Anti-il-18 antibody therapy for treating atopic dermatitis

Abstract

The invention relates to interleukin 18 (IL-18) antibody therapy, and to low dosage formulations of an anti-IL-18 neutralizing antibody, and their use in treating IL-18-associated diseases via sub-cutaneous delivery. The invention further relates to the use of the low dose formulations of the anti-IL-18 neutralizing antibody for treating Still's diseases, such as adult-onset Still's disease (AOSD) or the juvenile-onset form know as systemic-onset juvenile idiopathic arthritis (SoJIA)), atopic eczema or atopic dermatitis (AD), inflammatory bowel disease, such as ulcerative colitis (UC) and Crohn's disease (CD), and eosinophilic esophagitis (EoE).

Description

[0001] ANTI-IL-18 ANTIBODY THERAPY FOR TREATING ATOPIC DERMATITIS

[0002] The present invention relates to interleukin 18 (IL-18) antibody therapy, and in particular, to low dosage formulations of an anti-IL-18 neutralizing antibody, and their use in treating IL-18-associated diseases via sub-cutaneous delivery. The invention further relates to the use of the low dose formulations of the anti-IL-18 neutralizing antibody for treating Still's diseases, such as adult-onset Still's disease (AOSD) or the juvenile-onset form know as systemic-onset juvenile idiopathic arthritis (SoJIA)), atopic eczema or atopic dermatitis (AD), inflammatory bowel disease, such as ulcerative colitis (UC) and Crohn's disease (CD), and eosinophilic esophagitis (EoE).

[0003] Interleukin-18 (IL-18) is a pro- inflammatory cytokine that is produced by immune cells to activate the immune system in response to the detection of a pathogen. In a healthy individual, IL-18 levels return to normal after the pathogen has been removed by the immune system. However, elevated IL-18 levels strongly correlate with active disease in patients with Still's diseases (AOSD and SoJIA). In healthy individuals, total serum levels of IL-18 are normally in the range of 100-400 pg / ml. In patients with Still's disease this can be elevated to greater than 500,000 pg / ml. In a study by Kudela et al., IL-18 levels above 1,000 pg / ml were shown to be associated with active disease, with an average of 20,000 pg / ml. Girard et al. studied IL-18 levels in a cohort of 37 AOSD patients and demonstrated that 68% had IL-18 levels that were elevated above normal controls. Similarly, in a study by Weiss et al., a cohort of 29 patients with SoJIA were examined and 79% were shown to have IL-18 levels above 1,000 pg / ml. It is believed that these high levels of IL-18 are a key component in driving disease pathogenesis.

[0004] Adult-onset Still's disease is an inflammatory disorder characterized by daily fevers, arthritis, and an evanescent rash. It was first described in children by George Still in 1897, but later described in adult patients who had features similar to children with systemic juvenile idiopathic arthritis and did not fulfill criteria for classic rheumatoid arthritis. (Bywaters, EG, Ann Rheum Dis. 30(2), 121-133 (1971)). Adult-onset Still's disease is a rare disease. A retrospective French study estimated the annual incidence of AOSD to be 0.16 cases per 100,000 people, with an equal distribution between the sexes. (Magadur-Joly G, et al., Ann Rheum Dis. 54(7): 587 (1995)). It is estimated that there are approximately 3,500 to 7,000 AOSD patients in the United States. (Gerfaud-Valentin M, et al., Medicine (Baltimore) 93(2) :91 (2014)). There is a bimodal age distribution, with one peak between the ages of 15 and 25 years and the second between the ages of 36 and 46 years. (Magadur-Joly G, et al., Ann Rheum Dis. 54(7): 587 (1995)). However, patients older than 70 years have also been reported. (Steffe LA & Cooke CL, JAMA 249(15): 2062 (1983)).

[0005] Treatment is tailored to disease stage, symptoms and presence of end organ damage, and the minimization of corticosteroid adverse effects. Initial therapy is usually with non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. Refractory patients are treated with immunosuppressive agents including methotrexate. Patients who remain refractory may be treated empirically with biologic agents including anti-TNF antibodies (adalimumab), anakinra (anti-IL-1), canakinumab (anti-IL-1) or tocilizumab (anti-IL-6). Patients must be carefully monitored for the development of macrophage activation syndrome (MAS). While many patients may derive at least partial benefit from this approach, others remain refractory or partially refractory. (Jamilloux, Y., et al., Therapeutics and Clinical Risk Management (2014)). Thus, there is a need for new targeted therapies.

[0006] The clinical course of AOSD can be divided into three main patterns: monophasic (or monocyclic), intermittent, and chronic, with approximately one-third of patients falling into each category. (Kontzias, A. & Efthimiou, P., Drugs 68(3): 319 (2008); Gerfaud-Valentin M, et al., Medicine (Baltimore) 93(2) :91 (2014)). Patients with monophasic or intermittent disease frequently progress to the chronic articular pattern. (Kontzias, A. & Efthimiou, P., Drugs 68(3):319 (2008); Gerfaud-Valentin M, et al., Medicine (Baltimore) 93(2):91 (2014); Fautrel, B., Best Pract. Res. Clin. Rheumatol. 22(5): 773 (2008)).

[0007] Most active AOSD patients have fever, evanescent rash, arthralgias and arthritis. The most commonly involved joints are the knees, wrists, ankles, elbows, proximal interphalangeal joints, and shoulders. (Elkon, KB, et al., Arthritis Rheum. 25(6):647 (1982)). Many patients also have myalgia (Pouchot, J, et al., Medicine (Baltimore)

[0008] 70(2): 118 (1991)), pharyngitis (Nguyen, KH 8<. Weisman MH, J Rheumatol.

[0009] 24(3): 592 (1997)), and liver disease (Gerfaud-Valentin, M, et al., Autoimmun Rev. Jul;13(7):708-722 (2014)). Fulminant hepatic failure has also been reported in AOSD. (Dino, O, et al., J Rheumatol. 23(4):784-785 (1996)). Cardiopulmonary disease (Gerfaud-Valentin, M, et al., Autoimmun Rev. Jul; 13(7): 708-722 (2014); Cheema, GS & Quismorio, FP Jr. Curr Opin Pulm Med. 5(5):305 (1999)), lymphadenopathy (Gerfaud-Valentin, M, et al., Autoimmun Rev. Jul;13(7):708-722 (2014)), and splenomegaly (Gerfaud-Valentin, M, et al., Autoimmun Rev.

[0010] Jul;13(7):708-722 (2014)) can also be present.

[0011] Adult-onset Still's disease can be complicated by macrophage activation syndrome (MAS), which is also referred to as hemophagocytic lymphohistiocytosis (HLH) in 12% to 19% of patients. (Arlet, JB, et al., Ann Rheum Dis. 65(12): 1596. (2006); Bae, CB, et al., Medicine (Baltimore) 94(4):e451 (2015); Hot, A, et al., Medicine (Baltimore) 89(1): 37 (2010)). Other hematological disorders that can be associated with AOSD include microangiopathic hemolytic anemia associated with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. (Diamond, JR, G. J

[0012] Nephrol. 10(5):253 (1997); Perez, MG & Rodwig, FR Jr., South Med J. 96(1):46 (2003); Arlet, JB, et al., Ann Rheum Dis. 65(12) : 1596. (2006)). Abdominal pain may occur in up to half of patients with AOSD (Gerfaud-Valentin, M, et al., Autoimmun Rev. Jul; 13(7): 708-722 (2014)) and symptoms may be related to lymphadenitis, aseptic peritonitis, or acute pancreatitis (Fautrel, B., Best Pract Res

[0013] Clin Rheumatol. 22(5): 773 (2008)).

[0014] Adult-onset Still's disease is diagnosed if > 5 diagnostic criteria are present with >

[0015] 2 being major criteria and no exclusion criteria. (Jamilloux, Y, et al., Therapeutics and Clinical Risk Management Dec. (2014)). The major diagnostic criteria are: fever

[0016] > 39°C lasting > 2 weeks; arthralgia or arthritis lasting > 2 weeks; typical nonpruritic salmon-colored rush; leukocytosis >10,000 / mm3; and granulocytes >80%. (Jamilloux, Y, et al., Therapeutics and Clinical Risk Management Dec. (2014)). The minor diagnostic criteria are: sore throat; lymphadenopathy; splenomegaly; abnormal liver function tests; and negative tests for antinuclear Camoteskimab and rheumatoid factor. (Jamilloux, Y, et al., Therapeutics and Clinical Risk Management Dec. (2014)). The exclusion criteria are: infection; malignancy; and other rheumatic disease (vasculitis). (Jamilloux, Y, et al., Therapeutics and Clinical Risk Management Dec. (2014)).

[0017] Some of the treatment goals of AOSD are: control of the physical signs and symptoms of inflammation (fever, rash, morning stiffness, joint pain, and swelling); control of laboratory indices of inflammation; prevention of end organ damage, including joint injury and other major organ complications; and minimization of the risk of adverse effects of therapy, including short and long-term adverse effects of glucocorticoids. IL-18 is a pro-inflammatory cytokine that plays a role in both innate and acquired immune responses. In many patients with AOSD, IL-18 is markedly elevated. Concentrations of IL-18 have been found to be > 100,000 pg / ml in active AOSD and correlate with disease severity. (Kudela, H, et al., BMC Rheum 3:4 (2019)). The elevation appears to be more specific for AOSD than for other systemic rheumatic diseases (Kawashima, M, et al., Arthritis Rheum. 44(3): 550 (2001); Kudela, H., et al., BMC Rheum 3:4 (2019)). A 12-week study of 23 AOSD patients treated with tadekinig alfa (an IL-18 binding protein [IL-18 BP]) showed moderate efficacy in approximately half of the patients treated, suggesting that targeting IL- 18 in AOSD may be an effective treatment strategy (Gabay, C, et al. Ann Rheum

[0018] Dis. Jun;77(6):840-847 (2018)).

[0019] Systemic-onset juvenile idiopathic arthritis (SoJIA) is similar to AOSD, but differs in terms of classification criteria. (Silva, JR, and Brito, I, Acta Reumatol Port. 45(2): 150-151. (2020)). It has been argued that SoJIA and AOSD are the same disease, just happening in different age groups. (Silva, JR, and Brito, I, Acta Reumatol Port. 45(2): 150-151. (2020)). SoJIA is a subset of juvenile idiopathic arthritis marked by more severe extra-articular manifestations (fever, cutaneous eruptions). See NIH Genetic and Rare Diseases Information Center, Systemic onset juvenile idiopathic arthritis available at https: / / rarediseases.info.nih.gov / diseases / 10966 / systemic-onset-juvenile- idiopathic-arthritis) (last accessed on December 14, 2021). It represents 10-11% of cases of juvenile idiopathic arthritis. Id. Onset usually occurs between 3 and 5 years of age. Id.

[0020] The clinical signs include fever with oscillating temperatures over a 24-hour period and peaks of over 39°C or more, which are associated with transient cutaneous eruptions and diffuse erythematosus or urticarial-like lesions. Id. Another symptom is arthritis. Id. The number of sites of the body affected by the arthritis vary but affect both the small and large joints in a nearly symmetrical manner. Id. Some patients may also have adenopathy and / or hepatosplenomegaly. Id. Other symptoms such as pericarditis, pleural effusion, or serous peritonitis with abdominal pain may be present. Id. SoJIA patients typically have severe inflammatory disease with a large increase in ferritin levels and a decrease in the percentage of glycosylated ferritin. Id. Physicians often use a "clinical triad" to diagnose this disease: daily fever lasting more than 2 weeks, arthritis, and cutaneous eruptions. See Petty, R et al., J. Rheumatol. 31(2) 390-392 (2004). If the patient does not have cutaneous eruptions, the presence of an adenopathy, hepatosplenomegaly, or serous effusion can also confirm the diagnosis.

[0021] Atopic eczema or atopic dermatitis (AD) is a chronic inflammatory skin disorder with an estimated prevalence in adults of between 2.1% and 4.9% across North America, Europe and Japan (Barbarot 2018). The primary pathogenesis of AD includes the skin barrier defect and immune dysregulation, especially innate and Th2 immune response. Until recently, the treatment of moderate-to-severe AD relied on potent corticosteroids and systemic immunosuppressants, which can produce significant undesirable side effects (Newsom 2020). As moderate-to-severe AD can lead to poor quality of life, the development of targeted, well-tolerated immunomodulators remains important.

[0022] Studies of total serum levels of IL-18 in patients with moderate to severe AD have shown that these are elevated compared with healthy control subjects (Trzeciak 2011; Zedan 2015). Increased serum levels of IL-18 have been shown to correlate with disease severity, using the SCORing Atopic Dermatitis (SCORAD) tool (Trzeciak 2011; Zedan 2015). Of note, IL-18 levels appear to be elevated to more pathogenic levels in the affected skin cells of AD patients (Inoue 2011) and again correlate with disease severity. Furthermore, Mendelian Randomization studies have generated data that supports a causal role for IL-18 in atopic dermatitis (McGowan 2019).

[0023] Inflammatory bowel disease (IBD) is a complex and debilitating disorder that can be sub-classified into the distinct multifactorial disorders Crohn's disease (CD) and ulcerative colitis (UC) (Kaser 2010). While both are characterized by chronic relapsing pathogenic inflammation and intestinal epithelial cell injury, they differ in their clinical manifestations. CD patients exhibit discontinuous lesions throughout the entirety of the intestinal tract and disease pathology is closely associated with a dysregulation of the antimicrobial peptide (AMP) response (Fellermann 2003). In UC patients, defining feature of human pathology is major depletion of mucinproducing goblet cells and the mucus layer, which correlates with increased microbiota-induced colonic inflammation and disease pathology (McCormick 1990). Although a number of treatment options targeting specific pro-inflammatory cytokines have been approved for the treatment of CD and UC, a significant proportion of patients fail to respond to therapy and there remains a large unmet need. In an animal model of colitis, IL-18 was shown to be critical in driving the pathologic breakdown of barrier integrity (Nowarski 2015). Deletion of IL-18 in intestinal epithelial cells in this model conferred protection from colitis and mucosal damage in mice. Conversely, deletion of the IL-18 negative regulator (IL-18bp) resulted in severe colitis associated with loss of mature goblet cells, implicating a pathogenic role for free unbound IL-18.

[0024] In addition to animal model data, IL-18 has been assessed in patients with UC (Wiercinska-Drapalo 2005). Serum levels of IL-18 were shown to be elevated in patients with UC and correlated with severity of disease. Furthermore, mutations in the NLRC4 inflammasome, which lead to increases in IL-18 levels, have been shown increase the risk of developing UC (Steiner 2022).

[0025] The role of IL-18 has also been examined in CD. IL-18 expression was shown to be increased in inflamed intestinal sections taken from patients with Crohn's Disease, compared to non-affected intestinal sections (Pizarro 1999).

[0026] Further evidence of a role for IL-18 in IBD comes from genetic analyses. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation

[0027] Studies using this technique have identified that an increase in IL18 was associated with an increase in IBD susceptibility (Mokry 2019; McGowan 2019).

[0028] Eosinophilic esophagitis (EoE) is a chronic immune mediated inflammatory condition of the esophagus with an incidence of approximately 5-10 cases per 100,000 per year (Muir and Falk 2021). It is characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophilic infiltration of the esophageal epithelium and belongs to the spectrum of eosinophilic gastrointestinal disorders whereby eosinophilic inflammation of the gastrointestinal tract occurs in the absence of secondary causes (Reed and Dellon 2019).

[0029] Biologically there is a mechanistic overlap with atopic dermatitis, where a clear pathogenic role for IL-18 exists. Indeed, atopy is commonly encountered in EoE cohorts, and for adult EoE patients, the prevalence of any atopic condition is 20- 80% (Dellon 2014). The potential involvement of IL-18 has been further demonstrated in animal studies. Induction of IL-18 was shown to promote EoE in a mouse model, whereas mice in which the gene for IL-18 had been knocked out were protected from the disease (Dutt 2015). In a separate study, inhibitors of caspase-1 or NLRP3 that prevent the maturation and release of active IL-18 were shown to protect from pathogen-induced EoE in a mouse model of disease (Yadavalli 2023).

[0030] In patients with EoE, IL-18 has been shown to be upregulated in serum and tissue of EoE patients (Niranjan 2015). In addition, IL-18 has been shown to be required for the differentiation, maturation, activation and transformation of naive eosinophils to pathogenic eosinophils that are believed to drive pathology of the disease (Venkateshaiah 2018).

[0031] The pro-inflammatory effects of IL-18 are controlled by the presence of the IL- 18- binding protein (IL-18BP) which binds to IL-18 with high affinity and inhibits its function. In this way, the pro-inflammatory IL-18 signal can be switched off. In the AD disease setting, it is hypothesized that the level of IL- 18 is too great for the IL- 18BP to control, resulting in an abnormal concentration of "free IL-18" which is available to drive a pro-inflammatory signal.

[0032] The inventors conducted their research into the anti-IL-18 antibody known as camoteskimab (previously known as AVTX-007; CERC-007; AEVI-007; MEDI2338), which is extensively described in WO 2012 / 085015. Camoteskimab binds to IL-18 at the same epitope as the IL-18BP. This means that camoteskimab will only target the "free IL-18", which is driving the disease. The inventors of the present invention believe that lower doses of camoteskimab can be therapeutically effective because camoteskimab will only target the active pool of "free IL- 18".

[0033] Similarly in Still's disease, the level of IL-18 is too great for the IL-18BP to control, resulting in a large concentration of "free IL-18" which is available to drive a pro- inflammatory signal. Accordingly, for a therapeutic agent to be effective, it is the pathogenic levels of free IL-18, which should be targeted, rather than IL-18BP- bound IL-18, or IL-18 bound to its corresponding receptor.

[0034] The majority of therapeutic antibodies used to treat disease are usually administered through intravenous injection (IV). However, some therapeutic antibodies are formulated for subcutaneous administration (SC). SC delivery presents several advantages over standard IV delivery. These include reduced administration time, decreased patient discomfort, reduced drug wastage, and potentially fewer medication errors due to fixed dosing. Additionally, SC administration is easier to access and maintain compared to IV placement. A single site of SC injection may be used for 7 days or more, and patients are free of the burden of IV pumps, allowing for greater mobility. Furthermore, SC injections are typically associated with a lower risk of systemic infection than that of IV infection.

[0035] However, SC injections are mostly suitable for the delivery of lower dosages (i.e., less than 4 mg / kg). Typically, therapeutic antibodies administered via a SC injection are generally formulated to a concentration of 100-200mg / ml with the aim of delivering a total volume per dose of 1-1.5 ml. These low dosages are typically associated with reduced efficacy of the antibody. Therefore, there is a need to provide a low dosage formulation of an anti-IL-18 antibody for treating IL- 18- associated diseases, including Still's diseases, atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and eosinophilic esophagitis (EoE).

[0036] The inventors have constructed a population pharmacokinetics (PK) model using camoteskimab's plasma concentrations and PK data derived from two completed clinical studies in adults (NCT01322594 and NCT04671251). In these clinical studies, the half-life of camoteskimab supports a dosage regimen of every 4 weeks (Q4W). The PK model was then used to simulate low dosage regimens on a Q4W schedule.

[0037] Unexpectedly, the results of the PK model simulations revealed that low doses (i.e. <4mg / kg) of camoteskimab are suitable for sub-cutaneous administration.

[0038] In addition, the PK model was also used to estimate the level of IL-18 engagement using low doses and / or longer treatment intervals. Currently approved biologic treatments for atopic dermatitis often need to use short treatment intervals, such as every week (Q1W) or every 2weeks (Q2W) to achieve an optimal clinical response. Conversely, the inventors have simulated low doses (up to 4 mg / kg) on a Q12W schedule (every 12 weeks).

[0039] Surprisingly, the results of these simulations have shown that not only low doses of camoteskimab, but also longer and more convenient dosing intervals, achieve IL-18 blockade that translates into meaningful clinical efficacy. Therefore, in a first aspect of the invention, there is provided an anti-IL-18 antibody or an antigen-binding fragment thereof, for use in treating, preventing or ameliorating adult-onset Still's disease (AOSD), systemic-onset juvenile idiopathic arthritis (SoJIA), atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE) in a subject, wherein the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 0.1 < 4mg / kg.

[0040] In a second aspect, there is provided a method of treating, preventing or ameliorating adult-onset Still's disease (AOSD), systemic-onset juvenile idiopathic arthritis (SoJIA), atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE), the method comprising subcutaneously administering to a subject in need of such treatment, a therapeutically active dose of 0.1 < 4mg / kg of an anti-IL-18 antibody or antigen-binding fragment thereof.

[0041] The inventors have surprisingly found that the low dose of the anti-IL-18 antibody or an antigen-binding fragment thereof (typically, camoteskimab) of only 0.1 < 4mg / kg is sufficient to bind to free IL- 18 in the subject (as opposed to receptor bound IL-18 and IL-18 bound to IL-18BP) at levels expected to be of therapeutic potential. For example, Figure 4 shows the lowest steady-state plasma levels of one embodiment of the anti-IL-18 antibody or antigen-binding fragment thereof (e.g. camoteskimab) that are achieved with exemplary low doses of 0.25 mg / kg, 1 mg / kg and 2 mg / kg. The mean levels of the anti-IL-18 antibody or antigen-binding fragment thereof for the 0.25, 1 and 2 mg / kg doses are surprisingly sufficient to neutralise 320,000 pg / ml, 1,300,000 pg / ml and 2,500,000 pg / ml of "free IL-18", respectively. According to the literature, levels of "free IL-18" are well below these concentrations in patients with Still's disease (adult or juvenile), atopic dermatitis, ulcerative colitis (UC), Crohn's disease (CD) and eosinophilic esophagitis (EoE). These PK simulations therefore demonstrate that low doses of camoteskimab are surprisingly suitable for SC administration. This is in part due to the unique way that camoteskimab binds to IL-18, meaning that it will only neutralise "free IL-18" and therefore targets the active pathogenic pool of IL-18.

[0042] Using the PK model further to estimate the level of IL-18 engagement using low doses and / or longer treatment intervals, the inventors were able to show that low doses of 30 mg, 100 mg and 300 mg (equivalent to 0.4 mg / kg, 1.4 mg / kg, and 4 mg / kg respectively) of camoteskimab on a Q12W schedule (every 12 weeks) achieved greater than 90% neutralisation of IL-18. Conversely, currently approved biologic treatments for atopic dermatitis often need to use short treatment intervals, such as every week (Q1W) or every 2weeks (Q2W) to achieve an optimal clinical response.

[0043] Advantageously, low doses of 0.1 to 4mg / kg of the anti-IL-18 antibody or an antigen-binding fragment thereof, coupled with longer and more convenient dosing intervals achieves IL-18 blockade that translates into meaningful clinical efficacy. Advantageously, the low dose of only 0.1 < 4mg / kg enables sub-cutaneous administration of the anti-IL-18 antibody or an antigen-binding fragment thereof resulting in reduced administration time, decreased patient discomfort, reduced drug wastage, and fewer medication errors due to fixed dosing. Moreover, subcutaneous administration is much easier to access and maintain compared to IV placement.

[0044] The anti-IL-18 antibody of the invention useful for the therapeutic purposes recited above may comprise the CDR sequences or heavy and light chain variable regions of the antibodies disclosed in WO 2012 / 085015. These include antibodies of Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Antibody 12_GL of WO 2012 / 085015.

[0045] Advantageously, the anti-IL-18 antibody of the invention binds to IL-18 at the same epitope used by the IL-18BP. Therefore, when administered to a patient, camoteskimab will only bind to and neutralise the "free IL-18", thus preventing the continued pro-inflammatory signal.

[0046] Thus, preferably the anti-IL-18 antibody or antigen-binding fragment thereof specifically binds to free IL-18, and preferably not to IL-18 when bound to its corresponding receptor or the IL-18 binding protein (IL-18bp).

[0047] Antibody 12_GL, also known as camoteskimab (previously known as AVTX-007; CERC-007; AEVI-007; MEDI2338) is extensively described in WO 2012 / 085015. Camoteskimab is a fully human IgGlK monoclonal antibody (mAb) binding and neutralizing IL-18. Camoteskimab inhibits the formation of IL-18 / Ro / RP active complex in-vitro and in-vivo. Camoteskimab demonstrates high affinity of 63 pM, - ii - which is 6 fold higher compared to IL-18's native inhibitor (IL-18 binding protein), and reduced Fc binding, to enable efficient anti-inflammatory role. As a fully human antibody, Camoteskimab is expected to demonstrate reduced anti-drug antibodies (ADA). Camoteskimab demonstrates IL-18 neutralization and bioactivity by reducing IL-18's effects in various in vitro models with IC50 of sub nanomolar, and has proven efficient in COPD model (NHBE cells infected with Human Rhinovirus (HRV) by inhibiting IFN-y release from PBMCs exposed to infected NHBE media). Camoteskimab has undergone 13 weeks IV toxicity studies complete with no toxicity up to 100 mg / kg / week.

[0048] Camoteskimab comprises (a) a HCDR1 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 122; (b) a HCDR2 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 123; (c) a HCDR3 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 124; (d) a LCDR1 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 126; (e) a LCDR2 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 127; and (f) a LCDR3 having an amino acid sequence identical to or comprising the amino acids of SEQ ID NO: 128.

[0049] Camoteskimab comprises VH domain (SEQ ID NO: 121) which may be paired with the Camoteskimab VL domain (SEQ ID NO: 125), so that an Camoteskimab antigen-binding site is formed comprising both the Camoteskimab VH and VL domains.

[0050] Therefore, in one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises Camoteskimab. Thus, in a most preferred embodiment, the anti- IL-18 antibody or antigen-binding fragment thereof comprises the following six CDRs: (a) a heavy chain CDR having an amino acid sequence of SEQ ID NO: 122;

[0051] (b) a heavy chain CDR having an amino acid sequence of SEQ ID NO: 123;

[0052] (c) a heavy chain CDR having an amino acid sequence of SEQ ID NO: 124;

[0053] (d) a light chain CDR having an amino acid sequence of SEQ ID NO: 126;

[0054] (e) a light chain CDR having an amino acid sequence of SEQ ID NO: 127; and

[0055] (f) a light chain CDR having an amino acid sequence of SEQ ID NO: 128. In another embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof may alternatively comprise the CDR sequences of other anti-IL-18 antibodies known in the art (see for example, US6706487, WO 2001 / 058956, EP 1621616, US 2005 / 0147610; EP 0 974 600; and WO 0158956).

[0056] In yet another embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof may alternatively comprise the CDR sequences or heavy and light chain variable regions of any of the humanized antibodies disclosed in US 8,133,978 B2. Alternatively, the anti-IL-18 antibody or antigen-binding fragment thereof is GSK1070806, which is a humanized IgGl / kappa antibody that binds to human IL-

[0057] 18 with a high affinity (Kd = 30.3 pM) and neutralizes its function (See, e.g., Reid, P. et al, Int J Clin Pharmacol Ther. 2014 Oct;52(10):867-79. doi: 10.5414 / CP202087). Preferably, the anti-IL-18 antibody or antigen-binding fragment thereof may comprise one or more CDRs as described herein, e.g. a CDR3, and optionally also a CDR1 and CDR2 to form a set of CDRs. In some embodiments, the CDR or set of CDRs is a CDR or set of CDRs of any of Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Camoteskimab, or may be a variant thereof as described herein.

[0058] Therefore, in another aspect, there is provided Camoteskimab or an antigenbinding fragment thereof, for use in treating, preventing or ameliorating adult-onset Still's disease (AOSD), systemic-onset juvenile idiopathic arthritis (SoJIA), atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE) in a subject, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of 0.1 < 4mg / kg. In a further aspect, there is provided a method of treating, preventing or ameliorating adult-onset Still's disease (AOSD), systemic-onset juvenile idiopathic arthritis (SoJIA), atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE), the method comprising subcutaneously administering to a subject in need of such treatment, a therapeutically active dose of 0.1 < 4mg / kg of Camoteskimab or antigen-binding fragment thereof. Typically, therefore, there is provided Camoteskimab or an antigen-binding fragment thereof, for use in treating, preventing or ameliorating atopic dermatitis (AD), in a subject, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of 0.1 < 4mg / kg.

[0059] Typically, there is provided a method of treating, preventing or ameliorating atopic dermatitis (AD), the method comprising subcutaneously administering to a subject in need of such treatment, a therapeutically active dose of 0.1 < 4mg / kg of Camoteskimab or antigen-binding fragment thereof.

[0060] In one embodiment, HCDR1 may be about 7 amino acids long, comprising or consisting of Kabat residues 31-35b; HCDR2 may be about 16 amino acids long, comprising or consisting of Kabat residues 50-65; HCDR3 may be about 15 amino acids long, comprising or consisting of Kabat residues 95-102; LCDR1 may be about 11 amino acids long, comprising or consisting of Kabat residues 24-34; LCDR2 may be about 7 amino acids long, comprising or consisting of Kabat residues 50-56; and / or LCDR3 may be about 9 amino acids long, comprising or consisting of Kabat residues 89-97. As is known in the art, in the variable region of the heavy chain, the CDR may include residues 31 to 35 plus an insertion of 2 residues, 35a and 35b. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a HCDR1, HCDR2 and / or HCDR3 and / or an LCDR1, LCDR2 and / or LCDR3 as provided in Table 1 (the CDRs belonging to an individual antibody).

[0061] Preferably, the anti-IL-18 antibody or antigen-binding fragment thereof may comprise a VH as described in any one of the antibodies in the Table 1. Optionally, it may also comprise a VL of any one of these antibodies. The VL may be from the same or a different antibody or antigen-binding fragment thereof. A VH domain comprising a set of HCDRs of any of the antibodies listed in the Table 1, and / or a VL domain comprising a set of LCDRs of any of the antibodies listed in the Table 1, are also provided herein.

[0062] In a most preferred embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises Camoteskimab CDRs with amino acid residue substitutions: (a) a HCDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 122;

[0063] (b) a HCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 123; (c) a HCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4 or 5 amino acid residue substitutions relative to SEQ ID NO: 124;(d) a LCDR1 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 126; (e) a LCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 127; and (f) a LCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acid residue substitutions relative to SEQ ID NO: 128. In another embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain and / or light chain of a parent antibody. In yet another embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises any of the antibodies listed in the Table 1 with one or more substitutions within the CDRs. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises any of the antibodies listed in the Table 1 with one or more substitutions within the VH and / or VL. For example, an antibody molecule of the invention may comprise any one of Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Camoteskimab, with 17, 16 or 15 or fewer substitutions, e.g. 14, 13,

[0064] 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 substitutions within the VH and / or VL. Substitutions may potentially be made at any residue, including within the set of CDRs. Preferably, a VH domain is paired with a VL domain to provide an Camoteskimab- antigen-binding site, although as discussed above a VH or VL domain alone may be used to bind antigen. For example, the Camoteskimab VH domain (SEQ ID NO: 121) may be paired with the Camoteskimab VL domain (SEQ ID NO: 125), so that an Camoteskimab antigen-binding site is formed comprising both the Camoteskimab VH and VL domains. Similar configurations are provided for the VH and VL domains of the other antibodies disclosed herein.

[0065] In one embodiment, the Camoteskimab VH is paired with a VL domain other than that of Camoteskimab VL. Light-chain promiscuity is well established in the art. Again, similar configurations are provided by the invention for the other VH and VL domains disclosed herein. Thus, the VH of the parent Antibody 1 or of any of the optimised clones Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Camoteskimab may be paired with a VL domain from a different antibody e.g. the VH and VL domains may be from different antibodies selected from Antibody 1, Antibody 1_GL, Antibody 2, Antibody 3, Antibody 4, Antibody 5, Antibody 6, Antibody 6_GL, Antibody 7, Antibody 7_GL, Antibody 8_GL, Antibody 9, Antibody 10, Antibody 11, Antibody 11_GL, and Camoteskimab. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a VH domain and a VL domain wherein; (i) the VH domain amino acid sequence is shown in SEQ ID NO: 121 and the VL domain amino acid sequence is shown in SEQ ID NO: 125, (ii) the VH domain amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid substitutions as compared to SEQ ID NO: 121 and the VL domain amino acid sequence has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 amino acid substitutions as compared to SEQ ID NO: 125; or (iii) the VH domain amino acid sequence has at least 80%, at least 85%, at least 90% or at least 95% sequence identity with SEQ ID NO: 121 and the VL domain amino acid sequence has at least 80%, at least 85%, at least 90% or at least 95% sequence identity with SEQ ID NO: 125.

[0066] In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a VH domain having an amino acid sequence which is at least 90% identical to the full sequence of SEQ ID NO: 121. In some embodiments, the anti- IL-18 antibody or antigen-binding fragment thereof comprises a VH domain having an amino acid sequence which is identical to the full sequence of SEQ ID NO: 121. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a VL domain having an amino acid sequence which is at least 90% identical to the full sequence of SEQ ID NO: 125. In some embodiments, the anti- IL-18 antibody or antigen-binding fragment thereof comprises a VL domain having an amino acid sequence which is identical to the full sequence of SEQ ID NO: 125. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof an antibody VH domain and an antibody VL domain, wherein the amino acid sequence of the antibody VH domain and the antibody VL domain are at least 90% identical to the full sequence of SEQ ID NOS: 121 and 125. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain and light chain comprising the following complementarity determining regions (CDRs): (a) a HCDR1 comprising the amino acids of SEQ ID NO: 129; (b) a HCDR2 comprising the amino acids of SEQ ID NO: 130; (c) a HCDR3 comprising the amino acids of SEQ ID NO: 131; (d) a LCDR1 comprising the amino acids of SEQ ID NO: 132; (e) a LCDR2 comprising the amino acids of SEQ ID NO: 133; and (f) a LCDR3 comprising the amino acids of SEQ ID NO: 134.

[0067] In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises: a heavy chain and light chain comprising the following complementarity determining regions (CDRs): (a) a HCDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 129; (b) a HCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 130; (c) a HCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4 or 5 amino acid residue substitutions relative to SEQ ID NO: 131; (d) a LCDR1 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 132; (e) a LCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 133; and (f) a LCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, or 4 amino acid residue substitutions relative to SEQ ID NO: 134.

[0068] In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence identical to or comprising

[0069] 1 to 12 amino acid residue substitutions relative to a heavy chain selected from the group consisting of: SEQ ID NO: 137, SEQ ID NO: 145, and SEQ ID NO: 149; and a light chain having an amino acid sequence identical to or comprising 1 to 12 amino acid residue substitutions relative to a light chain selected from the group consisting of: SEQ ID NO: 141 and SEQ ID NO: 157. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof further comprises substituting the residue at position 71 of the light chain with the corresponding residue found in a donor antibody from which the CDRs are derived. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a tyrosine at position 71 of the light chain. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a phenylalanine at position 71 of the light chain. In one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 141. In one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 141. In one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 141. In one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 157. In one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 137 and a light chain of SEQ ID NO: 153.

[0070] In one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 145 and a light chain of SEQ ID NO: 153. In one embodiment, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a heavy chain of SEQ ID NO: 149 and a light chain of SEQ ID NO: 153.

[0071] In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof may lack antibody constant regions, for example a scFv. In other embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof may comprise an antibody constant region. The anti-IL-18 antibody or antigenbinding fragment thereof may be a whole antibody such as an IgG, i.e. an IgGl, IgG2, or IgG4, or may be an antibody fragment or derivative as described below. Antibody molecules can also have other formats, e.g. IgGl with YTE (Dall'Acqua et al. (2002) J. Immunology, 169: 5171-5180; Dall'Acqua et al. (2006) J Biol. Chem. 281(33):23514-24) and / or TM mutations (Oganesyan et al. (2008) Acta Cryst D64:700-4) in Fc region.

[0072] Suitably, the anti-IL-18 antibody or antigen-binding fragment thereof may be administered subcutaneously at a dose of between 0.1 and 3.9 mg / kg, or between 0.1 and 3.8 mg / kg. More suitably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between 0.1 and 3.5 mg / kg, or between 0.1 and 3mg / kg. Even more suitably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between 0.15 and 3.2 mg / kg, or between 0.15 and 3.2 mg / kg, or between 0.15 to 3 mg / kg. Yet more suitably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between 0.2 and 2.7 mg / kg, or between 0.2 and 2.5 mg / kg, or between 0.25 and 2.5 mg / kg.

[0073] More suitably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between 0.3 and 3.7 mg / kg, or between 0.4 and 3.6 mg / kg. Even more suitably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between 0.4 and 3.5 mg / kg, or between 0.5 and 3.2 mg / kg, or between 0.6 to 3.1 mg / kg. Yet more suitably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between 0.7 and 3.5 mg / kg, or between 0.8 and 3 mg / kg, or between 0.9 and 2.9 mg / kg.

[0074] Preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between 0.2 and 2.5 mg / kg, or between 0.25 and 2.5 mg / kg.

[0075] Most preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between dose of about 0.1 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, or about 0.75 mg / kg. Most preferably, the anti-IL-18 antibody or antigen- binding fragment thereof is administered subcutaneously at a dose of about 0.25 mg / kg. This dosage is described in the Examples.

[0076] Most preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 0.4 mg / kg. This dosage is also described in the Examples.

[0077] Most preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between dose of about 1 mg / kg, about 1.25 mg / kg, about 1.4 mg / kg about 1.5 mg / kg, or about 1.75 mg / kg. Most preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 1 mg / kg. This dosage is also described in the Examples. Most preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 1.4 mg / kg. This dosage is described in the Examples.

[0078] Most preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between dose of about 2 mg / kg, about 2.25 mg / kg, about 2.5 mg / kg, or about 2.75 mg / kg. Most preferably, the anti-IL- 18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 2 mg / kg. This dosage is also described in the Examples.

[0079] Most preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of between dose of about 3 mg / kg, about 3.25 mg / kg, about 3.5 mg / kg, about 3.75 mg / kg, or about 4 mg / kg. Most preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 4 mg / kg. This dosage is described in the Examples. It will be appreciated that any of the dosages given above may be used as an upper or lower value for any of the above ranges. For example, the anti-IL-18 antibody or antigen-binding fragment thereof may be administered subcutaneously at a dose of 0.15 < 4 mg / kg, or between 0.2 and 3 mg / kg, or between 0.25 and 2.7 mg / kg, and so on.

[0080] In a third aspect of the invention, there is provided an anti-IL-18 antibody or antigen-binding fragment thereof comprising an Camoteskimab antigen binding site or antibody molecule, for use in treating, preventing or ameliorating adult-onset Still's disease (AOSD), systemic-onset juvenile idiopathic arthritis (SoJIA), atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE) in a subject, wherein the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 0.1 < 4mg / kg, and wherein the anti-IL-18 antibody competes for binding to IL-18 with any antibody molecule which: (i) binds IL-18 and (ii) comprises an antibody molecule, VH and / or VL domain, CDR e.g. HCDR3, and / or set of CDRs listed in the Table 1. In a fourth aspect, there is provided a method of treating, preventing or ameliorating adult-onset Still's disease (AOSD), systemic-onset juvenile idiopathic arthritis (SoJIA), atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE) the method comprising subcutaneously administering, to a subject in need of such treatment, a therapeutically active dose of 0.1 < 4mg / kg of an anti-IL-18 antibody or antigen-binding fragment thereof comprising an Camoteskimab antigen binding site or antibody molecule, wherein the anti-IL-18 antibody competes for binding to IL-18 with any antibody molecule which: (i) binds IL-18 and (ii) comprises an antibody molecule, VH and / or VL domain, CDR e.g. HCDR3, and / or set of CDRs listed in the Table 1.

[0081] For example, in some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof may compete with an antibody molecule comprising: (i) a VH domain having the sequence of SEQ ID NO: 152 and a VL domain having the sequence of SEQ ID NO: 157; (ii) a VH domain having a sequence with 15 or fewer amino acid substitutions such as 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 as compared to SEQ ID NO: 152; and a VL domain having a sequence with 13 or fewer amino acid substitutions such as 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 as compared to or SEQ ID NO: 157, or; (iii) a VH domain and a VL domain having sequences with at least 90% sequence identity to SEQ ID NO: 152 and SEQ ID NO: 157, respectively.

[0082] Competition between anti-IL-18 antibodies may be assayed easily in vitro, for example using ELISA and / or by a biochemical competition assay such as one tagging a specific reporter molecule to one anti-IL-18 antibody which can be detected in the presence of one or more other untagged anti-IL-18 antibodies, to enable identification of anti-IL-18 antibodies which bind the same epitope or an overlapping epitope. Such methods are readily known to one of ordinary skill in the art and are described in more detail herein. Variable domain amino acid sequence variants of any of the VH and VL domains whose sequences are specifically disclosed herein may be employed in accordance with the present invention.

[0083] As described above, in some embodiments, the anti-IL-18 antibody or antigenbinding fragment thereof comprises a VH domain that has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least

[0084] 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with a VH domain of any of the antibodies listed herein, for which VH domain sequences are shown in the appended Table 1 below; and / or comprises a VL domain that has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with a VL domain of any of the antibodies listed herein, for which VL domain sequences are shown in the appended Table 1 below.

[0085] In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof comprises a VH domain having a set of VH CDRs that have at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with the set of VH CDRs of any of the antibodies listed herein, for which VH CDR sequences are shown in the appended Table 1; and / or comprising a VL domain having a set of VL CDRs that have at that has at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 96%, at least 95%, at least 97%, at least 98% or at least 99% amino acid sequence identity with the set of VL

[0086] CDRs of any of the antibodies listed herein, for which the VL CDR sequences are shown in the appended Table 1.

[0087] Algorithms that can be used to calculate % identity of two amino acid sequences are known in the art and include e.g. BLAST [Altschul et al. (1990) J. Mol. Biol.

[0088] 215: 405-410], FASTA [Pearson and Lipman (1988) PNAS USA 85: 2444-2448], or the Smith-Waterman algorithm [Smith and Waterman (1981) J. Mol Biol. 147: 195- 197] e.g. employing default parameters. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof inhibits the binding of IL-18 to one or both of the IL-18 receptor (IL-18R, which comprises IL-18Ro / IL-18R0) and IL-18BP and thereby reduces IL-18 activity. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof may bind to an epitope on the IL-18 molecule which wholly or partially overlaps the IL-18BP binding site.

[0089] For example, the anti-IL-18 antibody or antigen-binding fragment thereof may specifically bind to an epitope of IL-18 which comprises one or more of residues Tyrl, Gly3, Leu5, Glu6, Lys8, Met51, Lys53, Asp54, Ser55, Gln56, Pro57, Arg58, Gly59, Met60, Argl04, Serl05 and Prol07 of human IL-18 or the corresponding residues from IL-18 of other species, for example a primate such as Rhesus macaque. The anti-IL-18 antibody or antigen-binding fragment thereof may bind to an IL-18 epitope which comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all 17 residues selected from the group consisting of Tyrl, Gly3, Leu5, Glu6, Lys8, Met51, Lys53, Asp54, Ser55, Gln56, Pro57, Arg58, Gly59, Met60, Arg 104, Serl05, and Prol07 of human IL-18.

[0090] Preferably, the anti-IL-18 antibody or an antigen-binding fragment thereof is used to treat AOSD.

[0091] Preferably, the anti-IL-18 antibody or an antigen-binding fragment thereof is used to treat SoJIA.

[0092] Preferably, the anti-IL-18 antibody or an antigen-binding fragment thereof is used to treat AD. Preferably, the subject is a human subject diagnosed with any of AOSD, SoJIA, AD, ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE).

[0093] In some embodiments, the subject is diagnosed with SoJIA.

[0094] In some embodiments, the subject has elevated free or total serum IL-18 levels. In some embodiments, the level of serum IL-18 is measured prior to administration of the anti-IL-18 antibody or antigen-binding fragment thereof. In some embodiments, the level of serum IL-18 is measured after administration of the anti- IL-18 antibody or antigen-binding fragment thereof. In some embodiments, the level of serum IL-18 is measured as a marker for effectiveness of treatment. In some embodiments, the level of serum IL-18 is elevated as compared to levels in a subject without AOSD or SoJIA or as compared to a negative control. In some embodiments, the levels of serum IL-18 in the subject are measured after administration of the anti-IL-18 Camoteskimabs a marker for effectiveness of treatment. In some embodiments, the level of serum IL-18 is free IL-18. In some embodiments, the level of free IL-18 is calculated. In some embodiments, the level of serum IL-18 is total IL-18. In some embodiments, the subject has elevated serum free IL-18. In some embodiments, the subject has elevated serum total IL- 18. In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof is administered in the form of a pharmaceutically acceptable composition.

[0095] In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof is administered for a period of at least 16 weeks.

[0096] In some embodiments, the anti-IL-18 antibody or antigen-binding fragment thereof is administered once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks.

[0097] Preferably, the anti-IL-18 antibody or antigen-binding fragment thereof is administered once every four weeks.

[0098] Most preferably, however, the anti-IL-18 antibody or antigen-binding fragment thereof is administered once every twelve weeks.

[0099] In some embodiments, the subject achieves resolution of fever.

[0100] In some embodiments, the subject achieves a reduction of CRP. In some embodiments, the subject achieves a reduction of CRP of >.50% from baseline to week 4. In some embodiments, the subject achieves a reduction of CRP of >.50% from baseline to week 12.

[0101] In some embodiments, the subject achieves a reduction of serum IL-18 levels.

[0102] In some embodiments, the subject achieves a reduction of serum total IL-18 levels. In some embodiments, the subject achieves a reduction of serum free IL-18 levels. In some embodiments, the subject has undetectable levels of serum IL-18 at about 4 weeks after administration of the anti-IL-18 antibody or antigen-binding fragment thereof. In some embodiments, the subject has undetectable levels of serum IL-18 at about 12 weeks after administration of the anti-IL-18 antibody or antigen- binding fragment thereof. In some embodiments, the subject has undetectable levels of serum total IL-18 at about 4 weeks after administration of the anti-IL-18 antibody or antigen-binding fragment thereof. In some embodiments, the subject has undetectable levels of serum total IL-18 at about 12 weeks after administration of the anti-IL-18 antibody or antigen-binding fragment thereof. In some embodiments, the subject has undetectable levels of serum free IL-18 at about 4 weeks after administration of the anti-IL-18 antibody or antigen-binding fragment thereof. In some embodiments, the subject has undetectable levels of serum free IL-18 at about 12 weeks after administration of the anti-IL-18 antibody or antigen-binding fragment thereof.

[0103] Preferably, the anti-IL-18 antibody or an antigen-binding fragment thereof binds to free IL-18 in the subject. It will be appreciated that free IL-18 may also be known as unbound IL-18, i.e., not bound to its corresponding receptor or the IL-18 binding protein (IL-18bp).

[0104] Most currently available assays only measure total IL-18, which includes IL-18 bound to its receptors, including IL-18bp. Total IL-18 may not provide as accurate of a picture of the levels of IL-18 causing disease, which may be free, unbound IL-

[0105] 18. Thus, it may be desirable to use an assay that measures free IL-18 alone when the methods include detection of free IL-18. Alternatively, free IL-18 can be calculated based on total IL-18 and total IL-18bp concentration data using formulas known in the art.

[0106] The anti-IL-18 antibody or an antigen-binding fragment may be administered in the form of a pharmaceutically acceptable composition. In various embodiments, compositions comprising anti-IL-18 antibodies are provided in formulations with a wide variety of pharmaceutically acceptable carriers (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20thed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7thed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rded., Pharmaceutical Press (2000)). Various pharmaceutically acceptable carriers, which include vehicles, adjuvants, and diluents, are available. Moreover, various pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are also available. Non-limiting exemplary carriers include saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.

[0107] In various embodiments, compositions comprising anti-IL-18 or an antigen-binding fragment may be formulated for injection, by dissolving, suspending, or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids, or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0108] The compositions may also be formulated, in various embodiments, into sustained release microcapsules, such as with biodegradable or non-biodegradable polymers. A non-limiting exemplary biodegradable formulation includes poly lactic acid- glycolic acid polymer. A non-limiting exemplary non-biodegradable formulation includes a polyglycerin fatty acid ester. Certain methods of making such formulations are described, for example, in EP 1 125 584 Al.

[0109] Pharmaceutical packs and kits comprising one or more containers, each containing one or more doses of the anti-IL-18 antibody Camoteskimab are also provided. In some embodiments, a unit dosage is provided wherein the unit dosage contains a predetermined amount of a composition comprising the anti-IL-18 antibody or an antigen-binding fragment, with or without one or more additional agents. In some embodiments, such a unit dosage is supplied in single-use prefilled syringe for injection. In various embodiments, the composition contained in the unit dosage may comprise saline, sucrose, or the like; a buffer, such as phosphate, or the like; and / or be formulated within a stable and effective pH range. Alternatively, in some embodiments, the composition may be provided as a lyophilized powder that may be reconstituted upon addition of an appropriate liquid, for example, sterile water. In some embodiments, the composition comprises one or more substances that inhibit protein aggregation, including, but not limited to, sucrose and arginine. In some embodiments, a composition of the invention comprises heparin and / or a proteoglycan.

[0110] Any of the aforementioned methods can be implemented via kits for the detection and / or treatment of a condition associated with elevated IL-18, including AOSD or SoJIA, atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE). The kit may contain an antibody, one or more non- naturally occurring detectable labels, marker, or reporter, a pharmaceutically acceptable carrier, a physiologically acceptable carrier, instructions for use, a container, a vessel for administration, an assay substrate, or any combination thereof.

[0111] In some embodiments, the kit is for use in a method of detecting IL-18 in a biological sample. It may contain an anti-IL-18 Camoteskimab and reagents for carrying out the method. In some embodiments, the kit is for use in a method of detecting IL-18 in a biological sample from a subject having or suspected of having AOSD or SoJIA, atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE). It may contain an anti-IL-18 Camoteskimab and reagents for carrying out the method.

[0112] In some embodiments, the kit is for use in method of detecting elevated IL- 18 in a biological sample from a subject, optionally wherein the subject is suspected of AOSD or SoJIA, atopic dermatitis (AD), ulcerative colitis (UC), Crohn's disease (CD) and / or eosinophilic esophagitis (EoE) and also for treating the subject after diagnosis by administering an anti-IL-18 antibody in an effective amount. It may contain an anti-IL-18 Camoteskimab and reagents for carrying out the method.

[0113] In some embodiments, the kit for use in a method of detecting and / or treating comprises a solid phase to which the anti-IL-18 antibody reagent is attached. In some embodiments, the kit for use in a method of detecting and / or treating comprises a solid phase to which IL-18 derived from the biological sample will be attached.

[0114] The solid phase to be used in the kits of the present invention includes, but is not limited to microplates, magnetic particles, filter papers for immunochromatography, polymers such as polystyrene, glass beads, glass filters and other insoluble carriers. In one embodiment, a solid substrate containing many compartments or regions has at least one compartment coated with antibodies of the invention. The kits of the invention may also include a further component to the diagnostic agent, the anti-IL-18 antibody. The further component may include, but is not limited to, reagents, enzymes for labeling, substrates therefor, radioisotopes, light- reflecting substances, fluorescent substances, colored substances, buffer solutions, and plates, and those mentioned herein above.

[0115] According to the present invention, an "isolated," or "biologically pure" molecule is a compound that has been removed from its natural milieu. As such, the terms "isolated" and "biologically pure" do not necessarily reflect the extent to which the compound has been purified. An isolated compound of the present invention can be obtained from its natural source, can be produced using laboratory synthetic techniques or can be produced by any such chemical synthetic route.

[0116] "IL-18" or "Interleukin-18" or "interferon-gamma inducing factor" or "IFN-y- inducing factor" refers to a proinflammatory cytokine encoded by the IL18 gene that belongs to the IL-1 family of cytokines. Similar to IL-ip, it is synthesized as an inactive precursor called pro-IL-18 that is activated by cleavage by caspase-1. Pro- IL-18 is present in healthy cells and constitutively expressed by monocytes and epithelial cells. IL-18 has roles in stimulating both adaptive and innate immune response.

[0117] "Elevated IL-18" as used herein refers to a level of total IL-18 detected in a subject that is higher than a normal control. The normal control can be determined by those of skill in the art as applicable to the particular situation. In some instances, the normal control is an industry standard agreed upon by those of skill as being a level or range of levels that is typical of an individual without an IL-18-associated condition. In some instances, the normal control is a reference level of IL-18 from the same individual taken at a time point, and whether the subject has elevated IL- 18 is determined based on a sample from that same individual taken at a different, typically later, time point.

[0118] "Free IL-18" or "free (active) IL-18" herein refers to non-bound form IL-18, which is the active form of IL-18. In humans, free IL-18 is neutralized (inactivated) by IL- 18BP, which binds IL-18 and inhibits its activity by interfering with its interaction with IL-I8R0.

[0119] "Bound IL-18," or the like, refers to IL-18 that is bound to a natural ligand, optionally wherein the natural ligand is IL-I8R0 or IL-18BP. Free IL-18 may be calculated according to known methods, e.g., Palladino et al. (2012) J. Neuroinflammation 9(206). "Total IL-18," or the like, refers to the total amount of free IL-18 and bound IL-18. "Serum" or "circulating" IL-18 is IL-18 that is located in the serum. "Undetectable levels of serum IL-18" refers to levels of IL-18 that are below the level of quantification of an assay for measuring IL- 18.

[0120] The term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity. As used herein, the term refers to a molecule comprising at least complementaritydetermining region (CDR) 1, CDR2, and CDR3 of a heavy chain and at least CDR1, CDR2, and CDR3 of a light chain, wherein the molecule is capable of binding to antigen. As described herein, a "set of CDRs" comprises CDR1, CDR2 and CDR3.

[0121] Thus, a set of HCDRs refers to HCDR1, HCDR2 and HCDR3, and a set of LCDRs refers to LCDR1, LCDR2 and LCDR3. Unless otherwise stated, a "set of CDRs" includes HCDRs and LCDRs. The term antibody includes, but is not limited to, fragments that are capable of binding antigen, such as Fv, single-chain Fv (scFv), Fab, Fab', and (Fab')2.

[0122] The term "heavy chain" refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term "full- length heavy chain" refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.

[0123] The term "heavy chain variable region" or "VH domain" refers to a region comprising a heavy chain complementarity determining region (CDR) 1, framework region (FR) 2, CDR2, FR3, and CDR3 of the heavy chain. In some embodiments, a heavy chain variable region also comprises at least a portion of an FR1 and / or at least a portion of an FR4. In some embodiments, a heavy chain CDR1 corresponds to Kabat residues 31 to 35; a heavy chain CDR2 corresponds to Kabat residues 50 to 65; and a heavy chain CDR3 corresponds to Kabat residues 95 to 102. See, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH,

[0124] Bethesda, Md.). The term "light chain" refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term "full- length light chain" refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.

[0125] The term "light chain variable region" or "VL domain" refers to a region comprising a light chain CDR1, FR2, HVR2, FR3, and HVR3. In some embodiments, a light chain variable region also comprises an FR1 and / or an FR4. In some embodiments, a light chain CDR1 corresponds to Kabat residues 24 to 34; a light chain CDR2 corresponds to Kabat residues 50 to 56; and a light chain CDR3 corresponds to Kabat residues 89 to 97. See, e.g., Kabat Sequences of Proteins of Immunological Interest (1987 and 1991, NIH, Bethesda, Md.). A "chimeric antibody" refers to an antibody in which a portion of the heavy and / or light Chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species. In some embodiments, a chimeric antibody refers to an antibody comprising at least one variable region from a first species (such as mouse, rat, cynomolgus monkey, etc.) and at least one constant region from a second species (such as human, cynomolgus monkey, etc.). In some embodiments, a chimeric antibody comprises at least one mouse variable region and at least one human constant region. In some embodiments, a chimeric antibody comprises at least one cynomolgus variable region and at least one human constant region. In some embodiments, all of the variable regions of a chimeric Camoteskimab from a first species and all of the constant regions of the chimeric Camoteskimab from a second species.

[0126] A "humanized antibody" refers to an antibody in which at least one amino acid in a framework region of a non-human variable region has been replaced with the corresponding amino acid from a human variable region. In some embodiments, a humanized antibody comprises at least one human constant region or fragment thereof. In some embodiments, a humanized antibody is an Fab, an scFv, a (Fab')2, etc. A "human antibody" as used herein refers to antibodies produced in humans, antibodies produced in non-human animals that comprise human immunoglobulin genes, such as XenoMouse®, and antibodies selected using in vitro methods, such as phage display, wherein the antibody repertoire is based on human immunoglobulin sequences.

[0127] The term "leader sequence" refers to a sequence of amino acid residues located at the N terminus of a polypeptide that facilitates secretion of a polypeptide from a mammalian cell. A leader sequence may be cleaved upon export of the polypeptide from the mammalian cell, forming a mature protein. Leader sequences may be natural or synthetic, and they may be heterologous or homologous to the protein to which they are attached.

[0128] "Percent (%) amino acid sequence identity" and "homology" with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST- 2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. The terms "inhibition" or "inhibit" refer to a decrease or cessation of any event (such as protein ligand binding) or to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To "reduce" or "inhibit" is to decrease, reduce or arrest an activity, function, and / or amount as compared to a reference. It is not necessary that the inhibition or reduction be complete. For example, in certain embodiments, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 20% or greater. In another embodiment, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 50% or greater. In yet another embodiment, by "reduce" or "inhibit" is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater. "Sample" or "subject sample" or "biological sample" generally refers to a sample which may be tested for a particular molecule. Samples may include but are not limited to cells, bone marrow, body fluids, including blood, serum, plasma, urine, saliva, stool, tears, pleural fluid and the like.

[0129] The terms "agent" and "test compound" are used interchangeably herein and denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Biological macromolecules include siRNA, shRNA, antisense oligonucleotides, peptides, peptide / DNA complexes, and any nucleic acid based molecule which exhibits the capacity to modulate the activity of the SNP containing nucleic acids described herein or their encoded proteins. A "subject" can be mammalian. In any of the embodiments involving a subject, the subject can be human. In any of the embodiments involving a subject, the subject can be a cow, pig, monkey, sheep, dog, cat, fish, or poultry.

[0130] A "pediatric" subject herein is a human of less than 18 years of age, whereas an "adult" subject is 18 years or older.

[0131] The term "pharmaceutically acceptable composition" may refer to a composition comprising the anti-IL-18 antibody in formulations with a wide variety of pharmaceutically acceptable carriers.

[0132] The term "pharmaceutically acceptable carrier" refers to refers to an ingredient in a pharmaceutical formulation or composition, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, and / or preservative. "Treatment" or "treat" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in which the disorder is to be prevented. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0133] The term "effective amount" or "therapeutically effective amount" refers to an amount of a drug effective for treatment of a disease or disorder in a subject, such as to partially or fully relieve one or more symptoms. In some embodiments, an effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0134] "Adult-onset Still's disease" or "AOSD" can be diagnosed in several different ways. One accepted way to diagnose AOSD is based on classification criteria defined as having at least five or more of fever > 39°C, lasting 1 week or longer; arthralgia or arthritis, lasting 2 weeks or longer; typical rash; leukocytes > 10,000 mm3with >80% polymorphonuclear cells; sore throat; recent development of significant lymphadenopathy; hepatomegaly or splenomegaly; abnormal liver function tests; negative tests for antinuclear antibody (IF) and rheumatoid factor (IgM); and at least two or more of fever > 39°C, lasting 1 week or longer; arthralgia or arthritis, lasting 2 weeks or longer; typical rash; or leukocytes > 10,000 mm3with >80% polymorphonuclear cells.

[0135] "Systemic-onset juvenile idiopathic arthritis" or "systemic juvenile idiopathic arthritis" or "SoJIA" or "SJIA" or "sJIA" refers to a subset of juvenile idiopathic arthritis marked by more severe extra-articular manifestations (fever, cutaneous eruptions). It represents 10-11% of cases of juvenile idiopathic arthritis. Onset usually occurs between 3 and 5 years of age. The clinical signs include fever with oscillating temperatures over a 24-hour period and peaks of over 39°C or more, which are associated with transient cutaneous eruptions and diffuse erythematosus or urticarial-like lesions. Another symptom is arthritis. The number of sites of the body affected by the arthritis vary but affect both the small and large joints in a nearly symmetrical manner. Some patients may also have adenopathy and / or hepatosplenomegaly. Other symptoms such as pericarditis, pleural effusion, or serous peritonitis with abdominal pain may be present. SoJIA patients typically have severe inflammatory disease with a large increase in ferritin levels and a decrease in the percentage of glycosylated ferritin. Physicians often use a "clinical triad" to diagnose this disease: daily fever lasting more than 2 weeks, arthritis, and cutaneous eruptions. See Petty, R et al., J. Rheumatol. 31(2) 390-392 (2004). If the patient does not have cutaneous eruptions, the presence of an adenopathy, hepatosplenomegaly, or serous effusion can also confirm the diagnosis.

[0136] "Atopic eczema", "eczema" or "atopic dermatitis (AD)" refers to a chronic, long- lasting, inflammatory skin disorder that causes inflammation, redness, and irritation of the skin. It is a common condition that usually begins in childhood; however, anyone can get the disease at any age. Atopic dermatitis causes the skin to become extremely itchy. Scratching leads to further redness, swelling, cracking, "weeping" clear fluid, crusting, and scaling. In most cases, there are periods of time when the disease is worse, called flares, followed by periods when the skin improves or clears up entirely, called remissions. "Inflammatory bowel disease (IBD)" refers to a group of idiopathic chronic inflammatory disorders of the gastrointestinal tract, including Crohn's disease (CD), ulcerative colitis (UC), and unspecified forms of IBD. Collectively these are chronic remittent or progressive inflammatory conditions that may affect the entire gastrointestinal tract and the colonic mucosa.

[0137] "Ulcerative colitis (UC)" refers to a subset of IBD that is characterized by continuous inflammation that is localized to the colon.

[0138] "Crohn's disease (CD)" refers to a further subset of IBD that is characterized by discontinuous inflammation that affects the entire gastrointestinal tract from mouth to anus and long-term debilitating sequelae, such as fistulae and intestinal strictures.

[0139] "Eosinophilic esophagitis (EoE)" refers to a chronic disorder characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophilic infiltration of the esophageal epithelium. EoE represents an important contributor to upper gastrointestinal morbidity throughout the world, a growing health problem, and a significant burden for healthcare systems. In a further aspect of the invention, there is provided an anti-IL-18 antibody or an antigen-binding fragment thereof, for use in treating, preventing or ameliorating adult-onset Still's disease (AOSD), systemic-onset juvenile idiopathic arthritis (SoJIA), and / or atopic dermatitis (AD), in a subject, wherein the anti-IL-18 antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of 0.1 < 4mg / kg.

[0140] 5 In another aspect, there is provided a method of treating, preventing or ameliorating adult-onset Still's disease (AOSD), systemic-onset juvenile idiopathic arthritis (SoJIA), and / or atopic dermatitis (AD), the method comprising subcutaneously administering to a subject in need of such treatment, a therapeutically active dose of 0.1 < 4mg / kg of an anti-IL-18 antibody or antigenic binding fragment thereof.

[0141] All of the features described herein (including any accompanying claims, abstracts and drawings), and / or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except

[0142] 15 combinations where at least some features and / or steps are mutually exclusive.

[0143] For a better understanding of the invention, and to show how embodiments of the same may be carried into effect, reference will now be made, by way of example, to the accompanying Figures, in which:- 0

[0144] Figure 1 shows population pharmacokinetics (PK) model using camoteskimab's plasma concentrations and PK data derived from the clinical studies NCT01322594 and NCT04671251. As observed in these clinical studies, the half-life of camoteskimab supports a dosage regiment of every 4 weeks (Q4W). The PK model 25 was then used to simulate a dosage of 0.25 mg / kg. The X-axis refers to the time in days and the y-axis refers to serum concentration in pg / mL.

[0145] Figure 2 shows identical modelling as in Figure 1, but the results are shown for a PK model simulation of a dosage of 1 mg / kg. 0

[0146] Figure 3 shows identical modelling as in Figures 1 and 2, but the results are shown for a PK model simulation of a dosage of 2 mg / kg.

[0147] Figure 4 shows a summary table of the camoteskimab PK simulations results 35 shown in Figures 1, 2 and 3. Figure 5 shows PK model predictions of camoteskimab delivered subcutaneously using (A) 30mg Q12W, (B) lOOmg Q12W, (C) 300mg Q12W and (D) 300mg Q4W. The y-axis represents the fraction of remaining free IL- 18, and the x-axis is time (days). The coloured lines represent 100 individual simulations, the black solid line represents the geometric mean. The red horizontal line represents the point at which 90% of IL-18 is neutralized by camoteskimab. The vertical red line represents the end of the dosing interval used for the simulation.

[0148] EXAMPLES The inventors have constructed a population pharmacokinetics (PK) model using camoteskimab's plasma concentrations and PK data derived from two completed clinical studies in adults (NCT01322594 and NCT04671251). In these clinical studies, the half-life of camoteskimab supports a dosage regimen of every 4 weeks (Q4W). The PK model was then used to simulate low dosage regimens on a Q4W schedule. The PK model has been further used to estimate the level of IL-18 engagement using low doses on a Q12W schedule (longer treatment intervals) to assess the regimens for atopic dermatitis (AD).

[0149] The results of the PK model simulations are discussed below.

[0150] In addition, the inventors intend to confirm the pharmacokinetics with the resulting low dosages of camoteskimab as described and discussed below.

[0151] The following examples are provided to illustrate certain disclosed embodiments and are not to be construed as limiting the scope of this disclosure in any way. In the Examples discussed below, "Camoteskimab" refers to an anti-IL-18 antibody, wherein the anti-IL-18 antibody comprises the following six CDRs: a heavy chain CDR having an amino acid sequence of SEQ ID NO: 122; a heavy chain CDR having an amino acid sequence of SEQ ID NO: 123; a heavy chain CDR having an amino acid sequence of SEQ ID NO: 124; a light chain CDR having an amino acid sequence of SEQ ID NO: 126; a light chain CDR having an amino acid sequence of SEQ ID NO: 127; and a light chain CDR having an amino acid sequence of SEQ ID NO: 128. In some embodiments Camoteskimab has a variable heavy chain (VH) having an amino acid sequence of SEQ ID NO: 121 and a variable light chain (VL) having an amino acid sequence of SEQ ID NO: 125. Example 1 - Population pharmacokinetics models assessing subcutaneous administration of Camoteskimab in Subjects with adult onset of Still's disease A population pharmacokinetics (PK) model was constructed using camoteskimab's plasma concentrations and PK data derived from two completed clinical studies in adults. These include the clinical study with identifier NCT04671251 (AEVI-007-MM- 101 (n=13)) and the clinical study with identifier NCT0132259 (CD-RI-MEDI2338- 1033 (n=24)). A two-compartment model with linear clearance best described the data. "Goodness-of-Fit" plots were used to confirm that there was not any systematic bias or trends in the data. PK parameters, such as clearance and volume of distribution, were as expected for an antibody based on literature values. As observed in these clinical studies, the half-life of camoteskimab supports a dosage regiment of every 4 weeks (Q4W). The PK model was then used to simulate three dosage regimens of 0.25 mg / kg, 1 mg / kg and 2 mg / kg respectively, given on a Q4W schedule. The results of the model are presented in Figures 1-3, with summary data shown in Figure 4.

[0152] The mean Ctrough values in Figure 4 demonstrate the lowest steady-state plasma levels of camoteskimab that are achieved with these doses. The mean levels of camoteskimab for the 0.25, 1 and 2 mg / kg doses are sufficient to neutralise 320,000 pg / ml, 1,300,000 pg / ml and 2,500,000 pg / ml of "free IL-18", respectively. According to the available literature, levels of "free IL-18" are well below these levels in patients with Still's disease or atopic dermatitis. These PK simulations therefore demonstrate that low doses of camoteskimab are surprisingly suitable for SC administration.

[0153] Example 2 - Pharmacokinetic study assessing the ability of lower dosages of Camoteskimab to neutralise free IL-18 in animal serum. The standard 50 mg / ml formulation used in the clinical trials identified above will be concentrated to 100 mg / ml, or higher.

[0154] The new concentrated formulations will be used subcutaneously in a PK study (for example, human (healthy volunteer or patient) or monkey) to ensure that the physicochemical and biologic properties of the antibody have not been affected in lower dosages and that the low dose delivers sufficient serum levels of camoteskimab to effectively neutralise IL-18. The physicochemical properties of the antibody that will be assessed include but are not limited to the presence of absence of aggregation, and protein degradation (both of which can be assessed through and HPLC analysis) and / or antibody subunit molecular weights which can be measured using gel electrophoresis. In addition, the viscosity of the concentrated formulations will be analysed to ensure that the concentrated formulation is suitable for SC injection.

[0155] Similarly, the biological properties of the antibody that will be assessed include but are not limited to the assessments will include the confirmation that the binding affinity of camoteskimab for IL-18 (i.e., the antibody's potency) through antigen binding assay. In addition, cell-based assays testing the ability of IL-18 to induce the production of other cytokines (such as interferon gamma) will be used to determine that the camoteskimab is able to block the biological function of IL-18.

[0156] The pharmacokinetics (PK) of a subcutaneous administration will then be assessed in the animals or humans, alongside a control group challenged via IV injection. More specifically, a different dosage ranges will be administered to the animal either subcutaneously or intravenously, and blood samples will be taken and analysed at different time points over a define period of time to measure the serum concentration of camoteskimab. These analyses will confirm that subcutaneous injections can effectively deliver the required serum concentration of camoteskimab for use in clinical studies. Comparative analysis of the results obtained from the test and control group will then be conducted to determine how closely the PK profile and antibody clearance of a SC administration compares to IV. These data will be used to refine the PK model and dosage simulations prior to commencing clinical studies in human patients to test low SC dosages of camoteskimab.

[0157] Example 3 - Population pharmacokinetics models assessing subcutaneous administration of Camoteskimab in Subjects with atopic dermatitis (AD) The PK model described in Example 1 was further used to simulate three dosage regimens of low doses of 30 mg, 100 mg and 300 mg (equivalent to 0.4 mg / kg, 1.4 mg / kg, and 4 mg / kg respectively) given on a Q12W schedule (every 12 weeks). A simulation of the higher dose of 300mg given on a Q4W (every 4 weeks) was also included in the study. These simulations have been used to examine the remaining fraction of free IL-18 after camoteskimab treatment. The results of the model are presented in Figures 5. Given that the elevated levels of IL-18 in UC, CD and EoE are similar to those described for AD, these PK simulations would be equally relevant for the treatment of UC, CD and EoE with subcutaneous low doses administrations of camoteskimab.

[0158] Each graph represents 100 individual simulations, with the mean shown as a solid black line. These data show that all doses and dose regimens achieve greater than 90% neutralisation of IL-18. This indicates that not only low doses of camoteskimab, but also longer and more convenient dosing intervals, achieve IL-18 blockade that translates into meaningful clinical efficacy.

[0159] Example 4 - Formulation of anti-IL-18 antibody drug suitable for subcutaneous delivery.

[0160] The inventors prepared a concentrated formulation of 100 mg / ml camoteskimab and subsequently evaluated its characteristics and suitability for subcutaneous injection using a microinjector.. Preliminary results demonstrate that the concentrated formulation has the appropriate characteristics to allow subcutaneous administration and use of a microinjector device. Of note, the pH is in a range that is unlikely to cause any adverse injection site pain and the viscosity is suitable for use in standard autoinjector devices.

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[0180] Yadavalli CS, Upparahalli Venkateshaiah S, Kumar S, Kandikattu HK, Oruganti L, Kathera CS, Mishra A. Allergen-induced NLRP3 / caspasel / IL-18 signaling initiate eosinophilic esophagitis and respective inhibitors protect disease pathogenesis. Commun Biol. 2023 Jul 31;6(1):763.

[0181] Zedan K, Rasheed Z, Farouk Y, Alzolibani AA, Bin Saif G, Ismail HA, Al Robaee AA. Immunoglobulin e, interleukin-18 and interleukin-12 in patients with atopic dermatitis: correlation with disease activity. J Clin Diagn Res. 2015 Apr;9(4): WC01- 5. McGowan LM, Davey Smith G, Gaunt TR, Richardson TG. Integrating Mendelian randomization and multiple-trait colocalization to uncover cell-specific inflammatory drivers of autoimmune and atopic disease. Hum Mol Genet. 2019 Oct l;28(19):3293-3300. The following table provides the sequences referred to in this application. Table 1 - Table of Sequences

Claims

Claims1. Camoteskimab or an antigen-binding fragment thereof, for use in treating, preventing or ameliorating atopic dermatitis (AD), in a subject, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of 0.1 < 4mg / kg.

2. Camoteskimab or an antigen-binding fragment thereof for use according to claim 1, wherein the Camoteskimab or antigen-binding fragment thereof comprises the following six CDRs:(a) a heavy chain CDR having an amino acid sequence of SEQ ID NO: 122;(b) a heavy chain CDR having an amino acid sequence of SEQ ID NO: 123;(c) a heavy chain CDR having an amino acid sequence of SEQ ID NO: 124;(d) a light chain CDR having an amino acid sequence of SEQ ID NO: 126; (e) a light chain CDR having an amino acid sequence of SEQ ID NO: 127; and(f) a light chain CDR having an amino acid sequence of SEQ ID NO: 128.

3. Camoteskimab or an antigen-binding fragment thereof for use according to claim 2, wherein the anti-IL-18 antibody or antigen-binding fragment thereof comprises Camoteskimab CDRs with amino acid residue substitutions: (a) a HCDR1 having an amino acid sequence identical to or comprising 1, 2, or 3 amino acid residue substitutions relative to SEQ ID NO: 122; (b) a HCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 123; (c) a HCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4 or 5 amino acid residue substitutions relative to SEQ ID NO: 124; (d) a LCDR1 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 126; (e) a LCDR2 having an amino acid sequence identical to or comprising 1, 2, 3 or 4 amino acid residue substitutions relative to SEQ ID NO: 127; and (f) aLCDR3 having an amino acid sequence identical to or comprising 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acid residue substitutions relative to SEQ ID NO: 128.

4. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of:(i) between 0.1 and 3.9 mg / kg, between 0.1 and 3.8 mg / kg, between 0.1 and 3.5 mg / kg, or between 0.1 and 3mg / kg; or(ii) about 3 mg / kg, about 3.25 mg / kg, about 3.5 mg / kg, or about 3.75 mg / kg.

5. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of between 0.15 and 3.2 mg / kg, between 0.15 and 3.2 mg / kg, or between 0.15 to 3 mg / kg.

6. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of between 0.2 and 2.7 mg / kg, between 0.2 and 2.5 mg / kg, or between 0.25 and 2.5 mg / kg.

7. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 0.1 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, or about 0.75 mg / kg.

8. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 0.4 mg / kg.

9. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 0.25 mg / kg.

10. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 1 mg / kg, about 1.25 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, or about 1.75 mg / kg.

11. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 1 mg / kg.

12. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 1.4 mg / kg.

13. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 2 mg / kg, about 2.25 mg / kg, about 2.5 mg / kg, or about 2.75 mg / kg.

14. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 2 mg / kg.

15. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 3 mg / kg, about 3.25 mg / kg, about 3.5 mg / kg, about 3.75 mg / kg, or about 4 mg / kg.

16. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of about 4 mg / kg.

17. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered for a period of at least 16 weeks.

18. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered once per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every 12 weeks.

19. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered once every four weeks.

20. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof is administered once every twelve weeks.

21. Camoteskimab or an antigen-binding fragment thereof for use according to any preceding claim, wherein the Camoteskimab or antigen-binding fragment thereof specifically binds to free IL-18, and not to IL-18 bound to its corresponding receptor or the IL-18 binding protein (IL-18bp).

22. Camoteskimab or antigen-binding fragment thereof, for use in treating, preventing or ameliorating atopic dermatitis (AD), in a subject, wherein Camoteskimab or antigen-binding fragment thereof is administered subcutaneously at a dose of 0.1 < 4mg / kg, and wherein Camoteskimab competes for binding to IL-18 with any antibody molecule which: (i) binds IL-18 and (ii) comprises an antibody molecule, VH and / or VL domain, CDR e.g. HCDR3, and / or set of CDRs listed in the Table 1.

23. Camoteskimab or antigen-binding fragment thereof for use according to claim 22, wherein the Camoteskimab or antigen-binding fragment thereof is defined as in any one of claims 2-21.

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