (2019) Br J Dermatol 180:586-596, Hulshof et al. (2019) Br J Dermatol 180;621-630). Preclinical mouse models have demonstrated that IL-18 contributes to the development of AD-like inflammatory lesions (Konishi et al. (2002) Proc Natl Acad Sci USA 99:11340-11345; Tsutsui et al. (2011) Curr Probl Dermatol 41:93-103; Yamanaka et al. (2000) J Immunol 165:997-1003). However, despite IL-18 being a potential therapeutic target for AD, there is currently no evidence that antagonizing IL-18 could potentially treat AD. Furthermore, AD is thought to be driven by T helper 2 cells, which produce IL-13, whereas IL-18 has been described as a major stimulator of T helper 1 cells and NK cells. Therefore, the effects of IL-18 antagonists, such as anti-IL-18 antibodies or fragments thereof, on AD, as exemplified in the Examples herein, were unexpected.

[0012] In one aspect, provided herein is an IL-18 antagonist, eg, an anti-IL-18 antibody or fragment thereof, for use in the treatment and / or prevention of AD or an associated condition.

[0013] In another aspect, provided herein are methods for treating and / or preventing AD or related symptoms in a subject in need thereof, comprising administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof.

[0014] In a further aspect, provided herein is the use of an IL-18 antagonist, such as, for example, an anti-IL-18 antibody or fragment thereof, in the treatment and / or prevention of AD or related symptoms.

[0015] In a further aspect, provided herein is the use of an IL-18 antagonist, such as, for example, an anti-IL-18 antibody or fragment thereof, for the manufacture of a medicament for treating and / or preventing AD or an associated condition.

[0016] Other aspects and embodiments provided herein will become apparent upon review of the following detailed description. [Brief explanation of the drawings]

[0017] [Figure 1] IL-18 levels in ex vivo cultured skin. Non-lesional and lesional skin biopsies from patients with atopic dermatitis or skin biopsies from healthy volunteers were cultured for 24 hours. Total IL-18 supernatant levels were analyzed by the MSD assay (Meso Scale Discovery) (A). Mature IL-18 levels in the culture supernatants were analyzed by IL-18 ELISA (B and C). The measured IL-18 concentrations were normalized by the weight of each biopsy section. Values ​​below the detection level (due to insufficient sample volume remaining and the need to dilute the sample) are indicated by open symbols. [Figure 2]Soluble CD40 levels. Relative soluble CD40 levels (per mg biopsy) in the supernatants of untreated ex vivo cultured skin from healthy individuals and patients with atopic dermatitis (A and B). NL = non-lesional, L = lesional. Relative soluble CD40 levels (per mg biopsy) in the supernatants of ex vivo cultured skin from patients with atopic dermatitis in the absence (untreated) or presence of CMK389 (C). [Figure 3] IL-24 levels. Relative IL-24 levels (per mg biopsy) in the supernatants of untreated ex vivo cultured skin from healthy individuals and patients with atopic dermatitis (A and B). NL = non-lesional, L = lesional. Relative IL-24 levels (per mg biopsy) in the supernatants of ex vivo cultured skin from patients with atopic dermatitis in the absence (untreated) or presence of CMK389 (C). [Figure 4] TARC / CCL17 levels. Relative TARC / CCL17 levels (per mg biopsy) in the supernatants of untreated ex vivo cultured skin from healthy individuals and patients with atopic dermatitis (A and B). NL = non-lesional, L = lesional. Relative TARC / CCL17 levels (per mg biopsy) in the supernatants of ex vivo cultured skin from patients with atopic dermatitis in the absence (untreated) or presence of CMK389 (C). [Figure 5] IL-22 levels. Relative IL-22 levels (per mg biopsy) in the supernatants of untreated ex vivo cultured skin from healthy individuals and patients with atopic dermatitis (A and B). NL = non-lesional, L = lesional. Relative IL-22 levels (per mg biopsy) in the supernatants of ex vivo cultured skin from patients with atopic dermatitis in the absence (untreated) or presence of CMK389 (C). [Figure 6] Summary of Study Design: A randomized, subject- and investigator-blinded, placebo-controlled, multicenter study evaluating the efficacy and safety of CMK389 in patients with moderate to severe atopic dermatitis. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention demonstrates that IL-18 is a valid target for treating and / or preventing atopic dermatitis or related conditions.

[0019] Specific terms used herein are explained below. The compounds of the present invention are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. The following general definitions shall apply herein unless otherwise specified.

[0020] The terms "comprising" and "including" are used herein in their open-ended, non-limiting sense, unless otherwise indicated.

[0021] In describing the invention (particularly in the claims below), the terms "a," "an," and "the," and similar terms, shall be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural is used for compounds, salts, etc., this shall also refer to a single compound, salt, etc.

[0022] "About" and "approximately" are generally intended to mean an acceptable degree of error for the amount measured given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values. When a dose is described herein as "about" a particular amount, the actual dose may vary from the stated amount by up to 10%; this use of "about" recognizes that the exact amount in a given dosage form may differ slightly from the intended amount for a variety of reasons without substantially affecting the in vivo effects of the administered compound.

[0023] The terms "comprising" and "including" are used herein in an open-ended, non-limiting sense unless otherwise indicated. As used herein, the term "comprising" encompasses "including" and "consisting," e.g., a composition "comprising" X may consist exclusively of X or may include some additional elements (e.g., X+Y).

[0024] Treatment of atopic dermatitis (AD) or related conditions The present invention demonstrates that IL-18 is a valid target for treating and / or preventing AD or related conditions.

[0025] In one aspect, provided herein is an IL-18 antagonist, eg, an anti-IL-18 antibody or fragment thereof, for use in treating and / or preventing AD or a related condition.

[0026] In another aspect, provided herein are methods of treating and / or preventing AD or a related symptom in a subject in need thereof, comprising administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof.

[0027] In a further aspect, provided herein is the use of an IL-18 antagonist, such as, for example, an anti-IL-18 antibody or fragment thereof, in the treatment and / or prevention of AD or related symptoms.

[0028] In a further aspect, provided herein is the use of an IL-18 antagonist, such as, for example, an anti-IL-18 antibody or fragment thereof, for the manufacture of a medicament for treating and / or preventing AD or an associated condition.

[0029] Therapeutic uses and methods provided herein include administering a therapeutically effective amount of an IL-18 antagonist, such as an anti-IL-18 antibody or fragment thereof, to a subject in need of such treatment.

[0030] As used herein, the term "subject" or "patient" includes any human or non-human animal. In a preferred embodiment, the subject is a human. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.

[0031] As used herein, the terms "subject," "subject in need thereof," and the like refer to a human or non-human animal exhibiting one or more symptoms or indicators of AD or a related condition, and / or a human or non-human animal diagnosed with AD or a related condition. Preferably, the subject is a human. Preferably, the subject is a human, e.g., a human patient diagnosed with AD. In certain embodiments, the uses and methods may be used to treat patients exhibiting elevated levels of one or more AD-associated biomarkers (described elsewhere herein). For example, the uses and methods provided herein include administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, to a patient exhibiting elevated levels of IgE, hsCRP, CCL17 / TARC, CCL22 / MDC, CCL26 / eotaxin-3, CD40, IL-24, IL-22, or periostin. In some embodiments, the uses and methods provided herein involve administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, to a patient with elevated levels of IL-18 or IL18 BP. In some embodiments, the uses and methods provided herein may be used to treat AD in children <1 year of age. For example, the uses and methods may be used to treat infants <1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months of age. In other embodiments, the uses and methods may be used to treat children and / or adolescents <18 years of age. For example, the methods may be used to treat children or adolescents <17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, <3, or <2 years of age.

[0032] The term "atopic dermatitis (AD)" or "eczema," as used herein, refers to an inflammatory skin disease characterized by intense pruritus (e.g., severe itching) and scaling, dry eczema lesions. The term "atopic dermatitis" or "eczema" includes, but is not limited to, AD (eczema) caused by or associated with impaired epidermal barrier function, allergies (e.g., skin allergies, allergies to certain foods, pollen, mold, house dust mites, animals, etc.), radiation exposure, and / or asthma. The present disclosure encompasses methods of treating patients with mild, moderate-to-severe, or severe AD. As used herein, "moderate-to-severe AD" is characterized by intense pruritus, widespread skin lesions, and is often complicated by persistent bacterial, viral, or fungal infections. Moderate-to-severe AD also includes patients with chronic AD. Chronic lesions often include thickened patches of skin, lichenification, and fibrous papules. Furthermore, patients with moderate to severe AD typically have more than 10% or more than 20% of their body's skin affected, or 10% of the skin area in addition to the involvement of the eyes, hands, and body wrinkles. Patients with moderate to severe AD also typically have (i) an Investigator's Global Assessment (IGA) score of 3 or 4, (ii) an Eczema Area and Severity Index (EASI) score of at least 10, preferably at least 12, and (iii) itching. Moderate to severe AD is also considered to be present in patients who frequently require treatment with topical corticosteroids. Patients may also be said to have moderate to severe AD if they are resistant or refractory to treatment with topical corticosteroids, calcineurin inhibitors, or any other commonly used therapeutic agent known in the art.

[0033] In certain embodiments, provided herein are methods for treating moderate to severe AD. Preferably, moderate to severe atopic dermatitis can be characterized by (i) an Investigator's Global Assessment (IGA) score of 3 or 4, (ii) an Eczema Area and Severity Index (EASI) score of at least 10, preferably at least 12. More preferably, moderate to severe atopic dermatitis can be characterized by (i) an Investigator's Global Assessment (IGA) score of 3 or 4, (ii) an Eczema Area and Severity Index (EASI) score of at least 10, more preferably at least 12, and (iii) a minimum 10% body surface area (BSA) involvement.

[0034] In certain embodiments, methods are provided herein for treating both exogenous and endogenous forms of AD. The exogenous form of AD, associated with IgE-mediated sensitization and increased Th2 cytokine levels, is responsible for 70% to 80% of AD patients. The endogenous form, without IgE-mediated sensitization, is responsible for 20% to 30% of AD patients, and these patients have lower levels of IL-4 and IL-13 than extrinsic AD.

[0035] Individuals with atopic dermatitis are at increased risk of developing other inflammation-related conditions.Therefore, individuals with atopic dermatitis are at increased risk of developing associated conditions.The term "associated conditions" as used herein refers to allergies, such as skin allergies, food allergies, contact allergies, allergic rhinitis, allergic conjunctivitis, asthma (such as allergic or non-allergic asthma), inflammatory bowel disease, rheumatoid arthritis, and alopecia caused by immune response dysfunction (alopecia areata), prurigo nodularis, nummular eczema, dyshidrotic eczema, chronic hand eczema, stasis dermatitis, allergic or irritant contact dermatitis, chronic pruritus ( Hepatic or renal or other origin), nasal polyps or sinusitis (with or without aspirin intolerance), chronic spontaneous or idiopathic urticaria or other urticarial subtypes such as cholinergic urticaria, induced urticaria, eosinophilic esophagitis, eosinophilic gastritis, neutrophilic colitis, bullous pemphigoid, ichthyosis associated with eczema (such as Netherton syndrome), psoriasis, cutaneous lupus erythematosus, systemic lupus erythematosus, wound healing and other conditions related to inflammation. The term "associated conditions" as used herein also refers to infectious diseases such as skin infections, e.g., dermal infections, e.g., herpetic eczema, e.g., erysipelas, e.g., cellulitis; extradermal infections, e.g., encephalitis, e.g., endocarditis, e.g., infectious arthropathy, e.g., enteritis, e.g., sepsis; respiratory infections, e.g., upper respiratory tract infections, e.g., lower respiratory tract infections, e.g., lung infections; cardiac infections; brain infections; bone infections; and intestinal infections; impaired skin barrier function; reduced expression of antimicrobial peptides; abnormal Toll-like receptor signaling and innate immunity; and increased colonization of Staphylococcus aureus in lesional and non-lesional skin. The term "associated diseases" as used herein also refers to autoimmune disorders, respiratory disorders, neuropsychiatric disorders, musculoskeletal disorders, and cardiovascular disorders associated with atopic dermatitis.

[0036] Skin infections, particularly bacterial skin infections, are common in AD and are due in part to very dry, cracked skin and breakdown of the skin due to scratching the itchy areas. In certain embodiments, provided herein are methods of treating AD associated with infections, particularly skin infections, more particularly skin superinfections. In certain embodiments, provided herein are methods of treating AD-related symptoms in which the associated symptom is an infection, particularly skin infection, more particularly skin superinfection. In certain embodiments, the infection is (i) a bacterial infection, e.g., a staphylococcus infection, such as Staphylococcus (S.) aureus, or a streptococcus infection, such as Streptococcus (S.) epidermitis, and / or (ii) a viral infection, e.g., a herpes virus infection. The term "superinfection," as used herein, refers to a secondary infection superimposed on already established diseased tissue. Superinfections are complicated by skin lesions and / or result in colonization or infection with bacteria, such as commensals. The superinfection may be viral or bacterial and is due in part to very dry, cracked skin and breakdown of the skin due to scratching the itchy area.

[0037] The terms "treat," "treating," or "treatment" include therapeutic procedures, prophylactic treatments, and applications that reduce a subject's risk of developing a disorder or other risk factors. Treatment does not necessarily cure the disorder completely, but encompasses reducing symptoms or underlying risk factors. The present invention relates to uses or methods of treating AD, e.g., moderate to severe AD, where treatment includes treating or alleviating one or more symptoms of AD. Thus, as used herein, the terms "treat," "treatment," and "treating" refer to a reduction or amelioration of the worsening, severity, and / or duration of AD, or an improvement in one or more symptoms, preferably one or more discernible symptoms of AD, resulting from administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. In certain embodiments, the terms "treat," "treatment," and "treating" refer to an improvement in at least one measurable physical parameter of AD, although the physical parameter is not necessarily discernible by the patient.

[0038] As used in this context, "prevention" refers to a method aimed at preventing the onset of a disease or its symptoms, or a method that delays the onset of a disease or its symptoms.

[0039] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a therapy (e.g., an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, e.g., CMK389, or a pharmaceutical composition provided herein) sufficient to reduce and / or ameliorate the severity and / or duration of a given condition, disorder, or disease, and / or symptoms associated therewith. These terms also encompass the amount necessary to reduce, slow, or ameliorate the progression or worsening of a given condition, disorder, or disease, reduce, slow, or ameliorate the recurrence, occurrence, or onset of a given condition, disorder, or disease, and / or improve or enhance the prophylactic or therapeutic effects of another therapy (e.g., a therapy other than an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof). In some embodiments, "effective amount," as used herein, also refers to the amount of an antagonist, e.g., an antibody, described herein to achieve a particular result, e.g., an improvement in an AD-related parameter, e.g., a reduction in the Investigator's Global Assessment (IGA) score; a reduction from baseline in the Dermatological Life Quality Index (DLQI); a reduction from baseline in the Patient's Global Impression of Severity (PGIS); an improvement (e.g., a reduction from baseline) in the Patient's Global Impression of Change (PGIC); a reduction in the Atopic Dermatitis Body Surface Area Lesion (BSA) score; a reduction in the Eczema Area and Severity Index (EASI) score; a reduction in the SCORAD score; and / or a reduction in the Pruritus Numeric Rating Scale (NRS) score. In some aspects, "effective amount," as used herein, also refers to the amount of an antagonist, e.g., an antibody, described herein to achieve a particular result, e.g., a reduction in the expression levels of one or more AD-associated biomarkers, particularly one or more AD-associated biomarkers selected from the list consisting of CCL17 / TARC, IgE (e.g., serum IgE), CCL26 / Eotaxin-3, CCL22 / MDC, hsCRP, CD40, IL-24, IL-22, IL-18 (e.g., serum IL-18, serum-free IL-18 (bioactive)), and IL-18BP (e.g., serum IL-18BP), compared to levels before treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof.

[0040] According to certain exemplary embodiments, the present disclosure provides methods for improving one or more AD-related parameters. The AD-related parameters and their improvement are described below.

[0041] Improvements in AD-related parameters include, for example, a decrease in the Investigator's Global Assessment (IGA) score; a decrease from baseline in the Dermatological Life Quality Index (DLQI); a decrease from baseline in the Patient's Global Impression of Severity (PGIS); an improvement (e.g., a decrease from baseline) in the Patient's Global Impression of Change (PGIC); a decrease in the Atopic Dermatitis Body Surface Area Lesion (BSA) score; a decrease in the Eczema Area and Severity Index (EASI) score; a decrease in the SCORAD score; and / or a decrease in the Pruritus Numeric Rating Scale (NRS) score.

[0042] According to certain exemplary embodiments, the uses and methods of the present disclosure result in an improvement in atopic dermatitis-related parameters, the improvement in atopic dermatitis-related parameters being selected from the group consisting of: (a) a decrease from baseline in Investigator's Global Assessment (IGA) score; (b) a decrease from baseline in Dermatological Life Quality Index (DLQI); (c) an improvement (e.g., a decrease from baseline) in Patient's Global Impression of Severity (PGIS); (d) an improvement (e.g., a decrease from baseline) in Patient's Global Impression of Change (PGIC); (e) a decrease from baseline in Eczema Area and Severity Index (EASI) score; and (f) a decrease from baseline in Pruritus Numeric Rating Scale (NRS) score.

[0043] In exemplary embodiments, improvement in AD-related parameters is defined as: (a) a decrease from baseline in Investigator's Global Assessment (IGA) score of at least 2 points, particularly a decrease from baseline in IGA score of at least 2 points and disappearance or near disappearance; (b) a decrease from baseline in Dermatological Life Quality Index (DLQI) of at least 30%, preferably at least 40%, more preferably at least 50%; (c) a decrease from baseline in Patient Global Impression of Severity (PGIS) of at least 1 point, preferably at least 2 points, more preferably at least 3 points; (d) a change from baseline in Patient's Global Impression of Severity (PGIS) of at least 1 point, preferably at least 2 points, more preferably at least 3 points; (e) a reduction from baseline in Eczema Area and Severity Index (EASI) score of at least 45%, preferably at least 50%, and more preferably at least 60%; (f) the percentage of responders achieving a 50% improvement in EASI (EASI50); (g) the percentage of responders achieving a 75% improvement in EASI (EASI75); (h) the percentage of responders achieving a 90% improvement in EASI (EASI90); (i) the percentage of responders achieving a 100% improvement in EASI (EASI100); (f) a reduction from baseline in the Pruritus Numeric Rating Scale (NRS) score of at least 3 points, preferably at least 4 points.

[0044] In some embodiments, improvement in AD-related parameters is observed 4 weeks, 8 weeks, 12 weeks, 16 weeks or more after administration of the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof.

[0045] IL-18 antagonist The term "IL-18" is synonymous with IL-18 polypeptide, interleukin-18 polypeptide, IFN-gamma inducer, or interferon-gamma inducer or IFN-γ inducer. The term "IL-18" refers to human IL-18 comprising amino acids 37-193 of SEQ ID NO: 1. Throughout this specification, the term IL-18 interchangeably encompasses both pro-IL-18 (the mature IL-18 precursor before protease cleavage) and mature IL-18 (after protease cleavage), unless otherwise specified to refer to the pro- or mature form. The term "cynomolgus IL-18" refers to IL-18 from cynomolgus monkeys comprising amino acids 37-193 of SEQ ID NO: 2.

[0046] IL-18 binds with high affinity to and signals through the IL-18 receptor (IL-18R), a heterologous complex of α and β chains encoded by the genes IL18R1 and IL18RAP, respectively (Torigoe K et al (1997) J Biol Chem;272(41):25737-42). The biological activity of IL-18 is negatively regulated by a naturally occurring, highly specific inhibitor, IL-18 binding protein (IL-18BP). This soluble protein forms a complex with free IL-18, preventing its interaction with the IL-18 receptor and thereby neutralizing and inhibiting its biological activity (Dinarello CA (2000) Ann Rheum Dis;59 Suppl 1:i17-20). IL-18BP is a constitutively secreted protein that binds IL-18 with high affinity. Alternative mRNA splicing variants of IL-18BP result in four isoforms: the prominent "a" isoform is present in healthy human serum at a 20-fold molar excess compared to IL-18 (Dinarello and Kaplanski (2005) Expert Rev Clin Immunol, 1(4), 619-632).

[0047] As used herein, the terms "IL-18 antagonist" and "antagonist of IL-18" refer to a molecule capable of reducing or inhibiting IL-18 activity in vivo. Specifically, an "IL-18 antagonist" refers to a molecule that inhibits IL-18-dependent signaling activity in the presence of IL-18 in a human cell assay, such as an IL-18-dependent interferon-gamma (IFN-γ) production assay in human blood cells. An IL-18 antagonist can bind to IL-18R or block IL-18 from binding to IL-18R. Preferably, an IL-18 antagonist has the ability to neutralize IL-18, specifically the ability to neutralize the interaction between an IL-18 polypeptide and an IL-18 receptor. The term "neutralizing" and its grammatical variations are used throughout this specification to refer to a complete or partial reduction in a target biological activity, as the case may be, in the presence of a binding molecule or antibody.

[0048] The IL-18 antagonist may be, for example, a small molecule capable of specifically binding to IL-18 or IL-18R, an anti-IL-18 antibody or an anti-IL-18 antibody fragment (the anti-IL-18 antibody or antibody fragment described in WO 2014 / 037899, GSK-1070806 (GlaxoSmithKline), MEDI-2338 (AstraZeneca; also referred to as AEVI-007), an IL-18 binding protein (IL-18BP, e.g., tadekinig alfa (r-hIL-18BP manufactured by AB2 Bio), an IL-18BP fusion protein, e.g., an Fc fusion of IL-18BP or a soluble decoy receptor), an aptamer, an antisense nucleic acid molecule, an interfering RNA, a receptor protein, or the like.

[0049] In one embodiment, the IL-18 antagonist binds to IL-18R. In one embodiment, the IL-18 antagonist binds to IL-18. In a preferred embodiment, the IL-18 antagonist specifically binds to IL-18 and does not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex.

[0050] In one embodiment, the IL-18 antagonist is an IL-18BP or an IL-18BP fusion protein. The term "IL-18BP" or "IL-18 binding protein" refers to any isoform of human, murine, or viral IL-18 binding protein, whether naturally occurring, isolated, or genetically engineered, such as the IL-18BP disclosed in WO 2001 / 085201, which describes analogs ("muteins") of IL-18BP, in which one or more amino acids have been inserted, substituted with different conservative substitutions, or deleted; functional derivatives, such as IL-18BP fusion proteins (e.g., fusion proteins of IL-18BP with an immunoglobulin heavy chain region or Fc); and PEGylated IL-18BP.

[0051] In a preferred embodiment, the IL-18 antagonist is an anti-IL-18 antibody or an anti-IL-18 antibody fragment. Suitably, the anti-IL-18 antibody or antibody fragment of the present disclosure is a therapeutic antibody.

[0052] The term "antibody" refers to an intact immunoglobulin or a functional fragment thereof. Naturally occurring antibodies typically comprise a tetramer usually composed of at least two heavy (H) chains and at least two light (L) chains. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region, usually composed of three domains (CH1, CH2, and CH3). Heavy chains may be of any isotype, including IgG (IgG1, IgG2, IgG3, and IgG4 subtypes), IgA (IgA1 and IgA2 subtypes), IgM, and IgE. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region (CL). Light chains include kappa chains and lambda chains. While the heavy and light chain variable regions are typically responsible for antigen recognition, the heavy and light chain constant regions can mediate the binding of immunoglobulins to host tissues or host factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (Clq). The VH and VL regions can be further subdivided into hypervariable regions 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 from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The heavy and light chain variable regions contain a binding domain that interacts with an antigen.

[0053] The term "antigen-binding portion" of an antibody (or simply "antigen portion"), as used herein, refers to a full-length or one or more fragments of an antibody that retain the ability to specifically bind to IL-18. Fragments of full-length antibodies have been shown to be able to perform the antigen-binding function of an antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains, an F(ab)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, an Fd fragment consisting of the VH and CH1 domains, an Fv fragment consisting of the VL and VH domains of a single antibody arm, a dAb fragment consisting of the VH domain (Ward et al., (1989) Nature; 341:544-546), and isolated complementarity-determining regions (CDRs). As used herein, the term "antibody fragment" refers to one or more fragments ("antigen-binding portion") of an antibody that retain the ability to specifically bind to IL-18.

[0054] Furthermore, although the two domains of an Fv fragment, the VL domain and the VH domain, are encoded by separate genes, they can be recombinantly linked by a flexible linker and produced as a single protein chain, in which the VL and VH domains pair to form a monovalent molecule (known as a single-chain Fv (scFv); see, e.g., Bird et al., (1988) Science 242:423-426; and Huston et al., 1988 Proc Natl Acad Sc;. 85:5879-5883). Such single-chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as intact antibodies.

[0055] As used herein, the term "anti-IL-18 antibody or anti-IL-18 antibody fragment" or "anti-IL-18 antibody or fragment thereof" refers to an antibody, or a fragment thereof, that comprises the IL-18 binding domain.

[0056] Preferably, the IL-18 antagonist of the present disclosure is an isolated antibody or fragment thereof. The term "isolated" is used throughout this specification to mean that the immunoglobulin, antibody, or polynucleotide is present in a physical environment different from that in which it may, as the case may be, naturally occurring. However, an isolated antibody that specifically binds to IL-18 may be cross-reactive with other antigens, such as IL-18 from other species (e.g., cynomolgus monkey (cyno) IL-18). Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0057] Preferably, the IL-18 antagonist of the present disclosure is a monoclonal antibody or fragment thereof. The term "monoclonal antibody," as used herein, refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0058] Preferably, the IL-18 antagonist of the present disclosure is a fully human, humanized, or chimeric antibody or fragment thereof.

[0059] The term "human antibody," as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region also is derived from such human sequences, e.g., human germline sequences, or variants of human germline sequences, or from antibodies containing consensus framework sequences derived from human framework sequence analysis, e.g., as described in Knappik, et al., (2000) J Mol Biol; 296:57-86. The human antibodies of the present disclosure may include amino acid residues not encoded by human sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation). 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.

[0060] The term "human monoclonal antibody" refers to antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human sequences.

[0061] The term "recombinant human antibody," as used herein, includes all human antibodies prepared, expressed, produced, or isolated by recombinant means, e.g., antibodies isolated from transgenic or transchromosomal animals (e.g., mice) for human immunoglobulin genes or hybridomas prepared therefrom, antibodies isolated from host cells transformed to express human antibodies, e.g., transfectomas, antibodies isolated from recombinants, antibodies isolated from combinatorial human antibody libraries, and antibodies prepared, expressed, produced, or isolated by any other means involving splicing of all or part of a human immunoglobulin gene. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when transgenic animals for human Ig sequences are used, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences derived from and related to human germline VH and VL sequences, but which may not naturally occur in vivo within the human antibody germline repertoire.

[0062] In a preferred embodiment, the IL-18 antagonist is an anti-IL-18 antibody or antibody fragment described in WO 2014 / 037899, the contents of which are incorporated herein by reference. In another embodiment, the IL-18 antagonist is the anti-IL-18 antibody GSK-1070806 (GlaxoSmithKline) or a fragment thereof. In another embodiment, the IL-18 antagonist is the anti-IL-18 antibody MEDI-2338 (AstraZeneca; also referred to as AEVI-007) or a fragment thereof.

[0063] In one embodiment, the present invention relates to an IL-18 antagonist that specifically binds to IL-18, e.g., an anti-IL-18 antibody or fragment thereof. In a more specific embodiment, the present invention relates to an IL-18 antagonist that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, e.g., an anti-IL-18 antibody or fragment thereof.

[0064] As used herein, an "IL-18 antagonist that specifically binds to IL-18" is intended to refer to a compound or molecule that binds to human IL-18 with a KD of 100 nM or less, 10 nM or less, 1 nM or less, 100 pM or less, 10 pM or less, particularly when measured by SET. As used herein, an "antibody or fragment thereof that specifically binds to IL-18" is intended to refer to an antibody or fragment thereof that binds to human IL-18 with a KD of 100 nM or less, 10 nM or less, 1 nM or less, 100 pM or less, 10 pM or less, particularly when measured by SET.

[0065] In one embodiment, the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, binds to human IL-18 with a dissociation constant (KD) of 100 pM or less, e.g., 50 pM or less, 25 pM or less, 10 pM or less, 5 pM or less, preferably a KD of 0.5 pM to 20 pM, particularly when measured by SET.

[0066] An antibody or fragment thereof that "cross-reacts with an antigen other than IL-18" is intended to refer to an antibody or fragment thereof that binds to an antigen with a KD of 100 nM or less, 10 nM or less, 1 nM or less. An antibody or fragment thereof that "does not cross-react with a particular antigen" is intended to refer to a binding molecule that exhibits essentially undetectable binding to these proteins in standard binding assays.

[0067] As used herein, the term "does not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex" refers to a concentration of 1×10 -5The term "antibody" is intended to refer to an antibody or fragment thereof that binds to the IL-18 / IL-18 binding protein (IL-18 BP) complex with a KD of M or greater.

[0068] As used herein, the term "affinity" refers to the strength of the interaction between an antibody or fragment thereof and an antigen at a single antigenic site. Within each antigenic site, the variable regions of the antibody "arms" interact with the antigen at many sites through weak non-covalent forces, with the greater the interaction, the stronger the affinity. As used herein, the term "high affinity" of an antibody refers to an antibody having a KD of 1 nM or less for the target antigen.

[0069] The terms "kassoc" or "ka" or "kon", as used herein, are intended to refer to the association rate of a particular antibody-antigen interaction, while the terms "kdis" or "kd" or "koff", as used herein, are intended to refer to the dissociation rate of a particular antibody-antigen interaction. The term "KD", as used herein, is intended to refer to the dissociation constant obtained from the ratio of kd to ka (i.e., kd / ka) and is expressed as a molar concentration (M). The KD value of an antibody can be determined using methods well established in the art. Methods for determining the KD of an antibody include measuring surface plasmon resonance using a biosensor system such as a Biacore™ system, or measuring affinity in solution by solution equilibrium titration (SET).

[0070] In one embodiment, the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, inhibits IL-18-induced interferon gamma (IFN-γ) production from KG-1 cells with an IC50 of less than 5 nM, e.g., 0.1 to 1 nM.

[0071] In a further embodiment, the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, inhibits IL-18-induced interferon gamma (IFN-γ) production in whole blood with an IC50 of less than 150 nM, e.g., 5-10 nM.

[0072] The term "epitope" is the part of an antigen that is recognized by the immune system, such as an antibody or fragment thereof. Within this specification, the term "epitope" is used interchangeably for both conformational epitopes and linear epitopes. Conformational epitopes are composed of non-contiguous portions of the amino acid sequence of an antigen, while linear epitopes are formed by a contiguous sequence of amino acids from the antigen.

[0073] In one embodiment, the IL-18 antagonist of the present disclosure, particularly an IL-18 antagonist that binds to IL-18 and does not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex, binds to an IL-18 epitope on IL-18 as defined with reference to SEQ ID NO: 1, wherein the epitope is a. The following amino acids of IL-18 as defined with reference to SEQ ID NO: 1: i. amino acids 41 and 42 and amino acids 87-97; or ii. amino acids 138 to 160; or iii. amino acids 177 to 181; or iv. amino acids 41 and 42, amino acids 87 to 97, amino acids 138 to 160, and amino acids 177 to 181; or v. Amino acids 41, 42, 87; 89; 90; or vi. amino acids 93, 94; 95, 96; or vii. Amino acids 140, 141, 150, 177; or viii. Amino acids 92, 93, 94, 138, 140, 152, 157; or ix. Amino acids 142, 143, 150, 152; or x. Amino acids 143; 144; 145; 177; 180; or xi. Amino acids 41, 42, 87; 89; 90; 93, 94; 95, 96; 140; 141; 150; 177; or xii. Amino acids 92; 93; 94; 138; 140; 142; 143; 144; 145; 150; 152; 157; 177; 180; or xiii. Contained within amino acids 41; 42; 87; 89; 90; 92; 93; 94; 95; 96; 138; 140; 141; 142; 143; 144; 145; 150; 152; 157; 177; 180; or ba) containing at least one, two, three or four of the amino acids defined in any one of groups (i) to (xiii) listed in ca) contains an amino acid defined in any one of groups (iv) to (xii).

[0074] In another embodiment, an IL-18 antagonist of the present disclosure, particularly an IL-18 antagonist that binds to IL-18 but not to the IL-18 / IL-18 binding protein (IL-18 BP) complex, binds to an IL-18 epitope on IL-18 as defined with reference to SEQ ID NO: 1, wherein the epitope comprises amino acids Arg140 and Glu152. In one embodiment, the epitope further comprises any one or more of amino acids Gln92, Pro93, Gly95, Pro143, Glu157, or Glu177. In another embodiment, the epitope further comprises any one or more of amino acids Lys89, Arg94, Met96, Phel38, Ser141, Gly144, His145, Asp146, Gln150, or Leu180.

[0075] In one embodiment, the IL-18 antagonists of the present disclosure, particularly IL-18 antagonists that bind IL-18 and do not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex, do not bind to the IL-18 / IL-18 binding protein isoform a or isoform c (IL-18 BP or IL-18BPc) complex.

[0076] In another embodiment, in one embodiment, an IL-18 antagonist of the present disclosure, particularly an IL-18 antagonist that binds to IL-18 and does not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex, does not bind to the IL-18 / IL-18 binding protein isoform a or isoform c (IL-18 BPa or IL-18BPc) complex, and the IL-18 antagonist binds to an IL-18 epitope on IL-18 as defined with reference to SEQ ID NO: 1, wherein the epitope comprises amino acids Arg140 and Glu152. In one embodiment, the epitope further comprises any one or more of amino acids Gln92, Pro93, Gly95, Pro143, Glu157, or Glu177.

[0077] Preferably, the IL-18 antagonist of the present disclosure comprises an antibody or fragment thereof as described below.

[0078] The precise amino acid sequence boundaries of a given complementarity-determining region (CDR) can be determined using the methods of Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme), Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme), and ImMunoGenTics (IMGT) numbering (Lefranc, M.-P., The Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al. The CDR amino acid residues of the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) according to Kabat, and the CDR amino acid residues of the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). According to Kabat's and Chothia's definitions, the CDR amino acids of a VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3), and those of a VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). Combining the Kabat and Chothia CDR definitions, the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) of a human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) of a human VL.According to IMGT, the amino acid residues of the VH CDRs are numbered approximately as 26-35 (CDR1), 51-57 (CDR2), and 93-102 (CDR3), and the amino acid residues of the VL CDRs are numbered approximately as 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3) (numbering according to "Kabat"). According to IMGT, the CDR regions of an antibody can be determined using a program called IMGT / DomainGapAlign.

[0079] Throughout this specification, complementarity determining regions ("CDRs") are defined according to the Kabat definition, unless otherwise specified, where a CDR is defined according to the Chothia definition or by both the Chothia and Kabat definitions. By convention, the CDR regions of the heavy chain are typically referred to as H-CDR1, H-CDR2, and H-CDR3, and those of the light chain as L-CDR1, L-CDR2, and L-CDR3. They are numbered consecutively from the amino terminus to the carboxy terminus.

[0080] A "conservative variant" of a sequence encoding a binding molecule, antibody, or fragment thereof refers to a sequence containing conservative amino acid modifications. "Conservative amino acid modifications" is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of an antibody containing that amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. A conservative amino acid substitution is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Modifications can be introduced into the binding proteins of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions can also encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. Non-naturally occurring amino acids include, but are not limited to, peptidomimetics, reverse or inverted forms of amino acid moieties.

[0081] The term "identity" refers to similarity between at least two different sequences. This identity is expressed as a percentage identity and can be determined by standard alignment algorithms, such as the Basic Local Alignment Search Tool (BLAST) (Altshul et al., (1990) J Mol Biol; 215:403-410; Needleman et al., (1970) J Mol Biol; 48:444-453; or Meyers et al., (1988) Comput Appl Biosci; 4:11-17). As used herein, the percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that need to be introduced for optimal alignment of the two sequences (i.e., % identity = number of identical positions / total number of positions × 100). Comparison of sequences and determination of percent identity between two sequences can be performed using a mathematical algorithm as described below. Percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller, (1988) Comput. Appl. Biosci. 4:11-17, as incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. Alternatively, the percent identity between two amino acid sequences can be determined using the algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:444-453, as incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using a Blossom 62 matrix or a PAM250 matrix, and a gap weight of either 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[0082] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 or a conservative variant thereof; (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13, or a conservative variant thereof; (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 or a conservative variant thereof; (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 or a conservative variant thereof; (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 8 or a conservative variant thereof.

[0083] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 or a conservative variant thereof; (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4 or a conservative variant thereof; (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 or a conservative variant thereof; (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 or a conservative variant thereof; (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 8 or a conservative variant thereof.

[0084] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9 or a conservative variant thereof, and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 or a conservative variant thereof, and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 8 or a conservative variant thereof.

[0085] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly, that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, wherein the IL-18 antagonist binds to an epitope comprising Arg140 and Glu152 on IL-18 as defined with reference to SEQ ID NO: 1, wherein the IL-18 antagonist is i. a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 or a conservative variant thereof, and ii. a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9 or a conservative variant thereof, and iii. A heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 or a conservative variant thereof, and iv. A light chain variable region L-CDR1 comprising SEQ ID NO: 6 or a conservative variant thereof, and v. A light chain variable region L-CDR2 comprising SEQ ID NO: 7 or a conservative variant thereof, and vi. A light chain variable region L-CDR3 comprising SEQ ID NO: 8 or a conservative variant thereof.

[0086] Preferably, the IL-18 antagonist is an isolated human antibody, more preferably an isolated fully human antibody or fragment thereof, more preferably an isolated fully human monoclonal antibody or fragment thereof.

[0087] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 10 or a conservative variant thereof, and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 or a conservative variant thereof, and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 8 or a conservative variant thereof.

[0088] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 11 or a conservative variant thereof, and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 or a conservative variant thereof, and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 8 or a conservative variant thereof.

[0089] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 12 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 or a conservative variant thereof, and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 8 or a conservative variant thereof.

[0090] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 13 or a conservative variant thereof, and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 or a conservative variant thereof, and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 6 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 7 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 8 or a conservative variant thereof.

[0091] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly, that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, wherein the IL-18 antagonist binds to an epitope comprising Arg140 and Glu152 on IL-18 as defined with reference to SEQ ID NO: 1, wherein the IL-18 antagonist is i. a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 or a conservative variant thereof, and ii. a heavy chain variable region H-CDR2 comprising SEQ ID NO: 13 or a conservative variant thereof, and iii. A heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 or a conservative variant thereof, and iv. A light chain variable region L-CDR1 comprising SEQ ID NO: 6 or a conservative variant thereof, and v. A light chain variable region L-CDR2 comprising SEQ ID NO: 7 or a conservative variant thereof, and vi. A light chain variable region L-CDR3 comprising SEQ ID NO: 8 or a conservative variant thereof.

[0092] Preferably, the IL-18 antagonist is an isolated human antibody, more preferably an isolated fully human antibody or fragment thereof, more preferably an isolated fully human monoclonal antibody or fragment thereof.

[0093] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 74 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, or SEQ ID NO: 78, or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 79 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 80 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 81 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 82 or a conservative variant thereof.

[0094] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 74 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 75 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 79 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 80 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 81 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 82 or a conservative variant thereof.

[0095] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 74 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 76 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 79 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 80 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 81 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 82 or a conservative variant thereof.

[0096] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 74 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 77 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 79 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 80 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 81 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 82 or a conservative variant thereof.

[0097] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 74 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 78 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 79 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 80 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 81 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 82 or a conservative variant thereof.

[0098] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 106 or a conservative variant thereof; and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 107 or SEQ ID NO: 122 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 108 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 109 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 110, a conservative variant thereof, and (vi) a light chain variable region L-CDR3 comprising SEQ ID NO: 111 or SEQ ID NO: 126, or a conservative variant thereof.

[0099] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 106 or a conservative variant thereof; and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 107 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 108 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 109 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 110 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 111 or a conservative variant thereof.

[0100] Preferably, the IL-18 antagonist is an isolated human antibody, more preferably an isolated fully human antibody or fragment thereof, more preferably an isolated fully human monoclonal antibody or fragment thereof.

[0101] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 106 or a conservative variant thereof; and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 122 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 108 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 109 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 110 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 126 or a conservative variant thereof.

[0102] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 120 or a conservative variant thereof; and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 121 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 123 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 124 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 125 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 127, SEQ ID NO: 128, or SEQ ID NO: 129, or a conservative variant thereof.

[0103] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 120 or a conservative variant thereof; and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 121 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 123 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 124 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 125 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 127 or a conservative variant thereof.

[0104] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 120 or a conservative variant thereof; and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 121 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 123 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 124 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 125 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 128 or a conservative variant thereof.

[0105] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 120 or a conservative variant thereof; and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 121 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 123 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 124 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 125 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 129 or a conservative variant thereof.

[0106] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 59, SEQ ID NO: 65, or SEQ ID NO: 66, or a conservative variant thereof; and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 60 or SEQ ID NO: 67 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 61 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 62 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 63 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 64 or a conservative variant thereof.

[0107] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 59 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 60 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 61 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 62 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 63 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 64 or a conservative variant thereof.

[0108] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 65 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 60 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 61 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 62 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 63 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 64 or a conservative variant thereof.

[0109] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 66 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 67 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 61 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 62 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 63 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 64 or a conservative variant thereof.

[0110] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 68 or a conservative variant thereof, and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 69 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 70 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 71 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 72 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 73 or a conservative variant thereof.

[0111] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (i) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 162 or a conservative variant thereof; and (ii) a heavy chain variable region H-CDR2 comprising SEQ ID NO: 163 or a conservative variant thereof; and (iii) a heavy chain variable region H-CDR3 comprising SEQ ID NO: 164 or a conservative variant thereof; and (iv) a light chain variable region L-CDR1 comprising SEQ ID NO: 165 or a conservative variant thereof, and (v) a light chain variable region L-CDR2 comprising SEQ ID NO: 166 or a conservative variant thereof, and (vi) A light chain variable region L-CDR3 comprising SEQ ID NO: 167 or a conservative variant thereof.

[0112] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (a) a heavy chain variable region (VH) comprising SEQ ID NO: 14 or a conservative variant thereof or a sequence at least 90% identical thereto; and (b) a light chain variable region (VL) comprising SEQ ID NO: 16 or a conservative variant thereof or a sequence at least 90% identical thereto; The heavy chain variable region (VH) is i. H-CDR1 corresponding to amino acids 26 to 35 of SEQ ID NO: 14; and ii. H-CDR2 corresponding to amino acids 50 to 66 of SEQ ID NO: 14; and iii. comprises an H-CDR3 corresponding to amino acids 99 to 108 of SEQ ID NO: 14; The light chain variable region (VL) is iv. L-CDR1 corresponding to amino acids 23 to 35 of SEQ ID NO: 16; and v. L-CDR2 corresponding to amino acids 51 to 57 of SEQ ID NO: 16; and vi. Contains an L-CDR3 corresponding to amino acids 90 to 100 of SEQ ID NO: 16.

[0113] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (a) a heavy chain variable region (VH) comprising SEQ ID NO: 18 or a conservative variant thereof or a sequence at least 90% identical thereto; and (b) a light chain variable region (VL) comprising SEQ ID NO: 20 or a conservative variant thereof or a sequence at least 90% identical thereto; The heavy chain variable region (VH) is i. H-CDR1 corresponding to amino acids 26 to 35 of SEQ ID NO: 18; and ii. H-CDR2 corresponding to amino acids 50 to 66 of SEQ ID NO: 18; and iii. comprises an H-CDR3 corresponding to amino acids 99 to 108 of SEQ ID NO: 18; The light chain variable region (VL) is iv. L-CDR1 corresponding to amino acids 23 to 35 of SEQ ID NO: 20; and v. L-CDR2 corresponding to amino acids 51 to 57 of SEQ ID NO: 20; and vi. Contains an L-CDR3 corresponding to amino acids 90 to 100 of SEQ ID NO: 20.

[0114] Assuming that each of these human antibodies can bind to IL18 and that antigen-binding specificity is primarily conferred by the CDR1, CDR2, and CDR3 regions, the H-CDR1, H-CDR2, and H-CDR3 sequences and the L-CDR1, L-CDR2, and L-CDR3 sequences can be "mixed and matched" (i.e., CDRs from different human antibodies can be mixed and matched to create other anti-IL18 binding molecules of the invention, with each antibody containing a set of H-CDR1, H-CDR2, and H-CDR3 and a set of L-CDR1, L-CDR2, and L-CDR3). The IL18 binding of such "mixed and matched" antibodies can be verified using the binding assays described in the Examples (e.g., ELISA). Mixing and matching VH CDR sequences requires replacing the CDR1, CDR2, and / or CDR3 sequences from a particular VH sequence with structurally similar CDR sequence(s). Similarly, when mixing and matching VL CDR sequences, the CDR1, CDR2, and / or CDR3 sequences from a particular VL sequence must be replaced with structurally similar CDR sequences. It will be readily apparent to one of ordinary skill in the art that novel VH and VL sequences can be created by replacing one or more VH and / or VL CDR region sequences with structurally similar sequences from the CDR sequences set forth herein for the human antibodies of the disclosure (Figures 1 and 2).

[0115] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence selected from the sequences set forth in SEQ ID NOs: 14, 18, 22, 25, 28, 31, 34, 37, 40, 83, 87, 90, 93, 112, 130, and 138, and (b) a VL amino acid sequence selected from the sequences set forth in SEQ ID NOs: 16, 20, 85, 114, 132, 140, 147, and 153. Other antibodies of the present disclosure are mutated by amino acid deletion, insertion, or substitution, yet still comprise amino acids in the CDR regions having at least 60, 70, 80, 90, or 95 percent identity to the CDR regions set forth in the sequences set forth above. In some embodiments, other antibodies of the present disclosure comprise variant amino acid sequences in which no more than 1, 2, 3, 4, or 5 amino acids in the CDR regions have been mutated by amino acid deletion, insertion, or substitution compared to the CDR regions shown in the sequences set forth above.

[0116] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO: 28, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence comprising SEQ ID NO: 16, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0117] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises: (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO:28 or a conservative variant thereof or a sequence at least 90% identical thereto; and (b) a light chain variable region (VH) amino acid sequence comprising SEQ ID NO:16 or a conservative variant thereof or a sequence at least 90% identical thereto. The variable region (VL) also includes an amino acid sequence in which the asparagine (Asn; N) at amino acid position 30 of SEQ ID NO: 28 is replaced with an amino acid selected from lysine (Lys; K), serine (Ser; S), threonine (Thr; T), alanine (Ala; A), glutamate (Glu; E), histidine (His; H), leucine (Leu; L), glutamine (Gln; Q), arginine (Arg; R), valine (Val; V), tyrosine (Tyr; Y), isoleucine (Ile; I), and glycine (Gly; G).

[0118] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO: 14, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence comprising SEQ ID NO: 16, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0119] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises: (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO: 14, or a conservative variant thereof, or a sequence at least 90% identical thereto; and (b) a light chain variable region (VH) amino acid sequence comprising SEQ ID NO: 16, or a conservative variant thereof, or a sequence at least 90% identical thereto. The variable region (VL) comprises an amino acid sequence in which the lysine (Lys; K) at amino acid position 30 of SEQ ID NO: 14 is replaced with an amino acid selected from asparagine (Asn; N), serine (Ser; S), threonine (Thr; T), alanine (Ala; A), glutamate (Glu; E), histidine (His; H), leucine (Leu; L), glutamine (Gln; Q), arginine (Arg; R), valine (Val; V), tyrosine (Tyr; Y), isoleucine (Ile; I), and glycine (Gly; G).

[0120] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO: 18, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence comprising SEQ ID NO: 20, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0121] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO: 40, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence comprising SEQ ID NO: 20, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0122] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO: 40, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence comprising SEQ ID NO: 20, or a conservative variant thereof, or a sequence at least 90% identical thereto; i. the amino acid glutamate (Glu; E) at position 1 with reference to SEQ ID NO: 40 is replaced with the amino acid glutamine (Gln; Q); ii. The asparagine (Asn; N) at amino acid position 30 with reference to SEQ ID NO: 40 is replaced with an amino acid selected from serine (Ser; S), threonine (Thr; T) and aspartate (Asp; D).

[0123] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO: 40, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence comprising SEQ ID NO: 20, or a conservative variant thereof, or a sequence at least 90% identical thereto; i. the amino acid glutamate (Glu; E) at position 1 with reference to SEQ ID NO: 40 is replaced with the amino acid glutamine (Gln; Q); ii. the asparagine (Asn; N) at amino acid position 30 with reference to SEQ ID NO: 40 is replaced with an amino acid selected from serine (Ser; S), threonine (Thr; T) and aspartate (Asp; D); iii. The methionine (Met; M) at amino acid position 54 with reference to SEQ ID NO: 40 is replaced with an amino acid selected from tyrosine (Tyr; Y), asparagine (Asn; N), and isoleucine (Ile; I).

[0124] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO: 40, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence comprising SEQ ID NO: 20, or a conservative variant thereof, or a sequence at least 90% identical thereto; i. the amino acid glutamate (Glu; E) at position 1 with reference to SEQ ID NO: 40 is replaced with the amino acid glutamine (Gln; Q); ii. The serine (Ser; S) at amino acid position 31 with reference to SEQ ID NO: 40 is replaced with an amino acid selected from threonine (Thr; T), asparagine (Asn; N), and alanine (Ala; A).

[0125] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence comprising SEQ ID NO: 40, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence comprising SEQ ID NO: 20, or a conservative variant thereof, or a sequence at least 90% identical thereto; i. the amino acid glutamate (Glu; E) at position 1 with reference to SEQ ID NO: 40 is replaced with the amino acid glutamine (Gln; Q); ii. The serine (Ser; S) at position 31 of SEQ ID NO: 40 is replaced with an amino acid selected from the group consisting of threonine (Thr; T), asparagine (Asn; N), and alanine (Ala; A); iii. The methionine (Met; M) at amino acid position 54 with reference to SEQ ID NO: 40 is replaced with an amino acid selected from tyrosine (Tyr; Y), asparagine (Asn; N), and isoleucine (Ile; I).

[0126] In one embodiment, the IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence selected from the group consisting of SEQ ID NO:22, SEQ ID NO:25, SEQ ID NO:28, SEQ ID NO:31, SEQ ID NO:34, conservative variants thereof, and sequences at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence selected from the group consisting of SEQ ID NO:16, conservative variants thereof, and sequences at least 90% identical thereto.

[0127] In one embodiment, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a heavy chain variable region (VH) amino acid sequence comprising the sequence set forth in SEQ ID NO: 37, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a light chain variable region (VL) amino acid sequence comprising the sequence set forth in SEQ ID NO: 20, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0128] In one embodiment, the IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence selected from the group consisting of SEQ ID NOs: 43, 47, 50, 53, 56, 96, 100, 103, 116, 134, 142, 158, conservative variants thereof, and sequences at least 90% identical thereto, and (b) a VL amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 98, 118, 136, 144, 150, 156, 160, conservative variants thereof, and sequences at least 90% identical thereto.

[0129] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence comprising the sequence set forth in SEQ ID NO: 43, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a VL amino acid sequence comprising the sequence set forth in SEQ ID NO: 45, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0130] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence comprising the sequence set forth in SEQ ID NO: 158, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a VL amino acid sequence comprising the sequence set forth in SEQ ID NO: 160, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0131] In one embodiment, the IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence selected from the group consisting of SEQ ID NO: 47, SEQ ID NO: 50, SEQ ID NO: 56, conservative variants thereof, and sequences at least 90% identical thereto, and (b) a VL amino acid sequence selected from the group consisting of SEQ ID NO: 45, conservative variants thereof, and sequences at least 90% identical thereto.

[0132] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence selected from the group consisting of SEQ ID NO: 53, SEQ ID NO: 100, conservative variants thereof, and sequences at least 90% identical thereto, and (b) a VL amino acid sequence derived from the group consisting of SEQ ID NO: 160, conservative variants thereof, and sequences at least 90% identical thereto.

[0133] In one embodiment, the IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence selected from the group consisting of SEQ ID NO: 96, SEQ ID NO: 103, conservative variants thereof, and sequences at least 90% identical thereto, and (b) a VL amino acid sequence selected from the group consisting of SEQ ID NO: 98, conservative variants thereof, and sequences at least 90% identical thereto.

[0134] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence comprising the sequence set forth in SEQ ID NO: 116, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a VL amino acid sequence comprising the sequence set forth in SEQ ID NO: 118, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0135] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence comprising the sequence set forth in SEQ ID NO: 142, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a VL amino acid sequence comprising the sequence set forth in SEQ ID NO: 144, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0136] In one embodiment, an IL-18 antagonist of the disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises (a) a VH amino acid sequence comprising the sequence set forth in SEQ ID NO: 134, or a conservative variant thereof, or a sequence at least 90% identical thereto, and (b) a VL amino acid sequence comprising the sequence set forth in SEQ ID NO: 136, or SEQ ID NO: 150, or SEQ ID NO: 156, or a conservative variant thereof, or a sequence at least 90% identical thereto.

[0137] In one embodiment, an IL-18 antagonist, e.g., an anti-IL-18 antibody, of the present disclosure comprises a mutated or chemically modified amino acid Fc region, which inhibits or reduces ADCC activity and / or increases half-life compared to a wild-type Fc region. Preferably, the mutated or chemically modified amino acid Fc region is a silent IgG1 Fc region.

[0138] Also provided herein are IL-18 antagonists, e.g., anti-IL-18 antibodies or fragments thereof, e.g., anti-IL-18 antibodies or fragments thereof that specifically bind to IL-18, particularly IL-18, but do not bind to the IL-18 / IL-18 binding protein complex, and have heavy and light chain amino acid sequences of the variable regions or heavy and light chain amino acid sequences homologous to the amino acid sequences of the antibodies described herein, wherein the homologous antibodies or fragments thereof retain the desired functional properties of the IL-18 antagonists according to the present disclosure.

[0139] For example, the present disclosure provides an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, comprising a VH and a VL, wherein the VH is at least 80%, or at least 90%, identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 14; 18; 22; 25; 28; 31; 34; 37; 40; 83; 87; 90; 93; 112; 130, and 138, and the VL is at least 80%, or at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 16; 20; 85; 114; 132; 140; 147, and 153, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL18 and does not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex. Homologous antibodies may exhibit at least one additional functional property, such as inhibiting IL18 binding to IL18R or inhibiting IL18-dependent IFN-γ production.

[0140] In other embodiments, the VH and / or VL amino acid sequences may be 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequences set forth above, hi other embodiments, the VH and / or VL amino acid sequences may be identical except for amino acid substitutions at no more than 1, 2, 3, 4 or 5 amino acid positions. IL-18 antagonists, e.g., anti-IL-18 antibodies or fragments thereof, having VH and VL regions highly identical (i.e., greater than 80%) to the VH and VL regions of SEQ ID NOs: 14; 18; 22; 25; 28; 31; 34; 37; 40; 83; 87; 90; 93; 112; 130 or 138 and SEQ ID NOs: 16; 20; 85; 114; 132; 140; 147 or 153, respectively, can be used with the VH and VL regions of SEQ ID NOs: 15; 19; 23; 26; 29; 32; 35; 38; 41; 84; 88;91;94;113;131;139;146 or 152 and 17;21;24;27;30;33;36;39;42;86;89;92;95;115;133;141;148 or 154 can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of a nucleic acid molecule encoding the mutated antibodies, and the encoded mutated antibodies can then be verified for maintained function (i.e., the above-mentioned function) using the functional assays described herein.

[0141] The isotopic antibody may be, for example, a human antibody, a humanized antibody or a chimeric antibody. Preferably, the antibody is a fully human silenced IgG1 antibody.

[0142] In certain embodiments, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to an IL-18 / IL-18 binding protein complex, comprises a heavy chain variable region H-CDR1 comprising SEQ ID NO:3, a heavy chain variable region H-CDR2 comprising SEQ ID NO:9, a heavy chain variable region H-CDR3 comprising SEQ ID NO:5, a light chain variable region L-CDR1 comprising SEQ ID NO:6, a light chain variable region L-CDR2 comprising SEQ ID NO:7, and a light chain variable region L-CDR3 comprising SEQ ID NO:8.

[0143] In certain embodiments, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (a) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3, a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9, a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5, a light chain variable region L-CDR1 comprising SEQ ID NO: 6, a light chain variable region L-CDR2 comprising SEQ ID NO: 7, and a light chain variable region L-CDR3 comprising SEQ ID NO: 8, and (b) containing a mutation in the heavy chain framework replacing amino acid asparagine 30 with lysine (N30K).

[0144] In more specific embodiments, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (a) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3, a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9, a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5, a light chain variable region L-CDR1 comprising SEQ ID NO: 6, a light chain variable region L-CDR2 comprising SEQ ID NO: 7, and a light chain variable region L-CDR3 comprising SEQ ID NO: 8, and (b) a mutation in the heavy chain framework replacing amino acid asparagine 30 with lysine (N30K); and (c) a heavy chain variable domain comprising SEQ ID NO: 14, or a sequence at least 90% identical thereto, and a light chain variable domain comprising SEQ ID NO: 16, or a sequence at least 90% identical thereto.

[0145] In certain embodiments, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, comprises a heavy chain variable domain comprising SEQ ID NO: 14 and a light chain variable domain comprising SEQ ID NO: 16.

[0146] In more specific embodiments, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, is (a) a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3, a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9, a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5, a light chain variable region L-CDR1 comprising SEQ ID NO: 6, a light chain variable region L-CDR2 comprising SEQ ID NO: 7, and a light chain variable region L-CDR3 comprising SEQ ID NO: 8, and (b) a mutation in the heavy chain framework replacing amino acid asparagine 30 with lysine (N30K); and (c) a heavy chain comprising SEQ ID NO: 43, or a sequence at least 90% identical thereto, and a light chain comprising SEQ ID NO: 45, or a sequence at least 90% identical thereto.

[0147] In certain embodiments, an IL-18 antagonist of the present disclosure, e.g., an anti-IL-18 antibody or fragment thereof, e.g., an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18, particularly an anti-IL-18 antibody or fragment thereof that specifically binds to IL-18 but does not bind to the IL-18 / IL-18 binding protein complex, comprises a heavy chain comprising SEQ ID NO:43 and a light chain comprising SEQ ID NO:45.

[0148] In a preferred embodiment, the anti-IL-18 antibody or fragment thereof of the present disclosure used in the methods and uses of the present invention is the MOR9464_N30K antibody (also referred to herein as CMK389; see Table 1 of the present disclosure) or a fragment thereof, as described in WO 2014 / 037899, the entire contents of which are incorporated herein by reference.

[0149] [Table 1]

[0150] [Table 2]

[0151] [Table 3]

[0152] [Table 4]

[0153] Biomarkers According to other exemplary embodiments, the present disclosure provides a method for treating AD or a related symptom in a subject, the method comprising: (a) selecting a subject exhibiting an elevated level of at least one AD-associated biomarker; and (b) administering to the subject an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, or a pharmaceutical composition comprising a therapeutically effective amount of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. Exemplary AD-related biomarkers that may be elevated and / or measured in connection with the present disclosure include, but are not limited to, thymus and activation-regulated chemokine (TARC; also known as CCL17), immunoglobulin E (IgE), eotaxin-3 (also known as CCL26), MDC (also known as CCL22), hsCRP (high-sensitivity C-reactive protein), IL-18 (e.g., serum IL-18, serum-free IL-18 (bioactive)), IL-18BP (e.g., serum IL-18BP, serum-free IL-18BP), lactate dehydrogenase (LDH), eosinophils, antigen-specific IgE (e.g., Phadiatop™ test), CD40, IL-24, IL-22, and periostin. In some embodiments, the methods of the disclosure include measuring the level of an AD-associated biomarker in a subject, selecting a subject with an elevated level of the AD-associated biomarker, and administering a therapeutically effective amount of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. In some embodiments, the subject is selected by obtaining information about the level of the AD-associated biomarker in the subject. In some embodiments, the level of the AD-associated biomarker is measured by an assay or test known in the art. In one embodiment, the subject is selected based on exhibiting an IgE level greater than about 1500 kU / L before or during treatment. In one embodiment, the subject is selected based on exhibiting a TARC level greater than about 1000 pg / mL before or during treatment.According to a related aspect of the present disclosure, there is provided a method for treating AD, comprising administering to a subject a therapeutically effective amount of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, or a pharmaceutical composition comprising a therapeutically effective amount of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, wherein administering to the subject results in a decrease in at least one AD-associated biomarker in the subject at or after 4, 8, 15, 22, 25, 29, 36 days after administration. In certain embodiments, the subject exhibits a 5% to 20% decrease in IgE levels from baseline at or after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks after administration. In certain embodiments, the subject exhibits a 25% to 70% decrease in TARC levels from baseline at 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks or more after administration.

[0154] According to other exemplary embodiments, the present disclosure provides a method for treating AD or a related symptom in a subject, the method comprising: (a) selecting a subject exhibiting elevated levels of IL-18 or IL-18BP; and (b) administering to the subject an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, or a pharmaceutical composition comprising a therapeutically effective amount of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. In some embodiments, the disclosed methods comprise measuring the subject's level of IL-18 or IL-18BP, selecting a subject with elevated levels of IL-18 or IL-18BP, and administering to the subject a therapeutically effective amount of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. In some embodiments, the subject is selected by obtaining information regarding the subject's level of IL-18 or IL-18BP. In some embodiments, the level of IL-18 or IL-18BP is measured by an assay or test known in the art. According to a related aspect of the present disclosure, there is provided a method for treating AD, comprising administering to a subject a therapeutically effective amount of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, or a pharmaceutical composition comprising a therapeutically effective amount of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, wherein administration to the subject results in a decrease in the level of IL-18 or IL-18BP in the subject on or after day 4, 8, 15, 22, 25, 29, 36, or later after administration. Also provided herein are methods for reducing the level of one or more AD-associated biomarkers or improving one or more AD-associated parameters in a subject, comprising administering to a subject in need thereof a single initial dose of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, or a pharmaceutical composition comprising an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, followed by one or more sequential secondary doses of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, or a pharmaceutical composition comprising an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof.

[0155] 1. A method for observing the effectiveness of treating AD, particularly moderate to severe AD, or related symptoms, in a subject with an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, comprising: (a) measuring the expression levels of AD-associated biomarkers, e.g., CCL17 / TARC, IgE (e.g., serum IgE), CCL26 / eotaxin-3, CCL22 / MDC, hsCRP, IL-18 (e.g., serum IL-18, serum-free IL-18 (bioactive)), IL-18BP (e.g., serum IL-18BP, e.g., serum-free IL-18BP), CD40, IL-24, IL-22 in a biological sample obtained from the subject prior to treatment with an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof; (b) measuring the expression level of the same AD-related biomarkers as in step (a) in a biological sample obtained from the subject after treatment with an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof; Also provided herein are methods comprising: (c) comparing the level measured in step (a) with the level measured in step (b); and (d) concluding that the treatment is effective if the level measured in step (b) is lower than the level measured in step (a), or concluding that the treatment is not effective if the level measured in step (b) is equal to or higher than the level measured in step (a).

[0156] In one embodiment, the level in step (b) is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, or 16 weeks after measuring the level in step (a). In one embodiment, the biomarker is TARC, and if the TARC level decreases after administration of the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, is determined to be effective. In one embodiment, the biomarker is IgE, and if the IgE level decreases after administration of the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, is determined to be effective. In one embodiment, the biomarker is eotaxin-3, and if the eotaxin-3 level decreases after administration of the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, is determined to be effective. In one embodiment, the biomarker is CCL22 / MDC, and if the CCL22 / MDC level decreases after administration of the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, is determined to be effective. In one embodiment, the biomarker is IL-18 (e.g., serum IL-18, serum-free IL-18 (bioactive form)), and if the IL-18 level (e.g., serum IL-18 level, e.g., serum-free IL-18 (bioactive form) level) decreases after administration of the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, is determined to be effective.In one embodiment, the biomarker is IL-18BP, and if the IL-18BP level decreases after administration of an IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, is determined to be effective. The expression level of the biomarker can be measured, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, or more after administration of the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, and compared to the expression level before administration of the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof. The dose or administration regimen of the IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, can be adjusted after measurement. For example, if biomarker expression does not decrease within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, or more after administration of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, may be discontinued, or the dose of the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, may be increased. If biomarker expression decreases after administration of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, the dose of the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, may be maintained or reduced to identify a minimum effective dose. In some embodiments, treatment is maintained at a minimum effective dose.

[0157] Also provided is a method for monitoring the response of a subject having AD, particularly moderate to severe AD, or an associated symptom, to treatment with an IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, comprising: (a) measuring one or more AD-related biomarkers, particularly one or more AD-related biomarkers selected from the list consisting of CCL17 / TARC, IgE (e.g., serum IgE), CCL26 / eotaxin-3, CCL22 / MDC, hsCRP, CD40, IL-24, IL-22, IL-18 (e.g., serum IL-18, serum-free IL-18 (bioactive)), and IL-18BP (e.g., serum IL-18), in a biological sample from the subject after administration of an IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, to the subject; Also provided herein are methods comprising (a) obtaining information regarding the expression level of related biomarkers; and (b) providing an indication that treatment should be continued if the expression level of one or more AD-associated biomarkers, particularly one or more AD-associated biomarkers selected from the list consisting of CCL17 / TARC, IgE (e.g., serum IgE), CCL26 / eotaxin-3, CCL22 / MDC, hsCRP, CD40, IL-24, IL-22, IL-18 (e.g., serum IL-18, serum-free IL-18 (bioactive)), and IL-18BP (e.g., serum IL-18BP), is decreased compared to the level before treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. In one embodiment, the biomarker is TARC, and if a decrease in TARC levels is determined after administration of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, instructions are provided to continue treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. In one embodiment, the biomarker is IgE, and if a decrease in IgE levels is determined after administration of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, instructions are provided to continue treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof.

[0158] Resistant, non-responsive or inadequately responsive subjects In certain embodiments, provided herein are methods for treating a subject who is resistant, non-responsive, or inadequately responsive to a topical AD therapy, e.g., treatment with a topical corticosteroid (TCS) or a calcineurin inhibitor. In certain embodiments, provided herein are methods for treating a subject who is refractory to a topical AD therapy or who has not adequately responded to treatment with a topical AD therapy, e.g., treatment with a topical corticosteroid (TCS) or a calcineurin inhibitor.

[0159] As used herein, phrases such as "inadequately adjusted," "inadequate response," and "did not respond adequately" refer to a treatment that results in an inadequate response or therapeutic failure in a subject; for example, after treatment with a given drug, the subject still has one or more pathological signs and symptoms of the disorder; for example, in the case of AD, symptoms include intense pruritus (e.g., severe itching) and sleep disturbances caused by itching. In the acute phase, symptoms include scaly and dry lesions, sometimes with localized or widespread edema, often erythematous lesions, vesiculation with small itchy skin blisters called vesicles, and weeping and / or moistening; whereas in the chronic phase of dermatitis, symptoms include erosions and hardened and thickened areas of the skin (often referred to as lichenification due to repeated rubbing and scratching). In some embodiments, before administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, the subject has had an inadequate response to prior treatment with an atopic dermatitis therapy. In some embodiments, the subject has had an inadequate response to prior treatment with a topical AD therapy, e.g., a topical steroid (e.g., a topical corticosteroid). A subject who adequately responded to treatment with an atopic dermatitis therapy (a topical AD therapy, e.g., a topical steroid, e.g., a topical corticosteroid) but discontinued treatment due to side effects is referred to as "intolerant." In some embodiments, a subject with AD or related symptoms treated using the disclosed methods, uses, kits, etc. is intolerant to a previous AD treatment (a topical AD therapy, e.g., a topical steroid, e.g., a topical corticosteroid). In some embodiments, the subject is refractory to topical corticosteroid therapy. In some embodiments, the subject does not adequately respond to treatment with topical corticosteroid therapy.

[0160] Refractory refers to a specific type of inadequate response, i.e., "refractory" means that the subject has been treated with a high-potency AD therapy (topical AD therapy, e.g., topical steroids, e.g., topical corticosteroids) for at least 4 weeks without significant improvement. In some embodiments, a subject with AD or related symptoms treated in accordance with the disclosed methods, uses, kits, etc. is refractory to treatment with a previous AD therapy (topical AD therapy, e.g., topical steroids, e.g., topical corticosteroids). In some embodiments, the subject is refractory to topical corticosteroid therapy. In some embodiments, the subject does not respond adequately to treatment with topical corticosteroid therapy.

[0161] As used herein, "AD therapy" or "atopic dermatitis therapy" refers to atopic dermatitis treatment using an atopic dermatitis agent (e.g., small molecule, biological therapy) or atopic dermatitis treatment means (e.g., phototherapy), and includes topical therapy, systemic therapy, phototherapy, and combinations thereof. "AD therapy" includes topical therapy. "Topical AD therapy" or "topical atopic dermatitis therapy" specifically refers to AD therapy in the form of a cream, ointment, lotion, gel, or spray (e.g., low- to medium-potency corticosteroids [Groups IV to VII according to WHO guidelines, Bolognia JL, Jorizzo JL, Schaffer JV. Glucocorticosteroids. Dermatology. 3rd ed. 2012. Ch 125, 2075-88; Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009 Jan 12, 2009]. 15;79(2):135-40]); over-the-counter (OTC) emollients and medical devices or so-called barrier creams (such as Atopiclear); and lubricants for treating itching and / or pain, such as anti-itch lotions containing menthol, pramoxine, or antihistamines; local anesthetics, systemic drugs (e.g., biologics, e.g., IL-4R inhibitors such as dupilumab); IL-13 inhibitors such as tralokinumab and lebrikizumab; IL-13Ra1 inhibitors such as ASLAN-004; IL-13Ra2 inhibitors; IL-31 inhibitors such as nemolizumab; adalimumab, infliximab, cel TNFα inhibitors such as tolizumab, etanercept, and alefacept; IL-1a inhibitors such as bermekinumab (MABp1); IL-23 inhibitors such as briakinumab, ustekinumab, guselkumab, risankizumab, and tildrakizumab; IL-17 inhibitors such as brodalumab and ixekizumab; CD11a inhibitors such as efalizumab; IL-22 inhibitors such as fezalimumab, IL-22 binding proteins; IL-5 inhibitors such as mepolizumab and benralizumab; synthetic forms of IL-2 such as aldesleukin; recombinant IL-2 approaches targeting the interleukin-2 receptor complex.For example, LY3471851; OSMR inhibitors such as KPL-716; VAP-1 inhibitors; OX-40 or OX40L inhibitors such as GBR830 and KY1005; IgE inhibitors such as omalizumab and ligelizumab; TSLP inhibitors such as tezepelumab; IL-33 inhibitors such as MEDI3506; IL-36 inhibitors such as spesolimab and ANB019; B cell modulating approaches such as rituximab and ocrelizumab; non-biologic immunomodulatory therapeutics, for example, cyclosporine and other calcineurin inhibitors, JAK inhibitors such as tofacitinib, upadacitinib, abrocitinib, and baricitinib; TYK2 inhibitors such as ducravacitinib; methotrexate; PDE4 inhibitors such as apremilast; AK-00 Siglec inhibitors such as 2; S1P agonists or antagonists such as etrasimod or SCD-044; BTK inhibitors such as TAS-5315, IRAK4 antagonists, and CCR4 inhibition approaches such as RPT-193; systemic corticosteroids, cyclophosphamide, sulfasalazine, azathioprine, mycophenolate mofetil, dapsone, hydroxychloroquine); retinoids (e.g., alitretinoin); leukotriene inhibitors or anti-leukotrienes such as montelukast, pranlukast, or zafirlukast, as well as 5-LO inhibitors such as zileuton, and LTA4H inhibitors such as acebilstat, intralesional corticosteroid injections; phototherapy (e.g., high dose UVB and UVA). Photochemotherapy (e.g., psoralens and UVA (PUVA)); topical calcineurin inhibitors (cyclosporine, tacrolimus, pimecrolimus) or topical PDE4 inhibitors such as crisaborole, difamilast, or roflumilast; topical JAK inhibitors such as ruxolitinib, delgocitinib, or topical aryl hydrocarbon receptor (AhR) inhibitors such as topical vitamin D analogs and benvitimide / tapinarof; high to very high potency topical corticosteroids (WHO Groups I, II, III); antifungal agents with known anti-inflammatory properties, such as griseofulvin, itraconazole, betamethasone, dexamethasone, INCB018424, triamcinolone, apremilast, turmeric paste, glucosamine sulfate, triamcinolone acetonide, sesame oil, betamethasone dipropionate,Clobetasol propionate, probiotics (e.g., Bifidobacterium animalis subst. lactis HN019, Lactobacillus reuteri), reuteri), omega-3, prednisone, prednisolone, platelet-rich plasma, Orabase paste, lycopene, topical chamomile, green tea, CO2 laser treatment, allergen-specific immunotherapy, polybiotics, photobiomodulation, metronidazole, doxycycline, minocycline, cedar honey, purslane, curcuminoids, alefacept, hexaminolevulinic acid, hydroxychloroquine, Adcortil, efalizumab, fluocinolone, coenzyme Q10 mucoadhesive tablets, Roman chamomile, sirolimus, tacrolimus, qingxuan decoction, NSAID topical rinse, NSAIDs, quercetin, NAVS naphthalane, valchlor, bupivacaine, and oatmeal baths. Preferably, the topical AD therapy is a topical steroid, e.g., a corticosteroid, tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, apremilast, a calcineurin inhibitor, e.g., a topical calcineurin inhibitor, a phosphodiesterase 4 (PDE4) inhibitor, e.g., a topical PDE4 inhibitor, e.g., crisaborole, adrenocorticotropic hormone analogs, dupilumab, etanercept, adalimumab, infliximab, omalizumab, or secukinumab, that is a standard therapy for atopic dermatitis. In certain embodiments, the topical AD therapy is a topical corticosteroid, particularly a low- to medium-potency topical corticosteroid. In certain embodiments, the topical corticosteroid (TCS) is selected from the group consisting of Group I TCS, Group II TCS, and Group III TCS. In some embodiments, the TCS is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate, and hydrocortisone butyrate. Preferred low-to-medium potency topical corticosteroids are:Desoximetasone cream 0.05%, fluocinolone acetonide ointment 0.025%, fludroxycortide ointment 0.05%, hydrocortisone valerate ointment 0.2%, triamcinolone acetonide cream 0.1%, betamethasone dipropionate lotion 0.02%, betamethasone valerate cream 0.1%, fluocinolone acetonide cream 0.025%, fludroxycortide cream 0.05% , hydrocortisone butyrate cream 0.1%, hydrocortisone valerate cream 0.2%, triamcinolone acetonide lotion 0.1%, betamethasone valerate lotion 0.05%, desonide cream 0.05%, fluocinolone acetonide solution 0.01%, dexamethasone sodium phosphate cream 0.1%, hydrocortisone acetate cream 1%, and methylprednisolone acetate cream 0.25%.

[0162] In a related embodiment, provided herein is a method for reducing the dependence of a subject with AD, e.g., moderate to severe AD, or a related symptom, on TCS, comprising co-administration of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, and TCS, wherein the dosage of TCS is reduced by 50% compared to a subject not administered the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. In one embodiment, provided herein is a method for reducing the dosage of TCS in the treatment of AD, e.g., moderate to severe AD, or a related symptom, comprising co-administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, with a reduced dosage of TCS. The dosage of TCS can be reduced, for example, by 10%, 20%, 30%, 40%, or more than 50%. In one embodiment, the dosage of TCS can be reduced, e.g., by more than 10%, 20%, 30%, 40%, or 50%, compared to the dosage used in the subject prior to treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof.

[0163] Administration and Combination Therapies According to certain exemplary embodiments, the uses and methods of the present disclosure comprise administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, subcutaneously, intravenously, intraarticularly, or intrathecally. In certain embodiments, the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, is administered subcutaneously or intravenously.

[0164] Preferably, the uses and methods of the present disclosure comprise administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, at a dose sufficient to achieve a therapeutically effective serum level. Preferably, the therapeutically effective serum level of the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, is maintained during the course of treatment.

[0165] As used herein, the term "therapeutically effective serum level" refers to a serum level of a therapy (e.g., an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, e.g., CMK389) in a subject sufficient to reduce and / or ameliorate the severity and / or duration of a given condition, disorder, or disease, and / or symptoms associated therewith. In some embodiments, "therapeutically effective serum level," as used herein also refers to the amount of an antagonist in the serum of a subject that achieves a particular result, e.g., an improvement in an AD-related parameter, such as a decrease in the Investigator's Global Assessment (IGA) score; a decrease from baseline in the Dermatological Life Quality Index (DLQI); a decrease from baseline in the Patient's Global Impression of Severity (PGIS); an improvement (e.g., a decrease from baseline) in the Patient's Global Impression of Change (PGIC); a decrease in the Atopic Dermatitis Body Surface Area Lesion (BSA) score; a decrease in the Eczema Area and Severity Index (EASI) score; a decrease in the SCORAD score; and / or a decrease in the Pruritus Numerical Rating Scale (NRS) score. In some aspects, a "therapeutically effective serum level," as used herein, also refers to the amount of antagonist in the serum of a subject that achieves a particular result, e.g., a reduction in the expression levels of one or more AD-associated biomarkers, particularly one or more AD-associated biomarkers selected from the list consisting of CCL17 / TARC, IgE (e.g., serum IgE), CCL26 / Eotaxin-3, CCL22 / MDC, hsCRP, CD40, IL-24, IL-22, IL-18 (e.g., serum IL-18, serum-free IL-18 (bioactive)), and IL-18BP (e.g., serum IL-18BP), compared to the level before treatment with the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof.

[0166] Suitably, the uses and methods of the present disclosure comprise administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, once per week, once every two weeks, once per three weeks, once per four weeks, once per eight weeks, or once per twelve weeks. According to certain exemplary embodiments, the uses and methods of the present disclosure comprise administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, once per four weeks.

[0167] According to certain exemplary embodiments, the uses and methods of the present disclosure comprise administering an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, and a second therapeutic agent. Preferably, the second therapeutic agent is administered to the subject before, after, or simultaneously with the IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. Preferably, the second therapeutic agent is an AD agent, e.g., a small molecule, a biological therapy, or an agent using an AD treatment modality, e.g., phototherapy, including topical therapy, systemic therapy, phototherapy, and combinations thereof. "AD agents" include topical treatments in the form of creams, ointments, lotions, gels, or sprays (e.g., low- to medium-potency corticosteroids [Groups IV to VII according to the WHO guidelines, Bolognia JL, Jorizzo JL, Schaffer JV. Glucocorticosteroids. Dermatology. 3rd ed. 2012. Ch 125, 2075-88; Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009 Jan 15;79(2):135-40]); over-the-counter (OTC) emollients and medical devices or so-called barrier creams (such as Atopiclear); and lubricants for treating itching and / or pain, such as anti-itch lotions containing menthol, pramoxine, or antihistamines; local anesthetics, systemic drugs (e.g., biologics, e.g., IL-4R inhibitors such as dupilumab); IL-13 inhibitors such as tralokinumab and lebrikizumab; IL-13Ra1 inhibitors such as ASLAN-004; IL-13Ra2 inhibitors; nemolizumab IL-31 inhibitors: TNFα inhibitors such as adalimumab, infliximab, certolizumab, etanercept, and alefacept; IL-1a inhibitors such as bermekimab (MABp1); IL-23 inhibitors such as briakinumab, ustekinumab, guselkumab, risankizumab, and tildrakizumab; IL-17 inhibitors such as brodalumab and ixekizumab; CD11a inhibitors such as efalizumab; IL-22 inhibitors, IL-22 binding proteins such as fezalimumab; IL-5 inhibitors such as mepolizumab and benralizumab;synthetic forms of IL-2 such as aldesleukin; recombinant IL-2 approaches targeting the interleukin-2 receptor complex, e.g., LY3471851; OSMR inhibitors such as KPL-716; VAP-1 inhibitors; OX-40 or OX40L inhibitors such as GBR830 and KY1005; IgE inhibitors such as omalizumab and ligelizumab; TSLP inhibitors such as tezepelumab; IL-33 inhibitors such as MEDI3506; IL-36 inhibitors such as spesolimab and ANB019; B-cell modulating approaches such as rituximab and ocrelizumab; non-biologic immunomodulatory therapies such as cyclosporine and other calcineurin inhibitors, JAK inhibitors such as tofacitinib, upadacitinib, abrocitinib, and baricitinib; TYK2 inhibitors such as deuclavacitinib; methotrexate sartan; PDE4 inhibitors such as apremilast; Siglec inhibitors such as AK-002; S1P agonists or antagonists such as etrasimod or SCD-044; BTK inhibitors such as TAS-5315, IRAK4 antagonists, and CCR4 inhibition approaches such as RPT-193; systemic corticosteroids, cyclophosphamide, sulfasalazine, azathioprine, mycophenolate mofetil, dapsone, hydroxychloroquine); retinoids (e.g., alitretinoin); leukotriene inhibitors or anti-leukotrienes such as montelukast, pranlukast, or zafirlukast, as well as 5-LO inhibitors such as zileuton, and LTA4H inhibitors such as acebilstat, intralesional corticosteroid injections; phototherapy (e.g., high dose UVB and UVA). Photochemotherapy (e.g., psoralens and UVA (PUVA)); topical calcineurin inhibitors (cyclosporine, tacrolimus, pimecrolimus) or topical PDE4 inhibitors such as crisaborole, difamilast, or roflumilast; topical JAK inhibitors such as ruxolitinib, delgocitinib, or topical aryl hydrocarbon receptor (AhR) inhibitors such as topical vitamin D analogs and benvitimod / tapinarolide; high- to very high-potency topical corticosteroids (WHO Groups I, II, and III);Antifungal agents with known anti-inflammatory properties, such as griseofulvin, itraconazole, betamethasone, dexamethasone, INCB018424, triamcinolone, apremilast, turmeric paste, glucosamine sulfate, triamcinolone acetonide, sesame oil, betamethasone dipropionate, clobetasol propionate, probiotics (e.g., Bifidobacterium animalis subst. lactis HN019, Lactobacillus reuteri), reuteri), omega-3, prednisone, prednisolone, platelet-rich plasma, Orabase paste, lycopene, topical chamomile, green tea, CO2 laser treatment, allergen-specific immunotherapy, polybiotics, photobiomodulation, metronidazole, doxycycline, minocycline, cedar honey, purslane, curcuminoids, alefacept, hexaminolevulinic acid, hydroxychloroquine, Adcortil, efalizumab, fluocinolone, coenzyme Q10 mucoadhesive tablets, Roman chamomile, sirolimus, tacrolimus, qingxuan decoction, NSAID topical rinse, NSAIDs, quercetin, NAVS naphthalane, valchlor, bupivacaine, and oatmeal baths. Preferably, the topical AD therapy is a standard therapy for atopic dermatitis, including, but not limited to, topical steroids, e.g., corticosteroids, tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, apremilast, calcineurin inhibitors, e.g., topical calcineurin inhibitors, phosphodiesterase 4 (PDE4) inhibitors, e.g., topical PDE4 inhibitors, e.g., crisaborole, adrenocorticotropic hormone analogs, dupilumab, etanercept, adalimumab, infliximab, omalizumab, secukinumab;

[0168] In certain embodiments, the topical AD therapy is a topical corticosteroid, particularly a low- to medium-potency topical corticosteroid. In certain embodiments, the second therapeutic agent is a low- to medium-potency steroid, e.g., a topical or oral steroid, e.g., a corticosteroid. According to certain exemplary embodiments, the second therapeutic agent is selected from the group consisting of Group I topical corticosteroids (TCS), Group II topical corticosteroids (TCS), and Group III topical corticosteroids (TCS). In some embodiments, the TCS is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate, and hydrocortisone butyrate. Preferred low-to-moderate potency topical corticosteroids are desoximetasone cream 0.05%, fluocinolone acetonide ointment 0.025%, fludroxycortide ointment 0.05%, hydrocortisone valerate ointment 0.2%, triamcinolone acetonide cream 0.1%, betamethasone dipropionate lotion 0.02%, betamethasone valerate cream 0.1%, fluocinolone acetonide cream 0.025%, and fludroxycortide. Cortide cream 0.05%, hydrocortisone butyrate cream 0.1%, hydrocortisone valerate cream 0.2%, triamcinolone acetonide lotion 0.1%, betamethasone valerate lotion 0.05%, desonide cream 0.05%, fluocinolone acetonide solution 0.01%, dexamethasone sodium phosphate cream 0.1%, hydrocortisone acetate cream 1%, and methylprednisolone acetate cream 0.25%. According to certain exemplary embodiments, the second therapeutic agent is selected from the group consisting of steroids, cyclosporine, tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, apremilast, calcineurin inhibitors, e.g., topical calcineurin inhibitors, phosphodiesterase 4 (PDE4) inhibitors, e.g., topical PDE4 inhibitors, e.g., crisaborole, adrenocorticotropic hormone analogs, dupilumab, etanercept, adalimumab, infliximab, omalizumab, and secukinumab.

[0169] Pharmaceutical Composition The uses and methods of the present disclosure include administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof. In certain aspects, the present disclosure provides compositions comprising an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, useful for the uses and methods of the present disclosure in treating atopic dermatitis or related conditions, the compositions further comprising one or more pharmaceutically acceptable carriers and / or diluents.

[0170] The compositions provided herein are preferably pharmaceutical compositions comprising an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, for the uses and methods of the present disclosure in treating atopic dermatitis or related conditions. Such carriers, diluents, and excipients are well known in the art, and one of ordinary skill in the art will find the most suitable formulation and route of administration for treating a subject with an IL-18 antagonist, e.g., an anti-IL-18 antibody or fragment thereof, of the present disclosure.

[0171] In one aspect, provided herein is a pharmaceutical composition comprising an IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, for use in treating and / or preventing AD or related symptoms. In certain embodiments, provided herein is a pharmaceutical composition comprising an IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, for use in improving one or more AD-related parameters in a subject in need thereof. In another embodiment, a pharmaceutical composition comprises an IL-18 antagonist, e.g., an anti-IL-18 antibody or a fragment thereof, for use in treating AD in a subject with elevated levels of a biomarker selected from the group consisting of CCL17 / TARC, IgE, CCL26 / eotaxin-3, CCL22 / MDC, hsCRP, CD40, IL-24, IL-22, IL-18 (e.g., serum IL-18, serum-free IL-18 (bioactive)), IL-18BP (e.g., serum IL-18BP, e.g., serum-free IL-18BP), and periostin.

[0172] In certain embodiments, the pharmaceutical composition is administered to a subject before, after, or simultaneously with a second therapeutic agent, hi some embodiments, the second therapeutic agent is a topical corticosteroid (TCS) or a calcineurin inhibitor.

[0173] The phrase "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The phrase "pharmaceutically acceptable formulation" or "pharmaceutical formulation" refers to formulations consisting of compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0174] The following examples are illustrative of the invention described above, but are not intended to be limiting in any way to the scope of the invention. It is not intended to limit the scope of such techniques. Other test models may similarly be used to determine the beneficial effects of the claimed invention. do. Various embodiments of the present invention are described below. 1. An IL-18 antagonist for use in the treatment and / or prevention of atopic dermatitis or related symptoms in a subject in need thereof. 2. An IL-18 antagonist for use according to 1 above, wherein said IL-18 antagonist specifically binds to IL-18 and does not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex. 3. The IL-18 antagonist for use according to any one of 1 to 2 above, wherein the IL-18 antagonist is an isolated antibody or antibody fragment. 4. The IL-18 antagonist for use according to any one of 1 to 3 above, wherein the IL-18 antagonist is a human, humanized or chimeric antibody or antibody fragment. 5. Use of the IL-18 antagonist according to any one of 1 to 4 above, wherein the IL-18 antagonist binds to human IL-18 with a dissociation constant (KD) of 100 pM or less, for example, 50 pM or less, 25 pM or less, 10 pM or less, 5 pM or less, preferably a KD of 0.5 pM to 20 pM, when measured, in particular, by SET. 6. An IL-18 antagonist for use according to any one of 1 to 5 above, wherein the IL-18 antagonist inhibits IL-18-induced interferon gamma (IFN-γ) production from KG-1 cells with an IC50 of less than 5 nM, for example, 0.1 to 1 nM. 7. An IL-18 antagonist for use according to any one of 1 to 6 above, wherein the antibody or antibody fragment inhibits the production of interferon gamma (IFN-γ) induced by IL-18 in whole blood with an IC50 of less than 150 nM, for example 5 to 10 nM. 8. An IL-18 antagonist for use according to any one of 1 to 7 above, wherein the IL-18 antagonist comprises a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3, a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9, a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5, a light chain variable region L-CDR1 comprising SEQ ID NO: 6, a light chain variable region L-CDR2 comprising SEQ ID NO: 7, and a light chain variable region L-CDR3 comprising SEQ ID NO: 8. 9. An IL-18 antagonist for use according to claim 8, wherein the IL-18 antagonist comprises a heavy chain variable domain comprising SEQ ID NO: 14 or a sequence at least 90% identical thereto, and a light chain variable domain comprising SEQ ID NO: 16 or a sequence at least 90% identical thereto. 10. An IL-18 antagonist for use according to claim 9, wherein said IL-18 antagonist comprises a mutation in the framework of said heavy chain, in which the asparagine at amino acid position 30 is replaced by a lysine (N30K; numbering according to Kabat). 11. The IL-18 antagonist for use according to any one of 8 to 10 above, wherein the IL-18 antagonist comprises a heavy chain comprising SEQ ID NO: 43 or a sequence at least 90% identical thereto, and a light chain comprising SEQ ID NO: 45 or a sequence at least 90% identical thereto. 12. The treatment results in an improvement in atopic dermatitis-related parameters, and the improvement in the atopic dermatitis-related parameters is (a) Reduction from baseline in investigator global assessment (IGA) score; (b) decrease from baseline in Dermatological Life Quality Index (DLQI); (c) reduction from baseline in Patient Global Impression of Severity (PGIS); (d) decrease from baseline in Patient Global Impression of Change (PGIC); (e) Reduction from baseline in Eczema Area and Severity Index (EASI) score; and (f) a decrease from baseline in the pruritus numerical rating scale (NRS) score. 13. The treatment results in an improvement in atopic dermatitis-related parameters, and the improvement in the atopic dermatitis-related parameters is (a) A decrease from baseline in the Investigator's Global Assessment (IGA) score of at least 2 points, specifically a decrease from baseline in the IGA score of at least 2 points that is eliminated or nearly eliminated; (b) a decrease from baseline in the Dermatological Life Quality Index (DLQI) of at least 30%, preferably at least 40%; (c) improvement from baseline in Patient Global Impression of Severity (PGIS) of at least 1 point; (d) improvement from baseline in Patient Global Impression of Clinical Outcome (PGIC) of at least a 1-point change; (e) at least a 50% reduction from baseline in Eczema Area and Severity Index (EASI) score; (f) proportion of responders with ≥50% improvement in EASI (EASI50); (g) proportion of responders with ≥75% improvement in EASI (EASI75); (h) proportion of responders with ≥90% improvement in EASI (EASI90); (i) the proportion of responders with ≥100% improvement in EASI (EASI100); (j) a reduction from baseline in the pruritus numerical rating scale (NRS) score of at least 3 points, preferably at least 4 points, from baseline. 14. The IL-18 antagonist for use according to any one of 1 to 13 above, wherein the atopic dermatitis is moderate to severe atopic dermatitis. 15. An IL-18 antagonist for use according to claim 14, wherein said moderate to severe atopic dermatitis is characterized by (i) an Investigator's Global Assessment (IGA) score of 3 or 4, and / or (ii) an Eczema Area and Severity Index (EASI) score of at least 10, particularly at least 12. 16. The IL-18 antagonist for use according to any one of 1 to 15 above, wherein the atopic dermatitis is complicated by an infection or the associated condition is an infection, particularly a skin infection, more particularly a skin superinfection. 17. An IL-18 antagonist for use according to claim 16, wherein the infection is (i) a bacterial infection, for example a staphylococcus infection such as Staphylococcus (S.) aureus or a streptococcus infection such as Streptococcus (S.) epidermitis, and / or (ii) a viral infection, for example a herpes virus infection. 18. An IL-18 antagonist for use according to any one of 1 to 17 above, wherein the subject has not responded adequately to treatment with a topical atopic dermatitis therapy. 19. The IL-18 antagonist for use according to any one of 1 to 18 above, wherein the subject has been refractory to topical atopic dermatitis therapy or has not responded adequately to treatment with topical atopic dermatitis therapy. 20. An IL-18 antagonist for use according to claim 18 or 19, wherein said topical atopic dermatitis therapy is selected from the group consisting of topical steroids, such as corticosteroids, tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, apremilast, calcineurin inhibitors, such as topical calcineurin inhibitors, phosphodiesterase 4 (PDE4) inhibitors, such as topical PDE4 inhibitors, e.g. crisaborole, adrenocorticotropic hormone analogues. 21. The IL-18 antagonist for use according to claim 20, wherein the topical steroid is selected from the group consisting of Group I topical corticosteroids (TCS), Group II topical corticosteroids (TCS) and Group III topical corticosteroids (TCS). 22. The IL-18 antagonist for use according to claim 20, wherein the topical corticosteroid (TCS) is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate and hydrocortisone butyrate. 23. The IL-18 antagonist for use according to any one of 1 to 22 above, wherein said IL-18 antagonist is administered subcutaneously or intravenously to a subject in need thereof. 24. An IL-18 antagonist for use according to any one of 1 to 23 above, wherein said IL-18 antagonist is administered at a dose sufficient to achieve a therapeutically effective serum level. 25. The IL-18 antagonist for use according to claim 24, wherein said serum level is maintained during said course of treatment. 26. The IL-18 antagonist for use according to any one of 1 to 25 above, wherein the IL-18 antagonist is administered once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 8 weeks, or once every 12 weeks, particularly once every 4 weeks. 27. An IL-18 antagonist for use according to any one of 1 to 26 above, wherein a second therapeutic agent is administered to the subject before, after, or simultaneously with the IL-18 antagonist according to any one of 1 to 11 above. 28. The IL-18 antagonist for use according to claim 27, wherein said second therapeutic agent is selected from the group consisting of steroids, cyclosporine, tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, apremilast, calcineurin inhibitors, such as topical calcineurin inhibitors, phosphodiesterase 4 (PDE4) inhibitors, such as topical PDE4 inhibitors, e.g. crisaborole, adrenocorticotropic hormone analogues, dupilumab, etanercept, adalimumab, infliximab, omalizumab, secukinumab. 29. An IL-18 antagonist for use according to claim 27, wherein said second therapeutic agent is a low to medium potency steroid, such as a topical or oral steroid, such as a corticosteroid. 30. The IL-18 antagonist for use according to claim 29, wherein the second therapeutic agent is selected from the group consisting of Group I topical corticosteroids (TCS), Group II topical corticosteroids (TCS) and Group III topical corticosteroids (TCS). 31. The IL-18 antagonist for use according to claim 29, wherein the topical corticosteroid (TCS) is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate and hydrocortisone butyrate. 32. A method of treating and / or preventing atopic dermatitis or related conditions in a subject in need thereof, comprising administering an IL-18 antagonist. 33. The method of claim 32, wherein the IL-18 antagonist specifically binds to IL-18 and does not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex. 34. The method of claim 32 or 33, wherein the IL-18 antagonist is an isolated antibody or antibody fragment. 35. The method according to any one of 32 to 34 above, wherein the IL-18 antagonist is a human, humanized, or chimeric antibody or antibody fragment. 36. The method according to any one of 32 to 35 above, wherein the IL-18 antagonist binds to human IL-18 with a dissociation constant (KD) of 100 pM or less, for example, 50 pM or less, 25 pM or less, 10 pM or less, 5 pM or less, preferably a KD of 0.5 pM to 20 pM, particularly when measured by SET. 37. The method according to any one of 32 to 36 above, wherein the IL-18 antagonist inhibits the production of interferon gamma (IFN-γ) induced by IL-18 from KG-1 cells with an IC50 of less than 5 nM, for example, 0.1 to 1 nM. 38. The method according to any one of 32 to 37 above, wherein the IL-18 antagonist inhibits the production of interferon gamma (IFN-γ) induced by IL-18 in whole blood with an IC50 of less than 150 nM, for example 5 to 10 nM. 39. The method described in any of 32 to 38 above, wherein the IL-18 antagonist comprises a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3, a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9, a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5, a light chain variable region L-CDR1 comprising SEQ ID NO: 6, a light chain variable region L-CDR2 comprising SEQ ID NO: 7, and a light chain variable region L-CDR3 comprising SEQ ID NO: 8. 40. The method of claim 39, wherein the IL-18 antagonist comprises a heavy chain variable domain comprising SEQ ID NO: 14 or a sequence at least 90% identical thereto, and a light chain variable domain comprising SEQ ID NO: 16 or a sequence at least 90% identical thereto. 41. The method of claim 40, wherein said IL-18 antagonist comprises a mutation in the framework of said heavy chain, in which asparagine at amino acid position 30 is replaced with lysine (N30K; numbering according to Kabat). 42. The method according to any one of 39 to 41 above, wherein the IL-18 antagonist comprises a heavy chain comprising SEQ ID NO: 43 or a sequence at least 90% identical thereto, and a light chain comprising SEQ ID NO: 45 or a sequence at least 90% identical thereto. 43. The treatment results in an improvement in atopic dermatitis-related parameters, and the improvement in the atopic dermatitis-related parameters is (a) Reduction from baseline in investigator global assessment (IGA) score; (b) decrease from baseline in Dermatological Life Quality Index (DLQI); (c) reduction from baseline in Patient Global Impression of Severity (PGIS); (d) decrease from baseline in Patient Global Impression of Change (PGIC); (e) Reduction from baseline in Eczema Area and Severity Index (EASI) score; and (f) a decrease from baseline in the pruritus numerical rating scale (NRS) score. 44. The treatment results in an improvement in atopic dermatitis-related parameters, and the improvement in the atopic dermatitis-related parameters is (a) A decrease from baseline in the Investigator's Global Assessment (IGA) score of at least 2 points, specifically a decrease from baseline in the IGA score of at least 2 points that is eliminated or nearly eliminated; (b) a decrease from baseline in the Dermatological Life Quality Index (DLQI) of at least 30%, preferably at least 40%; (c) improvement from baseline in Patient Global Impression of Severity (PGIS) of at least 1 point; (d) improvement from baseline in Patient Global Impression of Clinical Outcome (PGIC) of at least a 1-point change; (e) at least a 50% reduction from baseline in Eczema Area and Severity Index (EASI) score; (f) proportion of responders with ≥50% improvement in EASI (EASI50); (g) proportion of responders with ≥75% improvement in EASI (EASI75); (h) proportion of responders with ≥90% improvement in EASI (EASI90); (i) the proportion of responders with ≥100% improvement in EASI (EASI100); (j) a reduction from baseline in the pruritus numerical rating scale (NRS) score of at least 3 points, preferably at least 4 points. 45. The method according to any one of claims 32 to 44, wherein the atopic dermatitis is moderate to severe atopic dermatitis. 46. ​​The method of claim 45, wherein the moderate to severe atopic dermatitis is characterized by (i) an Investigator's Global Assessment (IGA) score of 3 or 4, and / or (ii) an Eczema Area and Severity Index (EASI) score of at least 10, particularly at least 12. 47. A method according to any one of claims 32 to 46, wherein the atopic dermatitis is complicated by an infection, or the associated condition is an infection, particularly a skin infection, more particularly a skin superinfection. 48. The method according to claim 47, wherein the infection is (i) a bacterial infection, for example, a staphylococcus infection such as Staphylococcus (S.) aureus or a streptococcus infection such as Streptococcus (S.) epidermitis, and / or (ii) a viral infection, for example, a herpes virus infection. 49. The method according to any one of claims 32 to 48, wherein the subject has not responded adequately to treatment with a topical atopic dermatitis therapy. 50. The method according to any one of claims 32 to 49, wherein the subject has been refractory to or has not responded adequately to treatment with a topical atopic dermatitis therapy. 51. The method of claim 49 or 50, wherein said topical atopic dermatitis therapy is selected from the group consisting of topical steroids, e.g., corticosteroids, tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, apremilast, calcineurin inhibitors, e.g., topical calcineurin inhibitors, phosphodiesterase 4 (PDE4) inhibitors, e.g., topical PDE4 inhibitors, e.g., crisaborole, adrenocorticotropic hormone analogues. 52. The method according to claim 51, wherein the topical steroid is selected from the group consisting of Group I topical corticosteroids (TCS), Group II topical corticosteroids (TCS), and Group III topical corticosteroids (TCS). 53. The method according to claim 51, wherein the topical corticosteroid (TCS) is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate and hydrocortisone butyrate. 54. The method according to any one of the above 32 to 53, wherein the IL-18 antagonist is administered subcutaneously or intravenously to a subject in need thereof. 55. The method according to any one of claims 32 to 54, wherein the IL-18 antagonist is administered at a dose sufficient to achieve a therapeutically effective serum level. 56. The method according to claim 55, wherein the serum level is maintained during the course of treatment. 57. The method according to any one of claims 32 to 56, wherein the IL-18 antagonist is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every eight weeks, or once every twelve weeks, in particular once every four weeks. 58. The method according to any one of claims 32 to 57, wherein a second therapeutic agent is administered to the subject before, after, or simultaneously with the isolated antibody or antibody fragment according to claims 1 to 11. 59. The method of claim 58, wherein said second therapeutic agent is selected from the group consisting of steroids, cyclosporine, tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, apremilast, calcineurin inhibitors, e.g., topical calcineurin inhibitors, phosphodiesterase 4 (PDE4) inhibitors, e.g., topical PDE4 inhibitors, e.g., crisaborole, adrenocorticotropic hormone analogs, dupilumab, etanercept, adalimumab, infliximab, omalizumab, and secukinumab. 60. The method of claim 58, wherein the second therapeutic agent is a low to medium potency steroid, such as a topical or oral steroid, such as a corticosteroid. 61. The method described in claim 60, wherein the second therapeutic agent is selected from the group consisting of Group I topical corticosteroids (TCS), Group II topical corticosteroids (TCS), and Group III topical corticosteroids (TCS). 62. The method according to claim 60, wherein the topical corticosteroid (TCS) is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate and hydrocortisone butyrate. 63. Use of an IL-18 antagonist for the manufacture of a medicament for treating and / or preventing atopic dermatitis or related symptoms in a subject in need thereof. 64. Use of an IL-18 antagonist in the treatment and / or prevention of atopic dermatitis or related symptoms in a subject in need thereof. 65. The use according to claim 63 or 64, wherein the IL-18 antagonist specifically binds to IL-18 and does not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex. 66. The use according to any one of 63 to 65 above, wherein the IL-18 antagonist is an isolated antibody or antibody fragment. 67. The use according to any one of 63 to 66 above, wherein the IL-18 antagonist is a human, humanized or chimeric antibody or antibody fragment. 68. The use according to any of the above items 63 to 67, wherein the IL-18 antagonist binds to human IL-18 with a dissociation constant (KD) of 100 pM or less, e.g., 50 pM or less, 25 pM or less, 10 pM or less, 5 pM or less, preferably with a KD of 0.5 pM to 20 pM, particularly when measured by SET. 69. The use according to any one of 63 to 68 above, wherein the IL-18 antagonist inhibits the production of interferon gamma (IFN-γ) induced by IL-18 from KG-1 cells with an IC50 of less than 5 nM, for example 0.1 to 1 nM. 70. The use according to any one of 63 to 69 above, wherein the IL-18 antagonist inhibits the production of interferon gamma (IFN-γ) induced by IL-18 in whole blood with an IC50 of less than 150 nM, for example 5 to 10 nM. 71. The use according to any one of 63 to 70 above, wherein the IL-18 antagonist comprises a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3, a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9, a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5, a light chain variable region L-CDR1 comprising SEQ ID NO: 6, a light chain variable region L-CDR2 comprising SEQ ID NO: 7, and a light chain variable region L-CDR3 comprising SEQ ID NO: 8. 72. The use according to claim 71, wherein the IL-18 antagonist comprises a heavy chain variable domain comprising SEQ ID NO: 14 or a sequence at least 90% identical thereto, and a light chain variable domain comprising SEQ ID NO: 16 or a sequence at least 90% identical thereto. 73. The use according to claim 72, wherein said IL-18 antagonist comprises a mutation in the framework of said heavy chain, in which the asparagine at amino acid position 30 is replaced by a lysine (N30K; numbering according to Kabat). 74. The use according to any one of 71 to 73 above, wherein the IL-18 antagonist comprises a heavy chain comprising SEQ ID NO: 43 or a sequence at least 90% identical thereto, and a light chain comprising SEQ ID NO: 45 or a sequence at least 90% identical thereto. 75. The treatment results in an improvement in atopic dermatitis-related parameters, and the improvement in the atopic dermatitis-related parameters is (a) Reduction from baseline in investigator global assessment (IGA) score; (b) decrease from baseline in Dermatological Life Quality Index (DLQI); (c) reduction from baseline in Patient Global Impression of Severity (PGIS); (d) decrease from baseline in Patient Global Impression of Change (PGIC); (e) Reduction from baseline in Eczema Area and Severity Index (EASI) score; and (f) a decrease from baseline in the pruritus numerical rating scale (NRS) score. 76. The treatment results in an improvement in atopic dermatitis-related parameters, and the improvement in the atopic dermatitis-related parameters is (a) A decrease from baseline in the Investigator's Global Assessment (IGA) score of at least 2 points, specifically a decrease from baseline in the IGA score of at least 2 points that is eliminated or nearly eliminated; (b) a decrease from baseline in the Dermatological Life Quality Index (DLQI) of at least 30%, preferably at least 40%; (c) improvement from baseline in Patient Global Impression of Severity (PGIS) of at least 1 point; (d) improvement from baseline in Patient Global Impression of Clinical Outcome (PGIC) of at least a 1-point change; (e) at least a 50% reduction from baseline in Eczema Area and Severity Index (EASI) score; (f) proportion of responders with ≥50% improvement in EASI (EASI50); (g) proportion of responders with ≥75% improvement in EASI (EASI75); (h) proportion of responders with ≥90% improvement in EASI (EASI90); (i) the proportion of responders with ≥100% improvement in EASI (EASI100); (j) a reduction from baseline in the pruritus numerical rating scale (NRS) score of at least 3 points, preferably at least 4 points. 77. The use described in any one of 63 to 76 above, wherein the atopic dermatitis is moderate to severe atopic dermatitis. 78. The use according to claim 77, wherein the moderate to severe atopic dermatitis is characterized by (i) an Investigator's Global Assessment (IGA) score of 3 or 4, and / or (ii) an Eczema Area and Severity Index (EASI) score of at least 10, particularly at least 10. 79. The use according to any one of 63 to 78 above, wherein the atopic dermatitis is complicated by an infection or the associated condition is an infection, particularly a skin infection, more particularly a skin superinfection. 80. The use according to claim 79, wherein the infection is (i) a bacterial infection, for example a staphylococcus infection such as Staphylococcus (S.) aureus or a streptococcus infection such as Streptococcus (S.) epidermitis, and / or (ii) a viral infection, for example a herpes virus infection. 81. The use according to any one of 63 to 80 above, wherein the subject has not responded adequately to treatment with a topical atopic dermatitis therapy. 82. The use according to any one of 63 to 81 above, wherein the subject has been refractory to or has not responded adequately to treatment with a topical atopic dermatitis therapy. 83. The use according to claim 81 or 82, wherein said topical atopic dermatitis therapy is selected from the group consisting of topical steroids, e.g., corticosteroids, tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, apremilast, calcineurin inhibitors, e.g., topical calcineurin inhibitors, phosphodiesterase 4 (PDE4) inhibitors, e.g., topical PDE4 inhibitors, e.g., crisaborole, adrenocorticotropic hormone analogues. 84. The use according to claim 83, wherein the topical steroid is selected from the group consisting of Group I topical corticosteroids (TCS), Group II topical corticosteroids (TCS) and Group III topical corticosteroids (TCS). 85. The use according to claim 83, wherein the topical corticosteroid (TCS) is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate and hydrocortisone butyrate. 86. The use according to any one of 63 to 85 above, wherein the IL-18 antagonist is administered subcutaneously or intravenously to a subject in need thereof. 87. The use according to any one of 63 to 86 above, wherein the IL-18 antagonist is administered at a dose sufficient to achieve a therapeutically effective serum level. 88. The use according to claim 87, wherein the serum level is maintained during the course of treatment. 89. The use according to any one of the above items 63 to 88, wherein the IL-18 antagonist is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every eight weeks, or once every twelve weeks, in particular once every four weeks. 90. The use according to any one of 63 to 89 above, wherein a second therapeutic agent is administered to the subject before, after, or simultaneously with the isolated antibody or antibody fragment according to 1 to 11 above. 91. The use according to claim 90, wherein the second therapeutic agent is selected from the group consisting of steroids, cyclosporine, tacrolimus, cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil, apremilast, calcineurin inhibitors, e.g., topical calcineurin inhibitors, phosphodiesterase 4 (PDE4) inhibitors, e.g., topical PDE4 inhibitors, e.g., crisaborole, adrenocorticotropic hormone analogues, dupilumab, etanercept, adalimumab, infliximab, omalizumab, and secukinumab. 92. The use according to claim 90, wherein the second therapeutic agent is a low to medium potency steroid, such as a topical or oral steroid, such as a corticosteroid. 93. The use according to claim 90, wherein the second therapeutic agent is selected from the group consisting of Group I topical corticosteroids (TCS), Group II topical corticosteroids (TCS) and Group III topical corticosteroids (TCS). 94. The use according to claim 90, wherein the topical corticosteroid (TCS) is selected from the group consisting of methylprednisolone aceponate, mometasone furoate, fluticasone propionate, betamethasone valerate and hydrocortisone butyrate. [Example]

[0175] Example 1: Detection of IL-18 IL-18 levels were measured in ex vivo cultured skin (Fig. 1 ).

[0176] Samples: 4 mm lesional and non-lesional biopsies were obtained from 10 AD patients, cut into two or three sections, and cultured in 80 μl of medium for 24 hours. Skin was obtained from five healthy individuals undergoing abdominal surgery. 4 mm biopsies were taken, divided in half, and cultured in 80 μl of medium for 24 hours. Skin was cultured in IMDM medium (Gibco; Catalog No. #21056-023) + 10% KnockOut™ Serum Replacement (KO serum; Gibco; Catalog No. #10828010) + 1% penicillin-streptomycin (P / S; Gibco; Catalog No. #15140122) at 37°C and 5% CO2. The culture supernatants were then analyzed by a 10-spot U-PLEX assay (Meso Scale Discovery assay, Meso Scale Diagnostics, MSD) containing IL-18 (total IL-18) using a Sector Imager S600 Reader (MSD). The remaining samples were stored at -80°C and later used to detect IL-18 by ELISA (MBL International, catalog number #7620), which specifically detects active IL-18. For ELISA, samples were diluted 1:10 or 1:20. All measured concentrations were normalized to the weight of the corresponding biopsy section and expressed as "pg / mL per mg," as illustrated in Figures 1A and 1B.

[0177] Samples: 4 mm lesion biopsies from eight AD patients were cut into four sections, and each biopsy section was cultured in 100 μl of IMDM medium (Gibco; Catalog No. #21056-023) + 10% KnockOut™ Serum Replacement (KO serum; Gibco; Catalog No. #10828010) + 1% penicillin-streptomycin (P / S; Gibco; Catalog No. #15140122) at 37°C and 5% CO for 24 hours. Skin was obtained from seven healthy individuals (5 women, 2 men) who underwent abdominal or breast surgery. The 4 mm biopsies were divided in half, and each section was cultured for 24 hours (same conditions as the AD biopsies). Samples were stored at -80°C until active IL-18 was detected by ELISA (MBL International, Catalog No. #7620). All measured concentrations were normalized to the weight of the corresponding biopsy section and expressed as "pg / mL per mg," as illustrated in Figure 1C.

[0178] Results: IL-18 was found to be upregulated in lesion biopsies from AD patients ( Figure 1 ).

[0179] Example 2: Treatment of human AD biopsies with CMK389 Samples: 4 mm biopsies from 10 AD patients were cut into four sections and cultured for 24 hours in 100 μl of medium with or without CMK389 (final concentration 150 μg / mL). Skin was cultured in IMDM medium (Gibco; Catalog No. #21056-023) + 10% KnockOut™ Serum Replacement (KO serum; Gibco; Catalog No. #10828010) + 1% penicillin-streptomycin (P / S; Gibco; Catalog No. #15140122) at 37°C and 5% CO2. Skin was obtained from eight healthy volunteers undergoing abdominal surgery. 4 mm biopsies were divided in half and cultured for 24 hours in the same medium used for the AD biopsies. The supernatant was centrifuged at low speed to remove cells without disruption and stored at -80°C until analysis.

[0180] Olink (CD40, IL-24): One microliter of supernatant per sample from the above samples was analyzed using the Olink Proteomics Inflammation panel (92 samples; Catalog No. #95302) on a BioMark™ HD real-time PCR platform (Fluidigm). Quality control of Olink chip data was performed using a standard quality control pipeline (QC) in the Olink NPX Manager Software. Protein expression was normalized to the weight of each corresponding biopsy section and presented as "relative protein expression per mg." The remaining sample was stored at -80°C and later used for detection by MSD.

[0181] MSD (IL-22, CCL17 / TARC): Twenty-five microliters of supernatant from the above samples was analyzed using a 10-spot U-PLEX assay (Meso Scale Discovery assay, Meso Scale Diagnostics, MSD) containing IL-22 and TARC (CCL17) on a Sector Imager S600 Reader (MSD). Measured concentrations were normalized to the weight of the corresponding biopsy section and expressed as pg / mL per mg.

[0182] result: Figures 2A-B show the relative levels of soluble CD40 (per mg of biopsy) in the supernatants of untreated ex vivo cultured skin from healthy individuals and patients with atopic dermatitis (NL = non-lesional, L = lesional). Figure 2C shows the relative levels of soluble CD40 (per mg of biopsy) in the supernatants of ex vivo cultured skin from patients with atopic dermatitis in the absence (untreated) or presence of CMK389.

[0183] Figures 3A-B show the relative levels of IL-24 (per mg biopsy) in the supernatants of untreated ex vivo cultured skin from healthy individuals and patients with atopic dermatitis (NL = non-lesional, L = lesional). Figure 3C shows the relative levels of IL-24 (per mg biopsy) in the supernatants of ex vivo cultured skin from patients with atopic dermatitis in the absence (untreated) or presence of CMK389.

[0184] Figures 4A-B show the relative levels of TARC / CCL17 (per mg biopsy) in the supernatants of untreated ex vivo cultured skin from healthy individuals and patients with atopic dermatitis (NL = non-lesional, L = lesional). Figure 4C shows the relative levels of TARC / CCL17 (per mg biopsy) in the supernatants of ex vivo cultured skin from patients with atopic dermatitis in the absence (untreated) or presence of CMK389.

[0185] Figures 5A-B show the relative levels of IL-22 (per mg biopsy) in the supernatants of ex vivo cultured skin from healthy individuals and patients with atopic dermatitis (NL = non-lesional, L = lesional). Figure 5C shows the relative levels of IL-22 (per mg biopsy) in the supernatants of ex vivo cultured skin from patients with atopic dermatitis in the absence (untreated) or presence of CMK389.

[0186] Conclusion: The reduction of TARC, soluble CD40, IL-22, and IL-24 proteins by CMK389 in the culture supernatants of ex vivo cultured skin biopsies from patients with atopic dermatitis, all of which are associated with the pathophysiology and / or disease activity of AD, indicates that IL-18 antagonists, such as CMK389, may have therapeutic benefits in patients with atopic dermatitis.

[0187] Example 3: A randomized, subject- and investigator-blinded, placebo-controlled, multicenter study evaluating the efficacy and safety of CMK389 in patients with moderate to severe atopic dermatitis. A randomized, subject- and investigator-blinded, placebo-controlled, multicenter study was conducted to evaluate the efficacy and safety of CMK389 in patients with moderate to severe atopic dermatitis (AD).

[0188] Test Objective: To evaluate the efficacy of CMK389 in participants with moderate to severe AD, specifically by looking at the Investigator Global Assessment (IGA) response rate (defined as clear or almost clear, with at least a 2-point reduction from baseline) at week 16. To evaluate the safety and tolerability of CMK389 in participants with AD, specifically by looking at the number, severity, and frequency of adverse events over time.

[0189] The efficacy and clinical response of CMK389 in participants with moderate to severe AD will be investigated by looking at: · Investigator Global Assessment (IGA) score; Investigator Global Assessment (IGA) response rate at week 16 (defined as clear or almost clear, with at least a 2-point reduction from baseline); · Change and rate of change from baseline over time in the Dermatological Life Quality Index (DLQI); Patient Global Impression of Change over Time (PGI-c) and Patient Global Impression of Severity (PGI-s); · EASI (Eczema Area and Severity Index) score assessed over time as absolute change from baseline and percentage change; · EASI75 response rate (defined as a ≥75% reduction in EASI score from baseline); · EASI90 response rate (defined as a ≥90% reduction in EASI score from baseline); · Reduction in mean NRS (Numeric Rating Scale) pruritus over time; · IGA scores over time; Change and percentage change from baseline in pruritus using the Pruritus Numeric Rating Scale (NRS).

[0190] Study design: This study is a randomized, placebo-controlled, parallel-group, non-confirmatory, investigator- and participant-blinded trial in adult participants with moderate to severe AD. The study consists of a maximum 4-week screening period to assess participant eligibility, a baseline visit, four weekly doses of CMK389 within the first 12 weeks of a 16-week treatment period, and an approximately 10-week follow-up period, culminating with the end of study visit (EoS). During the 16-week treatment period, CMK389 or placebo will be administered intravenously (iv) or subcutaneously (sc) at monthly intervals (Figure 6).

[0191] Eligible participants with AD will be randomized (4:1:2:1 randomization) to one of the following four treatment arms: Arm 1: participants treated iv with CMK389; Arm 2: participants treated iv with placebo; Arm 3: participants treated sc with CMK389; Arm 4: Participants treated sc with placebo.

[0192] Efficacy over time will be measured by clinical scores such as the IGA, as well as EASI and pruritus (as a numeric rating scale, or NRS). Quality of life will be measured by patient-reported outcomes (PROs) such as the Dermatology Life Quality Index (DLQI). Safety will be followed throughout the study by physical examinations, vital signs, ECG recordings, adverse events, and laboratory monitoring.

[0193] Study population: The study population consists of adult female and male participants with moderate to severe AD.

[0194] Key inclusion criteria: Adult male or female participants aged 18-65 years with chronic AD, present for at least 1 year prior to screening, according to the American Academy of Dermatology Consensus Criteria (Eichenfield et al., J. Am. Acad. Dermatol., 2014, p. 338-51). Moderate to severe AD, defined as: o Investigator's Global Assessment (IGA) score ≥ 3 at baseline (or screening if baseline is omitted) (on a scale of 0-4, with 3 being moderate and 4 being severe). Eczema Area and Severity Index (EASI) score ≥ 12 at baseline (or screening if baseline is omitted). o Pruritus Numeric Rating Scale (NRS) of at least ≥ 3 at baseline (or screening if baseline is omitted). Participants who are candidates for systemic treatment, as assessed by the investigator, defined as, for example, not responding adequately to topical treatment or where topical treatment is otherwise not medically advisable (e.g., patients with large affected body surface areas due to significant side effects or safety risks). Participants must be between 18 and 35 kg / m at screening. 2 Your body mass index (BMI) must be within the range of BMI = weight (kg) / [height (m)]. 2

[0195] Efficacy evaluation The severity of AD will be measured by clinical outcome measures (COA) such as Investigator's Global Assessment (IGA); Eczema Area and Severity Index (EASI); Pruritus NRS (Numerical Rating Scale); and patient-reported outcomes (PRO) such as DLQI (Dermatological Life Quality Index); Patient Global Impression of Severity (PGI-s) and PGI-c (Patient Global Impression of Change). The primary endpoint is the IGA response rate at 16 weeks.

[0196] In addition to clinical parameters, biomarkers are collected in the circulation and on the skin.

[0197] IGA The IGA scale used in this study was the vIGA-AD™ (Validated Investigator Global Assessment scale for Atopic Dermatitis). The IGA scale was used to assess the severity of AD symptoms and clinical response to treatment. This scale reflects the participant's overall overall severity on a 5-point scale, including clear, almost clear, mild, moderate, and severe (Table 2). An IGA response rate was defined as a reduction of at least 2 points from baseline and clear or almost clear after 16 weeks.

[0198] [Table 5]

[0199] EASI The EASI is used to assess the extent and severity of AD (Hanifin et al., Exp. Dermatol., 2001, p. 11-8). Each body region (head / neck [H], upper limbs [UL], trunk [T], and lower limbs [LL]) is assessed for: Severity of AD: The average severity of the following cardinal signs of AD (erythema, induration / papules, excoriation, and lichenification) is assigned a score of 0, 1, 2, or 3, representing absent (0), mild (1), moderate (2), and severe (3), respectively. Extent of AD: Based on the extent of AD in a particular body part (when each body part is considered as 100% overall), an area score is assigned to that body part.

[0200] Points to note: Only inflamed areas should be included in the evaluation, not changes due to dry skin or post-inflammatory hyperpigmentation. The neck is evaluated as part of the head region. The axillae and groin are evaluated as part of the trunk. The buttocks are evaluated as part of the lower extremity.

[0201] Calculation of BSA (total body surface area affected by AD): Multiply the percentage of each body part affected by AD by the corresponding coefficient for that body part (0.1 for head, 0.3 for trunk, 0.2 for upper limbs, and 0.4 for lower limbs): Total BSA affected by AD = (0.1 × neck area%) + (0.2 × upper limb area%) + (0.3 × trunk area%) + (0.4 × lower limb area%).

[0202] Pruritus NRS Participants were asked, "How would you rate the worst moment of itching in the last 24 hours?" Participants responded by rating on an 11-point Numerical Rating Scale (NRS) ranging from a low of 0 (no itching) to a high of 10 (worst itching imaginable).

[0203] DLQI The DLQI, or Dermatological Life Quality Index, is a 10-item general dermatological disability index designed to assess the health-related quality of life (HRQoL) of adult participants with skin conditions such as eczema. It is the most frequently used instrument in randomized controlled trials in dermatology (Finlay and Khan, Clin. Exp. Dermatol., 1994, pp. 210–216). This measure includes domains consisting of daily activities, leisure time, relationships, symptoms and emotions, treatment, and work / school. Each item has four response categories ranging from 0 (not at all) to 3 (very much). "Not applicable" is a valid response and is scored as 0. The DLQI total score is the sum of the 10 questions. Scores range from 0 to 30, with higher scores indicating worse HRQoL.

[0204] PGI-s The PGI-s assesses the severity of current eczema symptoms: "How would you rate your current eczema symptoms?": 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.

[0205] PGI-c The PGI-c assesses current eczema symptoms compared to the start of the study at visits specified in the assessment schedule: "How would you rate your current eczema symptoms compared to when you started this study?": 1 = very bad, 2 = moderately bad, 3 = slightly worse, 4 = about the same, 5 = slightly better, 6 = moderately better, 7 = very good.

[0206] [Table 6]

[0207] [Table 7]

[0208] [Table 8]

[0209] [Table 9]

[0210] [Table 10]

[0211] [Table 11]

[0212] [Table 12]

Claims

1. 1. A composition for the treatment and / or prevention of atopic dermatitis in a subject in need thereof, said composition comprising an isolated human IL-18 antibody comprising a heavy chain comprising SEQ ID NO: 43, or a sequence at least 90% identical thereto, and a light chain comprising SEQ ID NO: 45, or a sequence at least 90% identical thereto.

2. The composition of claim 1, wherein the IL-18 antibody specifically binds to IL-18 and does not bind to the IL-18 / IL-18 binding protein (IL-18 BP) complex.

3. The IL-18 antibody a) binds to human IL-18 with a dissociation constant (KD) of 100 pM or less, e.g., 50 pM or less, 25 pM or less, 10 pM or less, 5 pM or less, preferably a KD of 0.5 pM to 20 pM, particularly as measured by solution equilibrium titration (SET); b) inhibiting IL-18-induced interferon gamma (IFN-γ) production from KG-1 cells with an IC50 of less than 5 nM, e.g., 0.1-1 nM; and / or c) inhibiting IL-18-induced interferon gamma (IFN-γ) production in whole blood with an IC50 of less than 150 nM, e.g., 5-10 nM; The composition according to any one of claims 1 to 2.

4. 4. The composition of claim 3, wherein the IL-18 antibody comprises a mutation in the framework of the heavy chain, wherein the mutation is N30K, in which the asparagine at amino acid position 30 according to the Kabat numbering is replaced with a lysine.

5. wherein the treatment results in an improvement in an atopic dermatitis-associated parameter, and the improvement in the atopic dermatitis-associated parameter is (a) a reduction from baseline in Investigator Global Assessment (IGA) score; (b) decrease from baseline in Dermatological Life Quality Index (DLQI); (c) reduction from baseline in Patient Global Impression of Severity (PGIS); (d) reduction from baseline in Patient Global Impression of Change (PGIC); (e) a reduction from baseline in Eczema Area and Severity Index (EASI) score; and (f) a decrease from baseline in pruritus numerical rating scale (NRS) score.

6. The composition according to any one of claims 1 to 5, wherein the atopic dermatitis is moderate to severe atopic dermatitis.

7. The composition according to any one of claims 1 to 6, wherein the atopic dermatitis is complicated by an infection, particularly a skin infection, more particularly a skin co-infection.

8. 8. The composition of any one of claims 1 to 7, wherein the subject has been refractory to or has not responded adequately to treatment with a topical atopic dermatitis therapy.

9. The composition of any one of claims 1 to 8, wherein the IL-18 antibody is administered subcutaneously or intravenously to a subject in need thereof.

10. The composition of any one of claims 1 to 9, wherein the IL-18 antibody is administered at a dose sufficient to achieve therapeutically effective serum levels.

11. The composition of claim 10, wherein the serum levels are maintained during the course of treatment.

12. 12. The composition of any one of claims 1 to 11, wherein the IL-18 antibody is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every eight weeks, or once every twelve weeks, particularly once every four weeks.

13. A composition described in any one of claims 1 to 12, further comprising a second therapeutic agent, wherein the second therapeutic agent is administered to the subject before, after, or simultaneously with the IL-18 antibody.

14. A composition described in any one of claims 1 to 13, wherein the IL-18 antibody comprises a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3, a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9, a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5, a light chain variable region L-CDR1 comprising SEQ ID NO: 6, a light chain variable region L-CDR2 comprising SEQ ID NO: 7, and a light chain variable region L-CDR3 comprising SEQ ID NO: 8.

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