IL-18 binding protein (IL-18BP) and antibodies in inflammatory diseases

Abstract

To provide compositions for treating Interleukin 18 (IL-18)-associated diseases and disorders.SOLUTION: The present invention discloses antibodies specific for free IL-18 and IL-18 Binding Protein (IL-18BP) for use in such treatments and for the diagnosis of the diseases and disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides means and methods for treating interleukin-18 (IL-18)-associated diseases and disorders, particularly for treating Still's disease. In particular, the present invention discloses antibodies that specifically bind to free IL-18 and IL-18 binding protein (IL-18BP) for use in such treatments and in assays to quantify free IL-18 in body fluids. [Background technology]

[0002] Interleukin-18 (IL-18), also known as interferon-γ inducer, is a cytokine produced by activated macrophages, Kupffer cells, and other cells. IL-18 binds to the IL-18 receptor to induce cell-mediated immunity. Deficiency (e.g., knockout) of the IL-18 cytokine receptor or IL-18 cytokine leads to impaired natural killer (NK) cell activity and TH1 responses. Apart from its physiological role, IL-18 can also induce severe inflammatory disorders. Therefore, quantifying the level of free IL-18 in the body fluids of subjects suspected of having such disorders is considered necessary for early diagnosis of such disorders.

[0003] However, currently, quantification of IL-18 levels in body fluids is typically performed using ELISA assays with antibodies that are nonspecific for detecting free IL-18. The results obtained by ELISA assays are limited by the specificity of the primary antibody used, which binds to the target antigen. To date, total IL-18 levels can only be detected using commercially available antibodies, but no antibodies against free IL-18 have been reported. Detection of total IL-18 is insufficient for assessing free IL-18 levels because IL-18 bound in complexes, such as IL-18 bound to its natural antagonist, IL-18 binding protein (IL-18BP), has reduced affinity for the IL-18 receptor. Furthermore, it is known that increased IL-18 levels are often accompanied by increased IL-18BP levels.

[0004] For the reasons mentioned above, determining total IL-18 is insufficient for adequate diagnosis of IL-18-related diseases. This means that in order to be able to assess the level of free IL-18 in a subject's body fluids and to adequately diagnose IL-18-related diseases, a detection means that specifically binds to free IL-18 but does not bind to IL-18 bound in a complex is considered necessary. For this reason, there is currently no effective treatment for IL-18-related diseases or disorders.

[0005] One such disease, which develops with elevated levels of free IL-18 in body fluids, is Still's disease.

[0006] Adult-onset Still's disease (AoSD), described in 1971 by E. Bywaters {Bywaters, 1971}, is a multifactorial autoinflammatory disease of unknown etiology. Various infectious agents appear to play an important role, likely acting as triggers in genetically predisposed hosts {Bagnari et al. 2010}. It is characterized by multiple pathological components with distinct clinical manifestations, clinical course, and prognosis. The most frequent components of active disease include spiking fever, a resolving salmon-pink rash, arthralgia or arthritis, pharyngitis, hepatosplenomegaly, and various multiorgan complications. A systemic inflammatory response, including various laboratory abnormalities indicative of liver damage, such as neutrophilia and acute-phase reactants including high levels of ferritin and a low proportion of its glycosylated forms, while rheumatoid factor and antinuclear antibodies are consistently negative, are key features of this condition {Bagnari et al. 2010}. In the absence of specific symptoms, diagnosis is often very complex, and classification criteria may be useful {Yamaguchi et al., 1992}.

[0007] Although the pathogenesis of AoSD remains unclear, activation of macrophages, Th1, and possibly Th17 cells appears to play a role in the cellular basis of the disease {Efthimiou et al., 2007}. Proinflammatory cytokines, such as IL-18, IL-1β, IL-6, TNF-α, and IFN-Y, produced by activated immune cells contribute to the clinical and biochemical components of the disease {Kawaguchi et al., 2001}. The cyclical nature of the disease course and the high levels of IL-18 and IL-1β suggest that innate immune activation plays a central pathogenic event. Furthermore, inflammasome activation has recently been implicated. Taken together, these features support the classification of this entity as part of a group of autoinflammatory diseases {Pouchot and Arlet, 2012} {Gattorno and Martini, 2013}.

[0008] In the case of AoSD, IL-18 appears to be the primary proximal mediator of the inflammatory cascade {Kawaguchi et al., 2001}. IL-18 reaches higher levels in AoSD than in any other rheumatic condition, and more importantly, there is a strong correlation between IL-18 levels and clinical and laboratory markers of disease activity {Kawashima et al., 2001}. Serum IL-18 levels decrease during remission due to successful treatment.

[0009] Current pharmacological treatment modalities for AoSD, such as disease-modifying antirheumatic drugs (DMARDs) and corticosteroids, are largely empirical and may have an unfavorable long-term risk / benefit profile. Novel biologics targeting proinflammatory cytokines, investigated in exploratory clinical trials enrolling small patient cohorts, have emerged as a treatment option for AoSD {Fautrel, 2008} {Pouchot and Arlet, 2012} {Mavragani et al., 2012}. To date, definitive and consistent safety and efficacy results have not been achieved. Summary of the Invention

[0010] The present invention provides new opportunities for treating Still's disease by combining true quantification of free IL-18 in the body fluids of patients to be treated with therapeutic targeting of IL-18 with IL-18 binding proteins (IL-18BPs) or antibodies that specifically bind to free IL-18, providing a significant competitive advantage over other anti-cytokine biologics by neutralizing IL-18 and blocking downstream cytokines such as IL-6 and TNF-α, which are also involved in the pathogenesis of AoSD.

[0011] Another group of diseases that develops with elevated levels of free IL-18 in body fluids are autoinflammatory diseases.

[0012] Autoinflammatory diseases are caused by dysregulation of innate immunity and typically present in early childhood with fever and disease-specific patterns of systemic and organ-specific inflammation and dysfunction. Numerous genetic causes of autoinflammatory diseases have been identified, and associations between specific genes and distinct autoinflammatory pathologies have been established. Molecular linkages between causative genes, specific inflammatory pathways, and defined disease phenotypes represent a significant advance in identifying rational therapies for frequently refractory clinical conditions.

[0013] IL-1 blockade therapy has been an important advance in the treatment of autoinflammatory conditions. IL-1 blockade is highly effective in NLRP3-associated cryopyrin-associated periodic syndromes (CAPS) and IL-1 receptor antagonist deficiency (DIRA). However, in other autoinflammatory conditions, responses to treatment are limited to unpublished anecdotes and case reports. Therefore, extending IL-1 blockade in CAPS to other autoinflammatory entities is largely empirical.

[0014] Other pediatric autoinflammatory conditions are associated with various genetic defects that trigger other cell activation pathways involving the production of various mediators. Spontaneously activating mutations in the inflammasome component NLRC4 are associated with severe, early-onset autoinflammatory conditions with recurrent MAS-like flares, and some patients present with severe enterocolitis. NLRC4 mutations also result in constitutively elevated IL-18 secretion.

[0015] X-linked inhibitor of apoptosis (XIAP) is often associated with hemophagocytic lymphohistiocytosis (HLH), a MAS-like syndrome, but can also have other disease phenotypes. Patients with XIAP deficiency and a MAS-like phenotype, as well as those with NLRC4-MAS and other MAS-prone disorders, also exhibit elevated serum levels of IL-18.

[0016] In contrast to other early-onset autoinflammatory conditions such as NOMID, the inventors observed constitutive production and secretion of IL-18 by monocytes, macrophages, and possibly other cell types, as well as the presence of free IL-18 in the serum, in pediatric MAS-like conditions, and concluded that IL-18 blockade may not just be another option for the treatment of autoinflammatory diseases, but may also be the most appropriate treatment for this category of patients.

[0017] Thus, the present invention provides new opportunities for treating pediatric autoinflammatory diseases accompanied by severe systemic inflammation (hereinafter referred to as MAS-like pediatric conditions) by combining the true quantification of free IL-18 in the body fluids of the patient to be treated with therapeutic targeting of IL-18 by IL-18 binding proteins (IL-18BPs) or antibodies that specifically bind to free IL-18. [The present invention 1001] 1. A composition comprising an IL-18 inhibitor or an active fragment thereof, or an IL-18BP or an active fragment thereof, for use in treating an IL-18-associated disease or disorder in a subject, comprising: The subject is suffering from such a disease or disorder, and the subject's body fluid has been determined to have an abnormal level of free IL-18, particularly 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the level of free IL-18 in the body fluid of a healthy control subject, using an assay capable of detecting free IL-18 in the body fluid, and the assay comprises an IL-18BP or an antibody or functional portion thereof, and the antibody or active portion thereof binds to the binding site of IL-18BP or IL-18B. the IL-18 inhibitor or composition binds to IL-18 near the binding site of P but does not bind to the IL-18 / IL-18BP complex, and the IL-18 inhibitor or composition is substantially free of N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP, wherein these mutants are present in an amount of less than 40%, particularly less than 30%, particularly less than 20%, particularly less than 15%, particularly less than 10%, particularly less than 7.5%, particularly less than 5%, particularly less than 2.5%, particularly less than 1%, particularly less than 0.5%, particularly less than 0.25%, particularly less than 0.1%, particularly less than 0.05%, particularly less than 0.01%. A composition comprising the IL-18 inhibitor or an active fragment thereof, or IL-18BP or an active fragment thereof. [The present invention 1002] 1. An IL-18 inhibitor or an active fragment thereof, or a composition comprising an IL-18 inhibitor or an active fragment thereof, for use in treating an IL-18-associated disease or disorder in a subject, comprising: the subject is suffering from such a disease, and the subject's body fluid has been determined to have an abnormal level of free IL-18, particularly 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the level of free IL-18 in the body fluid of a healthy control subject, using an assay capable of detecting free IL-18 in body fluids containing IL-18BP or an antibody or functional portion thereof, and the antibody or active portion thereof binds to the binding site of IL-18BP or an inhibitor of IL-18 that binds to IL-18 near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, the inhibitor being an IL-18BP or an antibody or a functional portion thereof, the antibody or an active portion thereof binding to IL-18 at the binding site of IL-18BP or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and the IL-18 inhibitor or composition comprises sodium chloride, and / or sodium hydroxide and / or sodium phosphate; A composition comprising the IL-18 inhibitor or an active fragment thereof, or IL-18BP or an active fragment thereof. [The present invention 1003] 1. An IL-18 inhibitor or an active fragment thereof, or a composition comprising an IL-18 inhibitor or an active fragment thereof, for use in treating an IL-18-associated disease or disorder in a subject, comprising: The subject is suffering from such a disease, and the subject's body fluid has been determined to have an abnormal level of free IL-18, particularly 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the level of free IL-18 in the body fluid of a healthy control subject, using an assay capable of detecting free IL-18 in body fluids containing IL-18BP or an antibody or functional portion thereof, and the antibody or active portion thereof binds to the binding site of IL-18BP or IL-1 the inhibitor binds to IL-18 near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, the inhibitor is an IL-18BP or an antibody or a functional portion thereof, the antibody or an active portion thereof binds to IL-18 at the binding site of IL-18BP or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and the IL-18 inhibitor or composition is administered to the subject to be treated in multiple doses per day, multiple doses per week, or multiple doses per month. A composition comprising the IL-18 inhibitor or an active fragment thereof, or IL-18BP or an active fragment thereof. [The present invention 1004] An IL-18 inhibitor or composition for use according to any of claims 1001 to 1003, wherein the level of free IL-18 in body fluids has been determined to be 5 pg / mL or more, particularly up to 10,000 pg / mL, compared to 4 pg / mL or less in healthy controls. [The present invention 1005] IL-18 inhibitor or composition for use in any of inventions 1001 to 1004, wherein the IL-18 inhibitor or active fragment thereof is IL-18BP or an active fragment thereof, and said IL-18 inhibitor or composition is substantially free of N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP, these mutants being present in an amount of less than 30%, particularly less than 20%, particularly less than 15%, particularly less than 10%, particularly less than 7.5%, particularly less than 5%, particularly less than 2.5%, particularly less than 1%, particularly less than 0.5%, particularly less than 0.25%, and particularly less than 0.1%. [The present invention 1006] IL-18 inhibitor or composition for use in the present invention 1005, wherein the deletion mutant comprises a deletion of 1 to 5 amino acid residues at the C-terminus of IL-18BP and / or 1 to 30 amino acid residues at the N-terminus of IL-18BP. [The present invention 1007] IL-18 inhibitor or composition for use according to the invention 1005 or 1006, wherein the proportion of deletion mutants in the composition is less than 30%, particularly less than 20%, particularly less than 15%, particularly less than 10%, particularly less than 7.5%, particularly less than 5%, particularly less than 2.5%, particularly less than 1%, particularly less than 0.5%, particularly less than 0.25%, particularly less than 0.1%. [The present invention 1008] Assays for quantifying levels of free IL-18 in body fluids include: a) contacting a sample of body fluid suspected of containing free IL-18 with an IL-18 inhibitor or an active fragment thereof, in particular an IL-18BP or an antibody or an active fragment thereof, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex and acts as a capture molecule for free IL-18; b) binding an IL-18 inhibitor or an active fragment thereof, in particular an IL-18BP or antibody, or an active fragment thereof, to free IL-18; c) determining the amount of free IL-18 in the sample by detecting the binding of an IL-18 inhibitor or an active fragment thereof, in particular an IL-18BP or an antibody, or an active fragment thereof IL-18 inhibitor or composition for use in any of the present inventions 1001 to 1007, comprising: [The present invention 1009] binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; a) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 sections set forth in SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 sections set forth in SEQ ID NO: 312, SEQ ID NO: 313 and SEQ ID NO: 314; b) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:315, SEQ ID NO:316 and SEQ ID NO:317, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:318, SEQ ID NO:319 and SEQ ID NO:320; c) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:321, SEQ ID NO:322 and SEQ ID NO:323, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:324, SEQ ID NO:325 and SEQ ID NO:326; d) CDR1, CDR2 and CDR3 of a heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, and CDR1, CDR2 and CDR3 of a light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 330, SEQ ID NO: 331 and SEQ ID NO: 332; e) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 333, SEQ ID NO: 334 and SEQ ID NO: 335; f) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:336, SEQ ID NO:337 and SEQ ID NO:338, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:345, SEQ ID NO:346 and SEQ ID NO:347; g) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 345, SEQ ID NO: 346 and SEQ ID NO: 347; h) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 342, SEQ ID NO: 343 and SEQ ID NO: 344, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 345, SEQ ID NO: 346 and SEQ ID NO: 347; i) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:348, SEQ ID NO:349 and SEQ ID NO:350, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:357, SEQ ID NO:358 and SEQ ID NO:359; j) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:351, SEQ ID NO:352 and SEQ ID NO:353, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:357, SEQ ID NO:358 and SEQ ID NO:359; k) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 354, SEQ ID NO: 355 and SEQ ID NO: 356, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359; l) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 360, SEQ ID NO: 361 and SEQ ID NO: 362, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365; m) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 360, SEQ ID NO: 361 and SEQ ID NO: 362, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 366, SEQ ID NO: 367 and SEQ ID NO: 368; n) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 372, SEQ ID NO: 373 and SEQ ID NO: 374; o) CDR1, CDR2 and CDR3 of a heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:375, SEQ ID NO:376 and SEQ ID NO:377, and CDR1, CDR2 and CDR3 of a light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:378, SEQ ID NO:379 and SEQ ID NO:380; or p) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 384, SEQ ID NO: 385 and SEQ ID NO: 386. any functionally equivalent antibody or functional portion thereof, including: [The present invention 1010] An antibody comprising any functionally equivalent antibody or portion thereof, wherein the antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and the antibody comprises CDR1, CDR2 and CDR3 of a heavy chain variable region having the sequence determined according to Chothia as shown in Table 8, and CDR1, CDR2 and CDR3 of a corresponding light chain variable region having the sequence determined according to Chothia as shown in Table 8. [The present invention 1011] binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO: 153, SEQ ID NO: 154 and SEQ ID NO: 155, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO: 156, SEQ ID NO: 157 and SEQ ID NO: 158; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:159, SEQ ID NO:160 and SEQ ID NO:161, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:162, SEQ ID NO:163 and SEQ ID NO:164; c) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 168, SEQ ID NO: 169 and SEQ ID NO: 170; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:171, SEQ ID NO:172 and SEQ ID NO:173, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:174, SEQ ID NO:175 and SEQ ID NO:176; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:171, SEQ ID NO:172 and SEQ ID NO:173, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:177, SEQ ID NO:178 and SEQ ID NO:179; f) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:180, SEQ ID NO:181 and SEQ ID NO:182, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:189, SEQ ID NO:190 and SEQ ID NO:191; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:183, SEQ ID NO:184 and SEQ ID NO:185, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:189, SEQ ID NO:190 and SEQ ID NO:191; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:186, SEQ ID NO:187 and SEQ ID NO:188, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:189, SEQ ID NO:190 and SEQ ID NO:191; i) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:192, SEQ ID NO:193 and SEQ ID NO:194, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:201, SEQ ID NO:202 and SEQ ID NO:203; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:195, SEQ ID NO:196 and SEQ ID NO:197, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:201, SEQ ID NO:202 and SEQ ID NO:203; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:198, SEQ ID NO:199 and SEQ ID NO:200, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:201, SEQ ID NO:202 and SEQ ID NO:203; l) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:204, SEQ ID NO:205 and SEQ ID NO:206, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:207, SEQ ID NO:208 and SEQ ID NO:209; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:204, SEQ ID NO:205 and SEQ ID NO:206, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:210, SEQ ID NO:211 and SEQ ID NO:212; n) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 213, SEQ ID NO: 214 and SEQ ID NO: 215, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 216, SEQ ID NO: 217 and SEQ ID NO: 218; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:219, SEQ ID NO:220 and SEQ ID NO:221, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:222, SEQ ID NO:223 and SEQ ID NO:224; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 225, SEQ ID NO: 226 and SEQ ID NO: 227, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 228, SEQ ID NO: 229 and SEQ ID NO: 230 The antibody of the present invention 1010, including any functionally equivalent antibody or functional portion thereof, comprising: [The present invention 1012] An antibody comprising any functionally equivalent antibody or portion thereof, wherein the antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and the antibody comprises CDR1, CDR2 and CDR3 of a heavy chain variable region having the sequence determined according to Kabat as shown in Table 8, and CDR1, CDR2 and CDR3 of a corresponding light chain variable region having the sequence determined according to Kabat as shown in Table 8. [The present invention 1013] binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:231, SEQ ID NO:232 and SEQ ID NO:233, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:234, SEQ ID NO:235 and SEQ ID NO:236; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:237, SEQ ID NO:238 and SEQ ID NO:239, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:240, SEQ ID NO:241 and SEQ ID NO:242; c) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:243, SEQ ID NO:244 and SEQ ID NO:245, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:246, SEQ ID NO:247 and SEQ ID NO:248; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:249, SEQ ID NO:250 and SEQ ID NO:251, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:252, SEQ ID NO:253 and SEQ ID NO:254; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:249, SEQ ID NO:250 and SEQ ID NO:251, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:255, SEQ ID NO:256 and SEQ ID NO:257; f) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:258, SEQ ID NO:259 and SEQ ID NO:260, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:267, SEQ ID NO:268 and SEQ ID NO:269; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:261, SEQ ID NO:262 and SEQ ID NO:263, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:267, SEQ ID NO:268 and SEQ ID NO:269; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:264, SEQ ID NO:265 and SEQ ID NO:266, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:267, SEQ ID NO:268 and SEQ ID NO:269; i) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:270, SEQ ID NO:271 and SEQ ID NO:272, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:279, SEQ ID NO:280 and SEQ ID NO:281; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:273, SEQ ID NO:274 and SEQ ID NO:275, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:279, SEQ ID NO:280 and SEQ ID NO:281; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:276, SEQ ID NO:277 and SEQ ID NO:278, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:279, SEQ ID NO:280 and SEQ ID NO:281; l) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:282, SEQ ID NO:283 and SEQ ID NO:284, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:285, SEQ ID NO:286 and SEQ ID NO:287; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 282, SEQ ID NO: 283 and SEQ ID NO: 284, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 288, SEQ ID NO: 289 and SEQ ID NO: 290; n) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 291, SEQ ID NO: 292 and SEQ ID NO: 293, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 294, SEQ ID NO: 295 and SEQ ID NO: 296; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:297, SEQ ID NO:298 and SEQ ID NO:299, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:300, SEQ ID NO:301 and SEQ ID NO:302; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 306, SEQ ID NO: 307 and SEQ ID NO: 308 The antibody of the present invention, including any functionally equivalent antibody or functional portion thereof, comprising: [The present invention 1014] An antibody comprising any functionally equivalent antibody or portion thereof, wherein the antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and wherein the antibody comprises CDR1, CDR2 and CDR3 of a heavy chain variable region having the sequence determined according to IMGT as shown in Table 8, and CDR1, CDR2 and CDR3 of a corresponding light chain variable region having the sequence determined according to IMGT as shown in Table 8. [The present invention 1015] binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:33, SEQ ID NO:34 and SEQ ID NO:35, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:36, SEQ ID NO:37 and SEQ ID NO:38; c) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:39, SEQ ID NO:40 and SEQ ID NO:41, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:42, SEQ ID NO:43 and SEQ ID NO:44; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:45, SEQ ID NO:46 and SEQ ID NO:47, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:48, SEQ ID NO:49 and SEQ ID NO:50; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:45, SEQ ID NO:46 and SEQ ID NO:47, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:51, SEQ ID NO:52 and SEQ ID NO:53; f) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:54, SEQ ID NO:55 and SEQ ID NO:56, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:104, SEQ ID NO:105 and SEQ ID NO:106, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:110, SEQ ID NO:111 and SEQ ID NO:112, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; i) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:60, SEQ ID NO:61 and SEQ ID NO:62, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:63, SEQ ID NO:64 and SEQ ID NO:65, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 122, SEQ ID NO: 123 and SEQ ID NO: 124, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 66, SEQ ID NO: 67 and SEQ ID NO: 68; I) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 130, SEQ ID NO: 131 and SEQ ID NO: 132, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 136, SEQ ID NO: 137 and SEQ ID NO: 138; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 130, SEQ ID NO: 131 and SEQ ID NO: 132, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 142, SEQ ID NO: 143 and SEQ ID NO: 144; n) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:69, SEQ ID NO:70 and SEQ ID NO:71, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:72, SEQ ID NO:73 and SEQ ID NO:74; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:75, SEQ ID NO:76 and SEQ ID NO:77, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:78, SEQ ID NO:79 and SEQ ID NO:80; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 54, SEQ ID NO: 55 and SEQ ID NO: 56, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 57, SEQ ID NO: 58 and SEQ ID NO: 59 The antibody of the present invention 1014, including any functionally equivalent antibody or functional portion thereof, comprising: [The present invention 1016] binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:33, SEQ ID NO:34 and SEQ ID NO:35, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:36, SEQ ID NO:37 and SEQ ID NO:38; c) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:39, SEQ ID NO:40 and SEQ ID NO:41, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:42, SEQ ID NO:43 and SEQ ID NO:44; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:45, SEQ ID NO:46 and SEQ ID NO:47, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:48, SEQ ID NO:49 and SEQ ID NO:50; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:45, SEQ ID NO:46 and SEQ ID NO:47, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:51, SEQ ID NO:52 and SEQ ID NO:53; f) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:54, SEQ ID NO:55 and SEQ ID NO:56, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:104, SEQ ID NO:105 and SEQ ID NO:106, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:110, SEQ ID NO:111 and SEQ ID NO:112, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; i) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:60, SEQ ID NO:61 and SEQ ID NO:62, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:63, SEQ ID NO:64 and SEQ ID NO:65, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 122, SEQ ID NO: 123 and SEQ ID NO: 124, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 66, SEQ ID NO: 67 and SEQ ID NO: 68; I) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 130, SEQ ID NO: 131 and SEQ ID NO: 132, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 136, SEQ ID NO: 137 and SEQ ID NO: 138; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 130, SEQ ID NO: 131 and SEQ ID NO: 132, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 142, SEQ ID NO: 143 and SEQ ID NO: 144; n) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:69, SEQ ID NO:70 and SEQ ID NO:71, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:72, SEQ ID NO:73 and SEQ ID NO:74; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:75, SEQ ID NO:76 and SEQ ID NO:77, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:78, SEQ ID NO:79 and SEQ ID NO:80; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 54, SEQ ID NO: 55 and SEQ ID NO: 56, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 57, SEQ ID NO: 58 and SEQ ID NO: 59 any functionally equivalent antibody or functional portion thereof, including: [The present invention 1017] binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; (a) the VH amino acid sequence of SEQ ID NO 9 and the VK amino acid sequence of SEQ ID NO 10; (b) the VH amino acid sequence of SEQ ID NO 11 and the VK amino acid sequence of SEQ ID NO 12; (c) the VH amino acid sequence of SEQ ID NO 13 and the VK amino acid sequence of SEQ ID NO 14; (d) the VH amino acid sequence of SEQ ID NO 15 and the VK amino acid sequence of SEQ ID NO 16; (e) the VH amino acid sequence of SEQ ID NO 15 and the VK amino acid sequence of SEQ ID NO 17; (f) the VH amino acid sequence of SEQ ID NO 18 and the VK amino acid sequence of SEQ ID NO 19; (g) the VH amino acid sequence of SEQ ID NO 103 and the VK amino acid sequence of SEQ ID NO 19; (h) the VH amino acid sequence of SEQ ID NO 109 and the VK amino acid sequence of SEQ ID NO 19; (i) the VH amino acid sequence of SEQ ID NO 20 and the VK amino acid sequence of SEQ ID NO 22; (g) the VH amino acid sequence of SEQ ID NO 21 and the VK amino acid sequence of SEQ ID NO 22; (k) the VH amino acid sequence of SEQ ID NO 121 and the VK amino acid sequence of SEQ ID NO 22; (l) the VH amino acid sequence of SEQ ID NO 129 and the VK amino acid sequence of SEQ ID NO 135; (m) the VH amino acid sequence of SEQ ID NO 129 and the VK amino acid sequence of SEQ ID NO 141; (n) the VH amino acid sequence of SEQ ID NO 23 and the VK amino acid sequence of SEQ ID NO 24; (o) a VH amino acid sequence of SEQ ID NO 25 and a VK amino acid sequence of SEQ ID NO 26; or (p) the VH amino acid sequence of SEQ ID NO 387 and the VK amino acid sequence of SEQ ID NO 19 Any of the antibodies of the present invention, including any functionally equivalent antibody or functional portion thereof, comprising: [The present invention 1018] Any of the antibodies 1009 to 1017 of the present invention, which is not antibodies 107C6, 108F8, 109A6, 111A6, 131B4, 131E8, 131H1, 132H4, or 133A6 specified in the Sequence Listing based on its VH sequence and VK sequence. [The present invention 1019] Any of the antibodies of the present invention 1009 to 1018, including any functionally equivalent antibody or functional part thereof, which is an antibody selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody, a bispecific antibody or a dual-effect antibody, a simianized antibody, a human antibody, and a humanized antibody. [The present invention 1020] The antibody of the present invention, which is a fully human antibody or a humanized antibody. [The present invention 1021] An IL-18 inhibitor or composition for use in any of the present inventions 1001 to 1008, wherein the antibody used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is any functionally equivalent antibody shown in any of the present inventions 1009 to 1020, or an antibody comprising a functional part thereof. [The present invention 1022] IL-18 inhibitor or composition for use according to the invention 1021, wherein the antibody used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is a human antibody or a humanized antibody. [The present invention 1023] IL-18 inhibitor or composition for use in any of inventions 1001 to 1008, wherein the IL-18 inhibitor is IL-18BP, particularly human IL-18BP, especially recombinant human interleukin-18 binding protein (rhIL-18BP). [The present invention 1024] 1023. An IL-18 inhibitor or composition for use in the present invention, wherein the human IL-18BP is selected from isoforms a, b, c and d of human IL-18BP, particularly isoform a, particularly isoform c, particularly isoforms a, b, c or d shown in Figure 12, especially isoform a of IL-18BP shown as SEQ ID NO:7 in Figure 12, or isoform c shown as SEQ ID NO:389 in Figure 12. [The present invention 1025] IL-18-associated diseases or disorders include chronic obstructive pulmonary disease (COPD), transfusion-associated lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), pediatric autoinflammatory diseases or conditions, Still's disease, particularly adult Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic juvenile-onset idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS), including primary, secondary, and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH), perforin, munc 13-4 and 18-2, synthaxin, and IL-18. Familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with 11 genetic defects; immunodeficiencies such as Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP); acquired hemophagocytic lymphohistiocytosis associated with infectious conditions, especially herpes viruses such as EBV and other pathogens; autoinflammatory syndromes associated with NLRC4 mutations; giant cell arteritis (GCA); septic arthritis, pyoderma gangrenosum, and acne (PAPA); pulmonary sarcoidosis (pulmonary sarcoidosis) sarcoidis), heart failure, ischemic heart disease, dry eye disease (DED), keratitis, corneal ulcers and abrasions, iritis, glaucoma, Sjögren's syndrome, autoimmune uveitis, Behçet's disease, conjunctivitis, allergic conjunctivitis, type 2 diabetes, parenchymal organ and blood stem cell transplantation, ischemia-reperfusion injury, familial Mediterranean fever (FMF), tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS), hyper-IgD syndrome (mevalonate kinase gene mutation), gout, IL-18 inhibitor or composition for use in any of claims 1001 to 1008 and 1021 to 1024, wherein the IL-18 inhibitor or composition is selected from the group consisting of Schnitzler syndrome, Wegener's granulomatosis also known as granulomatosis with polyangiitis (GPA), Hashimoto's thyroiditis, Crohn's disease, early-onset inflammatory bowel disease (EOIBD), very EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis, and Blau syndrome (NOD-2 mutation). [The present invention 1026] The target is the major items of the Yamaguchi Standards, especially: i. Fever above 39°C lasting more than one week; ii. 10,000 / mm with more than 80% PMNs 3 Leukocytosis above iii. Typical skin rash, iv. Joint pain lasting more than 2 weeks The IL-18 inhibitor or composition for use in the present invention 1025, wherein the patient has been diagnosed with Still's disease based on the presence of at least two of the Yamaguchi criteria selected from the group consisting of: and optionally, elevated inflammatory markers. [The present invention 1027] An IL-18 inhibitor or composition for use in the present invention 1025, wherein the IL-18-related disease or disorder is part of the chronic obstructive pulmonary disease (COPD) syndrome induced by smoking, exposure to secondhand smoke, or air pollutants in general, and is characterized by the presence of poorly reversible airflow limitation. [The present invention 1028] An IL-18 inhibitor or composition for use in any of claims 1001 to 1008 and 1021 to 1024, wherein the IL-18-related disease or disorder involves multiple components of heterogeneous COPD disease and COPD exacerbations induced by viral or bacterial infection. [The present invention 1029] IL-18 inhibitor or composition for use in any of inventions 1001 to 1008 and 1021 to 1028, wherein the disease or disorder associated with IL-18 is systemic symptoms of inflammation induced by IL-18 and accompanying comorbidities, and the accompanying comorbidities are selected from the group consisting of emphysema, tissue inflammation, tissue destruction, lung resection, loss of vasculature, endothelial cell apoptosis, mucosal metaplasia, cardiac hypertrophy, decreased VEGF in lung tissue, pulmonary vascular loss, vascular muscularization, vascular remodeling, collagen deposition, abnormal elastin layers in the lungs, fibrous airway remodeling, alveolar enlargement, chronic remodeling of airways and pulmonary vessels, and decreased pulmonary function. [The present invention 1030] An IL-18 inhibitor, particularly IL-18BP, or an active fragment or variant thereof, or a composition comprising said IL-18 inhibitor, particularly IL-18BP, or an active fragment or variant thereof, or any of the compositions of inventions 1001 to 1008 and 1021 to 1024, for use in treating a pediatric autoinflammatory disease or condition and / or symptoms associated with said disease or condition. [The present invention 1031] The IL-18 inhibitor or composition for use in accordance with the present invention 1030, wherein the pediatric autoinflammatory disease or condition is a MAS-like pediatric disease or condition, including primary, secondary and recurrent MAS. [The present invention 1032] The IL-18 inhibitor or composition for use in accordance with the present invention 1031, wherein the MAS-like pediatric disease or condition is an IL-18-associated pediatric autoinflammatory disease or condition accompanied by severe systemic inflammation. [The present invention 1033] The IL-18 inhibitor or composition for use in the present invention 1032, wherein the autoinflammatory disease or condition accompanied by severe systemic inflammation is caused by an NLRC4 mutation. [The present invention 1034] IL-18 inhibitor or composition for use in the present invention 1032, wherein the autoinflammatory disease or condition associated with severe systemic inflammation is associated with XIAP deficiency. [This invention 1035] The IL-18 inhibitor or composition for use in the present invention 1034, wherein the XIAP deficiency is caused by a mutation in XIAP / BIRC4. [The present invention 1036] IL-18 inhibitor or composition for use of invention 1034 or invention 1035 for the treatment of X-linked inhibitor of apoptosis protein deficiency (XIAP) and / or X-linked lymphoproliferative syndrome 2 (XLP2), particularly when caused by mutations in XIAP / BIRC4. [This invention 1037] IL-18 inhibitor or composition for use in the present invention 1036 for the treatment of severe early-onset hemophagocytic lymphohistiocytosis / MAS (HLH / MAS) with monogenic XIAP deficiency caused by mutations in XIAP / BIRC4. [The present invention 1038] The IL-18 inhibitor or composition of any of claims 1030 to 1007 of the present invention for treating enteritis, particularly Crohn's-like enteritis, caused by or accompanied by XIAP deficiency. [This invention 1039] IL-18 inhibitor or composition of the present invention for use in reducing the susceptibility of patients suffering from XIAP deficiency to viral infection, particularly EBV and / or CMV infection, either before viral infection occurs or after viral clearance through treatment with antiviral drugs. [The present invention 1040] IL-18 inhibitor or composition for use according to any of claims 1030 to 1039, wherein high levels of IL-18 and free IL-18 are associated with autoinflammatory diseases or conditions involving severe systemic inflammation. [The present invention 1041] An IL-18 inhibitor, particularly IL-18BP, or an active fragment or variant thereof, or a composition comprising said IL-18 inhibitor, particularly an IL-18 inhibitor or composition of any of 1001 to 1008 and 1021 to 1024 of the present invention, for the treatment of early-onset severe septic arthritis-pyoderma gangrenosum-acne (PAPA). [The present invention 1042] An IL-18 inhibitor, particularly IL-18BP, or an active fragment or variant thereof, or a composition comprising said IL-18 inhibitor, particularly the IL-18 inhibitor or composition of any of claims 1001 to 1008 and 1021 to 1024 of the present invention, for the treatment of early-onset inflammatory bowel disease (EOIBD), very EOIBD (VEOIBD), infantile IBD, and neonatal IBD. [This invention 1043] IL-18 inhibitor or composition for use in any of claims 1030 to 1042, wherein the IL-18 inhibitor is IL-18BP, particularly human IL-18BP, especially recombinant human interleukin-18 binding protein (rhIL-18BP). [This invention 1044] IL-18 inhibitor or composition for use in the present invention 1043, wherein human IL-18BP is selected from isoforms a, b, c and d of human IL-18BP, particularly isoform a, particularly isoform c, particularly isoforms a, b, c or d shown in Figure 12, especially isoform a of IL-18BP shown as SEQ ID NO:7 in Figure 12, or isoform c shown as SEQ ID NO:390 in Figure 12. [This invention 1045] An IL-18 inhibitor or composition for use according to any of claims 1030 to 1042, wherein the IL-18 inhibitor is an antibody, or a functionally equivalent antibody or a functional part thereof, which antibody binds to free IL-18 at the binding site of IL-18BP or in the vicinity of the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and in particular is an antibody according to any of claims 1009 to 1020 or a functionally equivalent antibody or a functional part thereof. [The present invention 1046] IL-18 inhibitor or composition for use in any of inventions 1001-1008 and 1021-1045, wherein treatment comprises preventing, arresting, alleviating or ameliorating symptoms associated with said disease or disorder. [This invention 1047] IL-18 inhibitor or composition for use in any of inventions 1001 to 1008 and 1021 to 1046, in which increased expression of IFNγ, IL-13 or IL-17A is modified, in particular inhibited, compared to an untreated subject suffering from said disease or disorder. [This invention 1048] An IL-18 inhibitor or composition for use in any of the present inventions 1001 to 1008 and 1021 to 1047, which corrects the IL-18 / IL-18BP imbalance by capturing and neutralizing excess free IL-18 in tissues and circulation through binding of free IL-18 by IL-18BP. [This invention 1049] An IL-18 inhibitor or composition for use in any of the present inventions 1001 to 1008 and 1021 to 1048, wherein IL-18BP inhibits neutrophil infiltration into the lungs, particularly through attenuation of G-CSF release in the pulmonary airways. [The present invention 1050] An IL-18 inhibitor or composition for use in any of the present inventions 1001 to 1008 and 1021 to 1049, in which the binding of IL-18, particularly the binding of free IL-18 to the IL-18 receptor (IL-18R), is limited or inhibited, and in particular the binding of free IL-18 to IL-18Rα is neutralized, limited or prevented. [This invention 1051] IL-18 inhibitor or composition for use in accordance with the present invention 1050, wherein the IL-18BP reduces the binding of IL-18 to the IL-18 receptor, in particular to IL-18Rα, by at least 5%, particularly at least 10%, particularly at least 15%, particularly at least 20%, particularly at least 25%, particularly at least 30%, particularly at least 40%, particularly at least 45%, particularly at least 50%, particularly at least 55%, particularly at least 60%, particularly at least 65%, particularly at least 70%, particularly at least 75%, particularly at least 80%, particularly at least 85%, particularly at least 90%, particularly at least 95%, particularly 100%. [This invention 1052] IL-18 inhibitor or composition for use in any of inventions 1001-1008 and 1021-1051, wherein the subject to be treated has been exposed to one or more compounds selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDS), prednisone, synthetic disease-modifying anti-rheumatic drugs (sDMARDs), immunosuppressants and biological immunosuppressants, but has not responded to treatment, particularly non-steroidal anti-inflammatory drugs (NSAIDs) and prednisone at a dose of at least 5 mg / day for one month or more, and / or synthetic disease-modifying anti-rheumatic drugs (sDMARDs) at a dose of at least 10 mg / day for three months or more, or has only an incomplete response to treatment. [This invention 1053] IL-18 inhibitor or composition for use according to any of claims 1001 to 1008 and 1021 to 1052, administered in multiple doses per day, multiple doses per week, or multiple doses per month to a subject in need thereof. [This invention 1054] IL-18 inhibitor or composition for use in any of inventions 1001-1008 and 1021-1053, administered in one dose per week, two doses per week, three doses per week, or four doses per week. [This invention 1055] An IL-18 inhibitor or composition for use in any of claims 1001 to 1008 and 1021 to 1054 of the present invention, administered every 24 to 48 hours. [This invention 1056] IL-18 inhibitor or composition for use in any of claims 1001 to 1008 and 1021 to 1055, wherein a single dose comprises 0.5 mg to 600 mg of IL-18BP, particularly 10 mg to 600 mg of IL-18BP, particularly 10 to 20 mg, particularly 20 to 40 mg, particularly 40 to 80 mg, particularly 80 to 160 mg, particularly 160 mg to 320 mg, or particularly 320 mg to 600 mg of IL-18BP. [This invention 1057] 10. An IL-18 inhibitor, particularly an IL-18BP, for use in accordance with the present invention, or a composition, wherein a single dose comprises from 0.5 mg IL-18 inhibitor / kg body weight to 10 mg IL-18 inhibitor / kg body weight, particularly from 1 mg IL-18 inhibitor / kg body weight to 8 mg IL-18 inhibitor / kg body weight, particularly from 2 mg IL-18 inhibitor / kg body weight to 6 mg IL-18 inhibitor / kg body weight, particularly from 1 mg IL-18 inhibitor / kg body weight to 5 mg IL-18 inhibitor / kg body weight. [This invention 1058] An IL-18 inhibitor, particularly an IL-18BP, or composition for use in any of inventions 1001 to 1008 and 1021 to 1057, wherein a single dose of 0.5 mg IL-18 inhibitor / kg body weight to 5 mg IL-18 inhibitor / kg body weight is administered every 24 hours or every 48 hours, particularly a single dose of 1 mg IL-18 inhibitor / kg body weight is administered every 48 hours. [This invention 1059] The treated subject demonstrates at least a therapeutic response, in particular (a) normalization of body temperature (normal range is 36.3–37.4°C measured in the axilla in the absence of NSAIDs in the 24 hours prior to measurement); (b) improvement in joint swelling and tenderness (20% or more); and (c) ≥70% decrease in CRP or normalization of CRP and ferritin to baseline levels IL-18 inhibitor or composition for use in any of claims 1001 to 1008 and 1021 to 1058, wherein treatment is continued until the patient shows a therapeutic response characterized by: [The present invention 1060] IL-18 inhibitor or composition for use according to any of claims 1001 to 1008 and 1021 to 1059 for treatment in a mammal, particularly a human. [This invention 1061] An IL-18 inhibitor or composition for use according to any one of present inventions 1001 to 1008 and 1021 to 1060, which is a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [This invention 1062] 1. A method for treating an IL-18 associated disease or disorder in a subject, comprising: the subject is suffering from such a disease or disorder, and in particular the subject's body fluid has been determined to have an abnormal level of free IL-18, particularly 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the level of free IL-18 in the body fluid of a healthy control subject, using an assay capable of detecting free IL-18 in the body fluid, and the assay comprises an IL-18BP or an antibody or functional portion thereof, wherein the antibody or active portion thereof binds to IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and the method comprises the step of administering to the subject an IL-18 inhibitor or an active fragment thereof of any of the inventions 1001 to 1008 and 1021 to 1061. [The present invention 1063] The method of claim 1062, wherein the disease or disorder is defined in any one of claims 1025 to 1042. [The present invention 1064] A method of the present invention 1063 for the treatment of a pediatric autoinflammatory disease or condition, particularly a MAS-like pediatric disease or condition, and / or symptoms associated with said disease or condition, comprising the step of administering an IL-18 inhibitor or a composition comprising an IL-18 inhibitor to a subject suffering from such a disease or condition. [This invention 1065] The method of claim 1064, wherein the pediatric autoinflammatory disease or condition is one of the diseases or conditions listed in any of claims 1030-1040. [The present invention 1066] The method of invention 1064 or invention 1065, wherein an IL-18 inhibitor, particularly IL-18BP, or an active fragment or variant thereof, and a composition comprising an IL-18 inhibitor, particularly IL-18BP, or an active fragment or variant thereof, is administered at a frequency and / or in a dosage as set out in any of inventions 1052 to 1058. [This invention 1067] The method of any one of claims 1062 to 1066, wherein the subject to be treated is a mammal or a human. [The present invention 1068] 1. A method for determining the amount of free IL-18 in a sample or in situ, comprising detecting specific binding of an antibody as defined in any of claims 1009 to 1020 to free IL-18 protein in the sample or in situ, a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any of claims 1009 to 1020, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample. The method comprising: [This invention 1069] 1. A method for diagnosing an IL-18-related disease or disorder in a patient, in particular an IL-18-related disease or disorder as defined in any of the present inventions, comprising the step of detecting specific binding of an antibody as defined in any of the present inventions 1009 to 1020 to free IL-18 protein in a sample or in situ, a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any of claims 1009 to 1020, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any of the present invention with the amount in a sample from a healthy subject. The method comprising: [The present invention 1070] 1. A method for diagnosing a predisposition to an IL-18 associated disease or disorder in a patient, in particular an IL-18 associated disease or disorder as defined in any of the present inventions, comprising the step of detecting specific binding of an antibody as defined in any of the present inventions 1009 to 1020 to free IL-18 protein in a sample or in situ, a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any of claims 1009 to 1020, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any of the present invention with the amount in a sample from a healthy patient. wherein a higher amount of free IL-18 in the sample compared to a normal control value obtained from a healthy patient indicates that the patient is suffering from or at risk of developing a disease or disorder as defined in any of the present inventions. [This invention 1071] 1. A method for monitoring minimal residual disease in a patient after treatment with an IL-18 inhibitor or composition as defined in any of claims 1001 to 1008 and 1021 to 1061, comprising: a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any of claims 1009 to 1020, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any of the present invention with the amount in a sample from a healthy patient. wherein an increased amount of free IL-18 in the sample compared to a normal control value obtained from a healthy patient indicates that the patient is still suffering from minimal residual disease. [This invention 1072] 1. A method for predicting the responsiveness of a patient to treatment with an IL-18 inhibitor or composition as defined in any of claims 1001 to 1008 and 1021 to 1061, comprising: a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any of claims 1009 to 1020, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a patient suffering from any of the diseases or disorders defined in the present invention with the amount in a sample from a healthy patient. wherein a low amount of free IL-18 in the sample indicates that the patient is likely to respond to treatment. [This invention 1073] The method of any of claims 1068 to 1072, comprising in step a) a further step of using an IL-18BP-specific binding molecule that binds to a site on IL-18BP that is different from the capture molecule, in particular one of these molecules binds to the IL-18 binding site on IL-18BP. [This invention 1074] The method of any of claims 1068 to 1072, comprising the further steps of: in step a), using an IL-18BP-specific capture molecule and an IL-18BP-specific detection molecule that binds to a site on IL-18BP that is different from the capture molecule, in particular one of these IL-18BP-specific molecules that binds to the IL-18-binding site on IL-18BP, and determining in step c) the amount of free and total IL-18 and free and total IL-18BP bound to the capture molecules in the sample; and in step d), determining the presence of free IL-18BP in the sample by comparing the amount of free and / or total IL-18 and free and / or total IL-18BP in a sample from a patient suffering from a disease or disorder as defined in any of the preceding claims with the amounts in a sample from a healthy patient. [This invention 1075] The capture molecule is a. IL-18BP, in particular as defined in any of claims 1023 and 1024 of the present invention; b. IL-18-specific antibody defined in any one of items 1009 to 1020 of the present invention Any of the methods of the present inventions 1068 to 1074. [This invention 1076] 1076. The method of any of claims 1068 to 1075, wherein the sample is selected from the group consisting of bronchoalveolar lavage fluid (BALF) circulating fluid, secretions, biopsies, and homogenized tissue, in particular serum, urine, tears, saliva, bile, sweat, exhaled or expired breath, sputum, bronchoalveolar fluid, sebum, cellular, glandular, mucosal or tissue secretions. [This invention 1077] Any of the methods of inventions 1068 to 1076, wherein the amount of free IL-18 in isolated serum of a subject, particularly a human, suffering from said disease is 5 pg / mL or more, and particularly up to 10,000 pg / mL, while the amount of free IL-18 in serum of a healthy subject, particularly a healthy human, is 4 pg / mL or less. [This invention 1078] A diagnostic kit for detecting free IL-18, comprising an antibody defined in any one of claims 1009 to 1020 as a capture molecule, a second IL-18-specific binding molecule as a detection molecule, and optionally a second IL-18-specific capture molecule, wherein the detection molecule binds to a site on IL-18 that is different from the capture molecule. [This invention 1079] 1. A method for treating an IL-18-associated disease or disorder in a subject, comprising: a. quantifying the amount of free IL-18 in the subject's body fluid using any of the methods of the present inventions 1068 to 1077; b. administering to a subject having an abnormal level of free IL-18 in a body fluid, determined to be 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more than 100% higher than the level of free IL-18 in the body fluid of a healthy control subject, a therapeutically or prophylactically effective amount of an IL-18 inhibitor or composition as defined in any of the preceding inventions, in particular by systemic, intranasal, buccal, oral, transmucosal, intratracheal, intravenous, subcutaneous, intraurinary, intravaginal, sublingual, intrabronchial, intrapulmonary, transdermal or intramuscular administration, in particular bronchopulmonary administration. The method comprising: DETAILED DESCRIPTION OF THE INVENTION

[0018] In particular, the present invention provides in a first aspect an IL-18 inhibitor, in particular an IL-18 binding protein (IL-18BP) as defined herein or an active fragment or variant thereof, or a composition comprising an IL-18 inhibitor, in particular an IL-18BP as defined herein, or an active fragment or variant thereof, for use in treating an IL-18 associated disease or disorder in a subject suffering from such disease or disorder, in particular wherein the body fluid in the subject is detected using an assay capable of detecting free IL-18 in (i) abnormal levels of free IL-18, particularly levels of free IL-18 that are 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or greater than 100% greater than the levels of free IL-18 in the body fluids of healthy control subjects; and / or (ii) an abnormal ratio of free IL-18 / IL-18BP in the body fluid compared to the levels in the body fluid of a healthy control subject, in particular a ratio of free IL-18 to IL-18BP that is 1%, 2.5%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% greater than the ratio in the body fluid of a healthy control subject; The assay comprises an IL-18BP or an antibody or functional portion thereof, wherein the antibody or active portion thereof binds to IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex.

[0019] In one specific embodiment of the present invention, said composition is substantially free of N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP.

[0020] In various further embodiments of the invention, the deletion mutant comprises a deletion of 1 to 5 amino acid residues from the C-terminus of IL-18BP and / or 1 to 30 amino acid residues from the N-terminus of IL-18BP.

[0021] In particular, the proportion of deletion mutants in the composition according to the invention is less than 30%, particularly less than 20%, particularly less than 15%, particularly less than 10%, particularly less than 7.5%, particularly less than 5%, particularly less than 2.5%, particularly less than 1%, particularly less than 0.5%, particularly less than 0.25%, particularly less than 0.1%.

[0022] Such compositions include: - Removing cells and cell debris from the harvested cell culture supernatant by centrifugation and diafiltration, and transferring it to a mixing tank; Concentration of heterogeneous IL-18BP and, in particular, diafiltration against basic borate buffers, especially above pH 7.5; · Capture of IL-18BP is performed on an anion exchange resin, specifically TMAE Hi-Cap anion exchange resin, to remove salts and cell culture nutrients; Elution of IL-18BP with basic buffers, especially borate buffers containing NaCl; applying five further chromatography steps to homogenize IL-18BP, including two tangential flow filtration steps and a viral clearance filtration step; It can be obtained by a purification process including

[0023] These further steps are, in particular: · Processing protein preparations through immobilized metal affinity chromatography, particularly with copper-activated Chelating Sepharose Fast Flow resin, to remove host cell proteins. Elution of proteins, especially with ammonium acetate. Loading the immobilized metal affinity chromatography eluate onto a hydrophobic charge induction chromatography column, especially MEP HyperCel, to further remove host cell proteins. Elution of the product with alkaline phosphate buffer, especially phosphate buffer containing propylene glycol. Concentrating the IL-18BP-containing eluate by diafiltration. Diluting the diafiltration retentate to an acidic pH, especially with 2-(N-morpholino)ethanesulfonic acid (MES) buffer. Separation of proteins by ion exchange chromatography, specifically by loading onto a CM Sepharose Fast Flow column in flow-through mode, to remove residual host cell proteins retained on the column. Adjusting the unbound fraction to a basic pH, especially with sodium tetraborate. Separation of fractions from an ion exchange chromatography step for further polishing by hydrophobic interaction chromatography columns, especially on Phenyl Sepharose Fast Flow. pre-equilibrating the column with a borate buffer containing a high molar concentration of ammonium sulfate and eluting the product from the column by decreasing the molar concentration of ammonium sulfate; Includes:

[0024] In a further embodiment, the composition of the invention, in particular the composition for use according to any one of the previous embodiments, comprises sodium chloride, and / or sodium hydroxide and / or sodium phosphate buffer, in particular at a concentration of 0.01 M to 0.1 M, in particular 0.01 M to 0.05 M, and most particularly 0.01 M.

[0025] In particular, the compositions of the present invention are formulated as sterile solutions for injection and contain sodium chloride, sodium hydroxide, and sodium phosphate buffer, particularly at a concentration of 0.01M.

[0026] In yet another embodiment, the IL-18 inhibitor of the present invention or a composition comprising an IL-18 inhibitor of the present invention, in particular the IL-18 inhibitor or composition for use according to any one of the previous embodiments, is administered to the subject to be treated in multiple doses per day, multiple doses per week, or multiple doses per month.

[0027] In particular, the IL-18 inhibitor of the present invention or a composition comprising an IL-18 inhibitor of the present invention is administered in two doses per week, three doses per week, or four doses per week.

[0028] In one specific embodiment of the present invention, the IL-18 inhibitor of the present invention or a composition comprising an IL-18 inhibitor of the present invention is administered every 24 to 48 hours.

[0029] In another specific embodiment, a single dose of the IL-18 inhibitor of the invention or the composition comprising the IL-18 inhibitor of the invention, in particular the IL-18 inhibitor or composition for use according to any one of the preceding embodiments, comprises between 10 mg and 600 mg of the IL-18 inhibitor, in particular IL-18BP or an active fragment or variant thereof as defined herein.

[0030] In particular, a single dose comprises 10 to 20 mg, 20 to 40 mg, 40 to 80 mg, 80 to 160 mg, 160 mg to 320 mg, or 320 mg to 600 mg of an IL-18 inhibitor, in particular an IL-18BP or an active fragment or variant thereof as defined herein.

[0031] In one specific embodiment, a single dose or dosage unit comprises from 0.5 mg of IL-18 inhibitor / kg body weight to 10 mg of IL-18 inhibitor / kg body weight, particularly from 1 mg of IL-18 inhibitor / kg body weight to 8 mg of IL-18 inhibitor / kg body weight, particularly from 2 mg of IL-18 inhibitor / kg body weight to 6 mg of IL-18 inhibitor / kg body weight, particularly from 1 mg of IL-18 inhibitor / kg body weight to 5 mg of IL-18 inhibitor / kg body weight.

[0032] The single dose or dosage unit as defined above can also be divided into several doses or dosage units to be administered to the subject to be treated over the course of several hours or over the course of a whole day.

[0033] An IL-18 inhibitor for use according to the present invention may be an antibody of the present invention as defined herein and set out in SEQ ID NO, or in particular an IL-18BP of the present invention as defined herein or an active fragment or variant thereof, in particular human IL-18BP, in particular recombinant human interleukin-18 binding protein (rhIL-18BP), among others isoform a of IL-18BP as shown in Figure 12 as SEQ ID NO:7, or isoform c as shown in Figure 12 as SEQ ID NO:390.

[0034] In one specific embodiment, the IL-18 inhibitor of the present invention, particularly IL-18BP, or a composition comprising the IL-18 inhibitor of the present invention, particularly IL-18BP, is administered every 24 hours or every 48 hours in a single dose of 0.5 mg IL-18 inhibitor / kg body weight to 5 mg IL-18 inhibitor / kg body weight.

[0035] In another specific embodiment, the IL-18 inhibitor of the present invention, in particular IL-18BP, or a composition comprising an IL-18 inhibitor of the present invention, in particular IL-18BP, in particular an IL-18 inhibitor or composition for use according to any one of the preceding embodiments, is administered to the subject to be treated until the treated subject shows at least a therapeutic response.

[0036] In one embodiment, the present invention relates to an IL-18 inhibitor of the present invention, in particular IL-18BP, or a composition comprising an IL-18 inhibitor of the present invention, in particular IL-18BP, for use according to any one of the preceding embodiments, wherein the level of free IL-18 in body fluids has been determined to be 5 pg / mL or more, in particular up to 10,000 pg / mL, compared to 4 pg / mL or less in healthy controls.

[0037] In another aspect, the present invention provides an IL-18 inhibitor of the present invention, in particular an IL-18BP, or a composition comprising an IL-18 inhibitor of the present invention, in particular an IL-18BP, for use according to any one of the preceding aspects, wherein the assay for quantifying the level of free IL-18 in a body fluid comprises: a) contacting a sample of a body fluid suspected of containing free IL-18 with an IL-18BP or antibody of the present invention that specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and serves as a capture molecule for free IL-18; b) binding the IL-18BP or antibody to free IL-18; c) detecting binding of IL-18 to the IL-18BP or antibody to determine the amount of free IL-18 in the sample. Includes:

[0038] In various embodiments, the antibodies of the invention, particularly those used in the compositions of the invention, for use according to any one of the above embodiments as inhibitors of IL-18 or as capture molecules in assays for quantifying free IL-18 in body fluids, are antibodies that bind to free IL-18 at or near the binding site of IL-18BP but do not bind to the IL-18 / IL-18BP complex, including any functionally equivalent antibody or functional portion thereof, and that comprise CDR1, CDR2, and CDR3 of a heavy chain variable (VH) region that are comprised in or essentially consist of the corresponding heavy chain CDR section of an antibody having the sequence identified in Table 8 and set forth in column 5 of Table 8, and CDR1, CDR2, and CDR3 of a light chain variable (VK) region that are comprised in or essentially consist of the corresponding light chain CDR section of an antibody having the sequence identified in Table 8 and set forth in column 5 of Table 8.

[0039] In one specific embodiment, the antibodies of the invention have an EC 20 saturation, calculated after titration of the antibody with a defined IL-18 molar concentration. 50 When calculated using the law of mass action from the above values, it binds to free IL-18 with an affinity of less than 2 pM to less than 20 pM, particularly less than 2 pM to less than 15 pM, particularly less than 2 pM to less than 10 pM, particularly less than 2 pM to less than 5 pM, and most particularly less than 2 pM.

[0040] The antibodies of the present invention do not bind to the epitopes disclosed in WO2014 / 037899, filed on September 5, 2013, particularly the epitopes disclosed on pages 28 and 29 of the specification.

[0041] In particular, the antibodies of the present invention do not comprise the CDR and / or variable light and heavy chain sequences disclosed in the sequence listing of WO2014 / 037899, filed September 5, 2013.

[0042] In particular, antibodies of the invention, in particular antibodies used in compositions of the invention, for use according to any one of the above aspects as inhibitors of IL-18 or as capture molecules in assays for quantifying free IL-18 in body fluids, are antibodies that bind to free IL-18 at or near the binding site of IL-18BP but do not bind to the IL-18 / IL-18BP complex, including any functionally equivalent antibody or functional part thereof, and include: a) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 sections set forth in SEQ ID NO: 309, SEQ ID NO: 310 and SEQ ID NO: 311, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 sections set forth in SEQ ID NO: 312, SEQ ID NO: 313 and SEQ ID NO: 314; b) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:315, SEQ ID NO:316 and SEQ ID NO:317, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:318, SEQ ID NO:319 and SEQ ID NO:320; c) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:321, SEQ ID NO:322 and SEQ ID NO:323, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:324, SEQ ID NO:325 and SEQ ID NO:326; d) CDR1, CDR2 and CDR3 of a heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, and CDR1, CDR2 and CDR3 of a light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 330, SEQ ID NO: 331 and SEQ ID NO: 332; e) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 333, SEQ ID NO: 334 and SEQ ID NO: 335; f) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:336, SEQ ID NO:337 and SEQ ID NO:338, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:345, SEQ ID NO:346 and SEQ ID NO:347; g) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 345, SEQ ID NO: 346 and SEQ ID NO: 347; h) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 342, SEQ ID NO: 343 and SEQ ID NO: 344, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 345, SEQ ID NO: 346 and SEQ ID NO: 347; i) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:348, SEQ ID NO:349 and SEQ ID NO:350, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:357, SEQ ID NO:358 and SEQ ID NO:359; j) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:351, SEQ ID NO:352 and SEQ ID NO:353, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:357, SEQ ID NO:358 and SEQ ID NO:359; k) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 354, SEQ ID NO: 355 and SEQ ID NO: 356, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359; l) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 360, SEQ ID NO: 361 and SEQ ID NO: 362, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365; m) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 360, SEQ ID NO: 361 and SEQ ID NO: 362, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 366, SEQ ID NO: 367 and SEQ ID NO: 368; n) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 372, SEQ ID NO: 373 and SEQ ID NO: 374; o) CDR1, CDR2 and CDR3 of a heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:375, SEQ ID NO:376 and SEQ ID NO:377, and CDR1, CDR2 and CDR3 of a light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:378, SEQ ID NO:379 and SEQ ID NO:380; or p) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions shown in SEQ ID NO:381, SEQ ID NO:382 and SEQ ID NO:383, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions shown in SEQ ID NO:384, SEQ ID NO:385 and SEQ ID NO:386.

[0043] The present invention further relates to an antibody of the invention, in particular a composition comprising an antibody of the invention, for use according to any one of the above aspects, wherein the antibody used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is an antibody, including any functionally equivalent antibody or functional part thereof, which antibody or functional part thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and which comprises CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region of an antibody identified in Table 8 and having the sequence set out in Table 8, and CDR1, CDR2 and CDR3 of the light chain (VK) variable region of an antibody identified in Table 8 and having the sequence set out in Table 8.

[0044] The present invention further relates to an antibody of the invention, in particular a composition comprising an antibody of the invention, for use according to any one of the above aspects, wherein the antibody to be used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is an antibody, including any functionally equivalent antibody or portion thereof, which antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and which comprises CDR1, CDR2 and CDR3 of the heavy chain variable region of an antibody identified in Table 8 and having the sequence determined according to Chothia as set out in Table 8, and CDR1, CDR2 and CDR3 of the corresponding light chain variable region of an antibody identified in Table 8 and having the sequence determined according to Chothia as set out in Table 8.

[0045] In particular, these are the CDR regions or CDRs of antibodies 107C6, 108F8, 109A6, 111A6, 131B4, 131E8, 131H1, 132H4, 133A6, 131B4-2 shown in Table 8.

[0046] In particular, the antibodies of the invention, in particular the antibodies used in compositions comprising the antibodies of the invention, for use according to any one of the above aspects as inhibitors of IL-18 or as capture molecules in assays for quantifying free IL-18 in body fluids, are antibodies including any functionally equivalent antibody or functional part thereof that binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and include: a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO: 153, SEQ ID NO: 154 and SEQ ID NO: 155, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO: 156, SEQ ID NO: 157 and SEQ ID NO: 158; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:159, SEQ ID NO:160 and SEQ ID NO:161, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:162, SEQ ID NO:163 and SEQ ID NO:164; c) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 168, SEQ ID NO: 169 and SEQ ID NO: 170; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:171, SEQ ID NO:172 and SEQ ID NO:173, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:174, SEQ ID NO:175 and SEQ ID NO:176; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:171, SEQ ID NO:172 and SEQ ID NO:173, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:177, SEQ ID NO:178 and SEQ ID NO:179; f) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:180, SEQ ID NO:181 and SEQ ID NO:182, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:189, SEQ ID NO:190 and SEQ ID NO:191; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:183, SEQ ID NO:184 and SEQ ID NO:185, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:189, SEQ ID NO:190 and SEQ ID NO:191; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:186, SEQ ID NO:187 and SEQ ID NO:188, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:189, SEQ ID NO:190 and SEQ ID NO:191; i) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:192, SEQ ID NO:193 and SEQ ID NO:194, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:201, SEQ ID NO:202 and SEQ ID NO:203; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:195, SEQ ID NO:196 and SEQ ID NO:197, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:201, SEQ ID NO:202 and SEQ ID NO:203; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:198, SEQ ID NO:199 and SEQ ID NO:200, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:201, SEQ ID NO:202 and SEQ ID NO:203; l) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:204, SEQ ID NO:205 and SEQ ID NO:206, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:207, SEQ ID NO:208 and SEQ ID NO:209; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:204, SEQ ID NO:205 and SEQ ID NO:206, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:210, SEQ ID NO:211 and SEQ ID NO:212; n) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 213, SEQ ID NO: 214 and SEQ ID NO: 215, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 216, SEQ ID NO: 217 and SEQ ID NO: 218; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:219, SEQ ID NO:220 and SEQ ID NO:221, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:222, SEQ ID NO:223 and SEQ ID NO:224; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:225, SEQ ID NO:226 and SEQ ID NO:227, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:228, SEQ ID NO:229 and SEQ ID NO:230.

[0047] The present invention further relates to an antibody of the invention, in particular a composition comprising an antibody of the invention, for use according to any one of the above aspects, wherein the antibody to be used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is an antibody, including any functionally equivalent antibody or portion thereof, which antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and which comprises CDR1, CDR2 and CDR3 of the heavy chain variable region of an antibody identified in Table 8 and having the sequence determined according to Kabat as set out in Table 8, and CDR1, CDR2 and CDR3 of the corresponding light chain variable region of an antibody identified in Table 8 and having the sequence determined according to Kabat as set out in Table 8.

[0048] In particular, these are the CDR regions or CDRs of antibodies 107C6, 108F8, 109A6, 111A6, 131B4, 131E8, 131H1, 132H4, 133A6, 131B4-2 shown in Table 8.

[0049] In particular, these are the CDR regions or CDRs of antibodies 107C6, 108F8, 109A6, 111A6, 131B4, 131E8, 131H1, 132H4, 133A6, 131B4-2 shown in Table 8.

[0050] In particular, the antibodies of the invention, in particular the antibodies used in compositions comprising the antibodies of the invention, for use according to any one of the above aspects as inhibitors of IL-18 or as capture molecules in assays for quantifying free IL-18 in body fluids, are antibodies including any functionally equivalent antibody or functional part thereof that binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and include: a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:231, SEQ ID NO:232 and SEQ ID NO:233, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:234, SEQ ID NO:235 and SEQ ID NO:236; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:237, SEQ ID NO:238 and SEQ ID NO:239, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:240, SEQ ID NO:241 and SEQ ID NO:242; c) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:243, SEQ ID NO:244 and SEQ ID NO:245, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:246, SEQ ID NO:247 and SEQ ID NO:248; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:249, SEQ ID NO:250 and SEQ ID NO:251, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:252, SEQ ID NO:253 and SEQ ID NO:254; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:249, SEQ ID NO:250 and SEQ ID NO:251, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:255, SEQ ID NO:256 and SEQ ID NO:257; f) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:258, SEQ ID NO:259 and SEQ ID NO:260, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:267, SEQ ID NO:268 and SEQ ID NO:269; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:261, SEQ ID NO:262 and SEQ ID NO:263, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:267, SEQ ID NO:268 and SEQ ID NO:269; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:264, SEQ ID NO:265 and SEQ ID NO:266, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:267, SEQ ID NO:268 and SEQ ID NO:269; i) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:270, SEQ ID NO:271 and SEQ ID NO:272, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:279, SEQ ID NO:280 and SEQ ID NO:281; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:273, SEQ ID NO:274 and SEQ ID NO:275, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:279, SEQ ID NO:280 and SEQ ID NO:281; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:276, SEQ ID NO:277 and SEQ ID NO:278, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:279, SEQ ID NO:280 and SEQ ID NO:281; l) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:282, SEQ ID NO:283 and SEQ ID NO:284, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:285, SEQ ID NO:286 and SEQ ID NO:287; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 282, SEQ ID NO: 283 and SEQ ID NO: 284, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 288, SEQ ID NO: 289 and SEQ ID NO: 290; n) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 291, SEQ ID NO: 292 and SEQ ID NO: 293, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 294, SEQ ID NO: 295 and SEQ ID NO: 296; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:297, SEQ ID NO:298 and SEQ ID NO:299, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:300, SEQ ID NO:301 and SEQ ID NO:302; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:303, SEQ ID NO:304 and SEQ ID NO:305, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:306, SEQ ID NO:307 and SEQ ID NO:308.

[0051] The present invention further relates to an antibody of the invention or a composition comprising an antibody of the invention for use according to any one of the above aspects, wherein the antibody used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is an antibody, including any functionally equivalent antibody or portion thereof, which antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and which comprises CDR1, CDR2 and CDR3 of the heavy chain variable region of an antibody identified in Table 8 and having the sequence determined according to IMGT as set out in Table 8, and CDR1, CDR2 and CDR3 of the corresponding light chain variable region of an antibody identified in Table 8 and having the sequence determined according to IMGT as set out in Table 8.

[0052] In particular, these are the CDR regions or CDRs of antibodies 107C6, 108F8, 109A6, 111A6, 131B4, 131E8, 131H1, 132H4, 133A6, 131B4-2 shown in Table 8.

[0053] In particular, the antibodies of the invention, in particular the antibodies used in compositions comprising the antibodies of the invention, for use according to any one of the above aspects as inhibitors of IL-18 or as capture molecules in assays for quantifying free IL-18 in body fluids, are antibodies including any functionally equivalent antibody or functional part thereof that binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and include: a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:33, SEQ ID NO:34 and SEQ ID NO:35, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:36, SEQ ID NO:37 and SEQ ID NO:38; c) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:39, SEQ ID NO:40 and SEQ ID NO:41, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:42, SEQ ID NO:43 and SEQ ID NO:44; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:45, SEQ ID NO:46 and SEQ ID NO:47, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:48, SEQ ID NO:49 and SEQ ID NO:50; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:45, SEQ ID NO:46 and SEQ ID NO:47, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:51, SEQ ID NO:52 and SEQ ID NO:53; f) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:54, SEQ ID NO:55 and SEQ ID NO:56, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:104, SEQ ID NO:105 and SEQ ID NO:106, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:110, SEQ ID NO:111 and SEQ ID NO:112, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; i) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:60, SEQ ID NO:61 and SEQ ID NO:62, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:63, SEQ ID NO:64 and SEQ ID NO:65, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 122, SEQ ID NO: 123 and SEQ ID NO: 124, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 66, SEQ ID NO: 67 and SEQ ID NO: 68; I) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 130, SEQ ID NO: 131 and SEQ ID NO: 132, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 136, SEQ ID NO: 137 and SEQ ID NO: 138; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 130, SEQ ID NO: 131 and SEQ ID NO: 132, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 142, SEQ ID NO: 143 and SEQ ID NO: 144; n) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:69, SEQ ID NO:70 and SEQ ID NO:71, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:72, SEQ ID NO:73 and SEQ ID NO:74; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:75, SEQ ID NO:76 and SEQ ID NO:77, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:78, SEQ ID NO:79 and SEQ ID NO:80; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:54, SEQ ID NO:55 and SEQ ID NO:56, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59.

[0054] In various embodiments, the antibodies of the invention, in particular the antibodies used in compositions comprising the antibodies of the invention, for use according to any one of the above embodiments as inhibitors of IL-18 or as capture molecules in assays for quantifying free IL-18 in body fluids, are antibodies that bind to free IL-18 at or near the binding site of IL-18BP but do not bind to the IL-18 / IL-18BP complex, including any functionally equivalent antibody or functional part thereof, and include: (a) the VH amino acid sequence of SEQ ID NO 9 and the VK amino acid sequence of SEQ ID NO 10; (b) the VH amino acid sequence of SEQ ID NO 11 and the VK amino acid sequence of SEQ ID NO 12; (c) the VH amino acid sequence of SEQ ID NO 13 and the VK amino acid sequence of SEQ ID NO 14; (d) the VH amino acid sequence of SEQ ID NO 15 and the VK amino acid sequence of SEQ ID NO 16; (e) the VH amino acid sequence of SEQ ID NO 15 and the VK amino acid sequence of SEQ ID NO 17; (f) the VH amino acid sequence of SEQ ID NO 18 and the VK amino acid sequence of SEQ ID NO 19; (g) the VH amino acid sequence of SEQ ID NO 103 and the VK amino acid sequence of SEQ ID NO 19; (h) the VH amino acid sequence of SEQ ID NO 109 and the VK amino acid sequence of SEQ ID NO 19; (i) the VH amino acid sequence of SEQ ID NO 20 and the VK amino acid sequence of SEQ ID NO 22; (g) the VH amino acid sequence of SEQ ID NO 21 and the VK amino acid sequence of SEQ ID NO 22; (k) the VH amino acid sequence of SEQ ID NO 121 and the VK amino acid sequence of SEQ ID NO 22; (l) the VH amino acid sequence of SEQ ID NO 129 and the VK amino acid sequence of SEQ ID NO 135; (m) the VH amino acid sequence of SEQ ID NO 129 and the VK amino acid sequence of SEQ ID NO 141; (n) the VH amino acid sequence of SEQ ID NO 23 and the VK amino acid sequence of SEQ ID NO 24; (o) a VH amino acid sequence of SEQ ID NO 25 and a VK amino acid sequence of SEQ ID NO 26; or (p) The VH amino acid sequence of SEQ ID NO 387 and the VK amino acid sequence of SEQ ID NO 19.

[0055] In various alternative embodiments, antibodies of the invention for use as inhibitors of IL-18 or as capture molecules in assays according to the invention for quantifying free IL-18 in biological fluids are antibodies having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of the antibodies specified in paragraphs (a) to (p) above. In particular, the antibodies do not have any sequence modifications within the CDRs. Modifications outside the CDRs within the framework domains may be made during antibody humanization and may be useful to avoid or suppress immune responses in humans.

[0056] Also included in the present invention are polynucleotides encoding the antibodies of the present invention, particularly those set forth in paragraphs (a) to (p) above. In various specific embodiments of the present invention, the polynucleotides have the sequences set forth in the Sequence Listing as SEQ ID NOs: 81 and 83; 85 and 87, 89 and 91, 93 and 95, 93 and 97, 99 and 113, 101 and 113, 107 and 113, 115 and 125, 117 and 125, 119 and 125, 127 and 133, 127 and 139, 145 and 147, and 149 and 151. Also included within the scope of the present invention are polynucleotides that are complements of the above sequence pairs or that hybridize to said sequences under stringent hybridization conditions and encode antibodies having 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of the antibodies specified in paragraphs (a) to (p) above, wherein said antibody does not have any sequence modifications within the CDRs.

[0057] The antibody of the present invention for use as an inhibitor of IL-18 or as a capture molecule in the assay according to the present invention for quantifying free IL-18 in body fluids according to the present invention may be an antibody selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody, a bispecific or dual-effect antibody, a simianized antibody, a human antibody and a humanized antibody.

[0058] In particular, the antibodies used as inhibitors of IL-18 or as capture molecules in the assay for quantifying free IL-18 in body fluids according to the invention are human or humanized antibodies.

[0059] The antibodies of the present invention can be prepared by vaccinating donor animals against human interleukin-18 using techniques that allow for immunization with properly folded proteins. In one specific embodiment, prior to immunization, genetically modified donor animals, particularly mice, are selected for major histocompatibility complexes presumed to be sensitive to IL-18 surface domain epitopes that bind to IL-18BP. After immunization, B cells are isolated from the spleen and hybridized according to standard hybridoma techniques. Hybridomas are sorted on solid supports, particularly microplates, and subsequently tested for the expression of monoclonal anti-IL-18 antibodies that target IL-18 epitopes contained in the IL-18BP binding site. Screening can be performed by three sequential selection steps: First step: To select cells expressing monoclonal anti-IL-18 antibodies, the first antibody is screened with IL-18 bound to a carrier, such as Luminex beads. Second step: Rescreening of potential antibodies targeting IL-18 at the IL-18BP binding site is performed in competition with IL-18BP, rather than with IL-18BP fusions with Fc antibody domains or other types of fusions, in order to prevent false-positive antibody candidates due to steric hindrance caused by the fusion peptide. The complex is subsequently exposed to biotinylated IL-18BP in order to identify interference with previously identified anti-IL-18 antibodies (see Table 7, column #2). Third stage: A third screening is carried out using, for example, carrier-bound IL-18BP, in particular Luminex beads to which IL-18BP is coupled, which is then complexed with interleukin-18 to ensure the presentation of properly folded recombinant IL-18 to positive antibody candidates.

[0060] The present invention further relates to an IL-18 inhibitor of the present invention, or a composition comprising an IL-18 inhibitor of the present invention, for use according to the various aspects of the invention described herein, wherein the IL-18 inhibitor is IL18BP, particularly human IL-18BP, especially recombinant human interleukin-18 binding protein (rhIL-18BP).

[0061] In particular, the IL-18BP is isoform a, b, c or d of IL-18BP, in particular isoform a, in particular isoform c, in particular isoform a, b, c or d shown in Figure 12 as SEQ ID NO 7 and SEQ ID NOs:388-390, and more particularly isoform a of IL-18BP shown in Figure 12 as SEQ ID NO:7, or isoform c shown in Figure 12 as SEQ ID NO:389.

[0062] Mixtures of the above isoforms, particularly mixtures of isoform a and isoform c, may also be used in the compositions of the present invention.

[0063] Also included within the scope of the present invention are muteins, fragments, peptides, functional derivatives, functional fragments, portions, circularly permuted derivatives, fusion proteins comprising IL-18BP, isoforms, or salts thereof.

[0064] In particular, the present invention relates to an IL-18BP that is a fusion protein, comprising all or part of an IL-18BP fused to all or part of an immunoglobulin, preferably an immunoglobulin constant region, wherein the fusion protein is still capable of binding to IL-18. More particularly, the immunoglobulin may be of the IgG1 or IgG2 isotype for use in a composition according to any one of the above aspects.

[0065] In various embodiments, the IL-18 inhibitors of the present invention, in particular the IL-18BP of the present invention as defined herein, or compositions comprising the IL-18 inhibitors of the present invention, in particular the IL-18BP of the present invention as defined herein, are useful in treating chronic obstructive pulmonary disease (COPD), transfusion-related lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), Still's disease, in particular adult Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic juvenile-onset idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS), including primary, secondary and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH), perforin, munc 13-4 and 18-2, synthaxin, Familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with 11 genetic defects; immunodeficiencies such as Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP); acquired hemophagocytic lymphohistiocytosis associated with infectious conditions, particularly herpesviruses such as EBV and other pathogens; cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID); autoinflammatory syndromes associated with NLRC4 mutations; giant cell arteritis (GCA); septic arthritis, pyoderma gangrenosum, and acne (PAPA); geographic atrophy; pulmonary sarcoidosis.sarcoidis), idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension, asthma, bronchiectasis, heart failure, ischemic heart disease, amyotrophic lateral sclerosis (ALS), atherosclerosis, xerophthalmia (DED), keratitis, corneal ulcers and abrasions, corneal neovascularization, pathological intraocular neovascularization, iritis, glaucoma, macular degeneration, Sjögren's syndrome, autoimmune uveitis, Behçet's disease, conjunctivitis, allergic conjunctivitis, eyelid dermatitis, type 1 diabetes, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), steatohepatitis, solid organ and blood stem cell transplantation, ischemia-reperfusion injury, familial Mediterranean fever (FMF), tumor necrosis factor receptor 1-associated periodic disorder In some embodiments, the present invention provides for use according to any one of the preceding aspects for the treatment of a disease or disorder associated with IL-18, which is selected from the group consisting of: inflammatory bowel disease (IBD) such as TRAPS, hyper-IgD syndrome (mevalonate kinase gene mutations), gout, Schnitzler syndrome, Wegener's granulomatosis also known as granulomatosis with polyangiitis (GPA), Hashimoto's thyroiditis, Crohn's disease, early-onset inflammatory bowel disease (EOIBD), very EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis, immunoglobulin-4 (IgG4)-associated disease, Blau syndrome (NOD-2 mutations), and stem cell therapy.

[0066] In one embodiment, an IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein, or a composition comprising an IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein, is provided for the treatment of a pediatric autoinflammatory disease or condition, in particular an MAS-like pediatric disease or condition.

[0067] In one specific embodiment, the MAS-like pediatric disease or condition to be treated with an IL-18 inhibitor of the present invention or a composition comprising said IL-18 inhibitor of the present invention is an IL-18-associated pediatric autoinflammatory disease or condition accompanied by severe systemic inflammation.

[0068] In particular, autoinflammatory diseases or conditions involving severe systemic inflammation are caused by NLRC4 mutations and / or involve XIAP deficiency, particularly XIAP deficiency caused by mutations in XIAP / BIRC4.

[0069] An IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein, or a composition comprising an IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein, can therefore be used for the treatment of X-linked lymphoproliferative syndrome 2 (XLP2), which is caused by mutations in XIAP / BIRC4, and / or for the treatment of severe early-onset hemophagocytic lymphohistiocytosis / MAS (HLH / MAS) with monogenic XIAP deficiency, which is caused by mutations in XIAP / BIRC4.

[0070] In one specific embodiment, an IL-18 inhibitor of the present invention, particularly an IL-18BP of the present invention as defined herein, or a composition comprising an IL-18 inhibitor of the present invention, particularly an IL-18BP of the present invention as defined herein, can be used for the treatment of enterocolitis, particularly Crohn's-like enterocolitis, caused by or associated with XIAP deficiency, particularly XIAP deficiency caused by mutations in XIAP / BIRC4.

[0071] In one specific embodiment, the IL-18 inhibitor of the present invention, in particular the IL-18BP of the present invention as defined herein, or a composition comprising an IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein, can be used for the treatment of early-onset inflammatory bowel disease (EOIBD), very EOIBD (VEOIBD), infantile IBD, neonatal IBD, particularly in the age group below 5 years, having various genetic defects such as mutations / variants in IL-10, XIAP, NCF2, MEFV, LRBA, IL-10R, common variable immunodeficiency (CVID), CD19, MSH5, etc., and which respond poorly to conventional treatments.

[0072] In another specific embodiment, an IL-18 inhibitor of the present invention, particularly an IL-18BP of the present invention as defined herein, or a composition comprising an IL-18 inhibitor of the present invention, particularly an IL-18BP of the present invention as defined herein, can be used to reduce susceptibility to viral infection, particularly EBV and / or CMV infection, in patients suffering from XIAP deficiency, particularly XIAP deficiency caused by mutations in XIAP / BIRC4, either before viral infection occurs or after viral clearance through treatment with antiviral drugs.

[0073] In various embodiments of the present invention, an autoinflammatory disease or condition involving severe systemic inflammation as defined herein is accompanied by high levels of IL-18 and free IL-18.

[0074] In one embodiment of the invention, the IL-18 inhibitor of the present invention, in particular the IL-18BP of the present invention as defined herein, or a composition comprising an IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein, is used for the treatment of a subject suffering from a pediatric autoinflammatory disease or condition, in particular a MAS-like pediatric disease or condition in its various aspects as defined herein, who has previously been treated with one or more compounds selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), prednisone; synthetic disease-modifying antirheumatic drugs (sDMARDs), immunosuppressants and biological immunosuppressants, but who has failed to respond to the treatment or has only an incomplete response to the treatment.

[0075] In another embodiment of the present invention, an IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein, or a composition comprising an IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein, is used for the treatment of early onset episodes of sterile arthritis, pyoderma gangrenosum and acne, which are part of PAPA syndrome.

[0076] In various embodiments of the present invention, the IL-18 inhibitor for use in treating a pediatric autoinflammatory disease or condition, particularly a MAS-like pediatric disease or condition as defined herein, is IL-18BP or an active fragment or variant thereof as defined herein, and the composition comprises IL-18BP or an active fragment or variant thereof as defined herein. In one specific embodiment of the present invention, the composition comprising IL-18BP or an active fragment or variant thereof as defined herein is substantially free of N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP.

[0077] In another specific embodiment of the present invention, the IL-18BP is human IL-18BP, in particular recombinant human interleukin-18 binding protein (rhIL-18BP).

[0078] In particular, the IL-18BP is selected from isoforms a, b, c and d of human IL-18BP, in particular isoform a, in particular isoform c, in particular isoforms a, b, c or d shown in Figure 12, especially isoform a of IL-18BP shown as SEQ ID NO:7 in Figure 12, or isoform c shown as SEQ ID NO:389 in Figure 12.

[0079] Mixtures of the above isoforms, particularly mixtures of isoform a and isoform c, may also be used in the compositions of the present invention.

[0080] Also included within the scope of the present invention are muteins, fragments, peptides, functional derivatives, functional fragments, portions, circularly permuted derivatives, fusion proteins comprising IL-18BP, isoforms, or salts thereof.

[0081] In various embodiments of the present invention, an IL-18 inhibitor, particularly an IL-18BP of the present invention, or a composition comprising said IL-18 inhibitor, particularly an IL-18BP of the present invention, is used for the treatment of mammals, particularly humans.

[0082] In one specific embodiment, the IL-18BP of the present invention or a composition comprising an IL-18BP of the present invention, in particular an IL-18BP for use according to any one of the above embodiments or a composition comprising an IL-18BP of the present invention, is administered to the subject to be treated in multiple doses per day, multiple doses per week, or multiple doses per month.

[0083] In particular, the IL-18BP of the present invention or a composition comprising an IL-18BP of the present invention is administered in two doses per week, three doses per week, or four doses per week.

[0084] In one specific embodiment of the present invention, the IL-18BP of the present invention or a composition comprising an IL-18BP of the present invention is administered every 24 to 48 hours.

[0085] In one specific embodiment, a single dose or dosage unit comprises between 0.5 mg IL-18BP / kg body weight and 10 mg IL-18BP / kg body weight, particularly between 1 mg IL-18BP / kg body weight and 8 mg IL-18BP / kg body weight, particularly between 2 mg IL-18BP / kg body weight and 6 mg IL-18BP / kg body weight, in particular between 1 mg IL-18BP / kg body weight and 5 mg IL-18BP / kg body weight.

[0086] In one embodiment of the invention, human IL-18BP isoform a or a composition comprising human IL-18BP isoform a is administered every 48 hours in a single dose of 1 mg IL-18BP / kg body weight to a pediatric patient suffering from a pediatric autoinflammatory disease or condition, particularly an MAS-like pediatric disease or condition as defined herein in various embodiments.

[0087] In one specific embodiment, the composition of the invention is for use according to any one of the preceding embodiments for the treatment of Still's disease, particularly juvenile Still's disease, and most especially adult-onset Still's disease (AoSD).

[0088] In particular, the composition comprises IL-18BP and the subject to be treated has been diagnosed as suffering from Still's disease, in particular based on the presence of at least two of the Yamaguchi criteria selected from the group consisting of the major items of the Yamaguchi criteria, and optionally, elevated inflammatory markers.

[0089] The at least two major items of the Yamaguchi Criteria are: i. Fever above 39°C lasting more than one week ii. 10,000 / mm3 with more than 80% polymorphonuclear neutrophils 3 Leukocytosis above iii. Typical skin rash iv. joint pain lasting more than 2 weeks; is selected from the group consisting of:

[0090] In one embodiment, the subject to be treated with the compositions of the present invention according to any one of the previously disclosed administration schemes has been exposed to a nonsteroidal anti-inflammatory drug (NSAID) and / or prednisone and / or a synthetic disease-modifying antirheumatic drug (sDMARD) but has not responded to the treatment or has only an incomplete response to the treatment.

[0091] In particular, the subject has been exposed to a nonsteroidal anti-inflammatory drug (NSAID) and / or prednisone, particularly at a dose of at least 5 mg / day for more than one month, and / or a synthetic disease-modifying antirheumatic drug (sDMARD) at a dose of at least 10 mg / day for more than three months.

[0092] In one specific embodiment of the invention, said composition for use according to any one of the above embodiments in the treatment of Still's disease, in particular juvenile Still's disease, and most especially adult-onset Still's disease (AoDS), is substantially free of N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP.

[0093] In various further embodiments of the invention, the deletion mutant comprises a deletion of 1 to 5 amino acid residues from the C-terminus of IL-18BP and / or 1 to 30 amino acid residues from the N-terminus of IL-18BP.

[0094] In particular, the proportion of deletion mutants in the composition according to the invention is less than 30%, particularly less than 20%, particularly less than 15%, particularly less than 10%, particularly less than 7.5%, particularly less than 5%, particularly less than 2.5%, particularly less than 1%, particularly less than 0.5%, particularly less than 0.25%, particularly less than 0.1%.

[0095] In a further embodiment, the composition of the invention, particularly the composition for use according to any one of the preceding embodiments in the treatment of Still's disease, particularly juvenile Still's disease, and more particularly adult-onset Still's disease (AoDS), comprises sodium chloride, and / or sodium hydroxide and / or sodium phosphate buffer, particularly in a concentration of 0.01M to 0.1M, particularly 0.01M to 0.05M, more particularly 0.01M.

[0096] In particular, the composition is formulated as a sterile solution for injection and contains sodium chloride, sodium hydroxide and sodium phosphate buffer, particularly at a concentration of 0.01M.

[0097] In one embodiment, the composition according to the present invention is administered by subcutaneous injection. In particular, the subcutaneous injection sites are alternated, particularly the outer thighs and different quadrants of the anterior abdominal wall. The separate injections that make up a single dose of the composition of the present invention are particularly administered in the same body area, but not at the exact same injection site.

[0098] In one embodiment, the composition is brought to room temperature, particularly 18-25°C, before administration.

[0099] In yet another embodiment, the compositions of the invention, particularly compositions for use according to any one of the preceding embodiments in the treatment of Still's disease, particularly juvenile Still's disease, and especially adult-onset Still's disease (AoDS), are administered to the subject to be treated in multiple doses per day, multiple doses per week, or multiple doses per month.

[0100] In particular, the composition is administered in two doses per week, three doses per week, or four doses per week.

[0101] In one particular embodiment, a single dose of a composition of the invention, in particular a composition for use according to any one of the above embodiments, comprises between 10 mg and 600 mg of IL-18BP.

[0102] In particular, a single dose comprises 10 to 20 mg, 20 to 40 mg, 40 to 80 mg, 80 to 160 mg, 160 mg to 320 mg, or 320 mg to 600 mg of IL-18BP.

[0103] In another specific embodiment, the composition of the invention, particularly a composition for use according to any one of the above embodiments, is administered to the subject to be treated until the treated subject exhibits at least a therapeutic response.

[0104] The therapeutic response may be, in particular, (a) normalized body temperature (normal range 36.3–37.4°C measured in the axilla) in the 24 hours prior to measurement, without the presence of secondary medication, e.g., NSAIDs; (b) Improvement in joint swelling and tenderness (20% or more); and (c) a 70% or greater decrease in C-reactive protein (CRP) or normalization of CRP and ferritin to baseline levels; It is characterized by:

[0105] In one embodiment of the invention, the composition for use according to any one of the preceding embodiments for the treatment of Still's disease, in particular juvenile Still's disease, and most especially adult-onset Still's disease (AoSD), comprises an antibody of the invention as disclosed herein in its various embodiments.

[0106] In one embodiment the invention relates to a composition of the invention for use according to any one of the preceding embodiments, wherein the level of free IL-18 in body fluids is 5 pg / mL or more, particularly up to 100 pg / mL, particularly between 6 pg / mL and 50 pg / mL, particularly between 8 pg / mL and 35 pg / mL, compared to 4 pg / mL or less in healthy controls.

[0107] In one embodiment, the invention provides a composition of the invention for use according to any one of the preceding embodiments, wherein said IL-18 associated disease or disorder is systemic symptoms of IL-18-induced inflammation and accompanying comorbidities selected from the group consisting of emphysema, tissue inflammation, tissue destruction, lung resection, loss of vasculature, endothelial cell apoptosis, mucosal metaplasia, cardiac hypertrophy, decreased VEGF in lung tissue, pulmonary vascular loss, vascular muscularization, vascular remodeling, collagen deposition, abnormal elastin layers in the lungs, fibrotic airway remodeling, alveolar enlargement, chronic remodeling of airways and pulmonary vessels, and decreased lung function.

[0108] In one embodiment, there is provided a composition of the invention for use according to any one of the preceding embodiments for the treatment of an IL-18-associated disease or disorder that is part of the chronic obstructive pulmonary disease (COPD) syndrome induced by smoking, exposure to secondhand smoke, or air pollutants in general, and that is characterized by the presence of poorly reversible airflow limitation.

[0109] In particular, IL-18-associated diseases or disorders involve multiple components of heterogeneous COPD disease and COPD exacerbations induced by viral or bacterial infections.

[0110] The present invention also provides a composition as disclosed in any one of the preceding aspects for use in treating chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), heart disease, amyotrophic lateral sclerosis (ALS), xerophthalmia, and / or type 1 and / or type 2 diabetes.

[0111] The present invention also provides a composition disclosed in any one of the above aspects for use in treating chronic obstructive pulmonary disease (COPD).

[0112] The present invention also provides a composition disclosed in any one of the above aspects for use in treating cardiac disease.

[0113] The present invention also provides a composition disclosed in any one of the above aspects for use in treating dry eye syndrome.

[0114] The present invention also provides a composition disclosed in any one of the above aspects for use in treating amyotrophic lateral sclerosis (ALS).

[0115] The present invention also provides a composition disclosed in any one of the above aspects for use in treating type 1 and / or type 2 diabetes.

[0116] The present invention also provides a composition disclosed in any one of the above aspects for use in treating Still's disease.

[0117] The present invention also provides a composition disclosed in any one of the above aspects for use in treating adult Still's disease.

[0118] The present invention also provides a composition disclosed in any one of the above aspects for use in treating juvenile Still's disease.

[0119] The present invention also provides a composition disclosed in any one of the above aspects for use in treating juvenile rheumatoid arthritis (JRA).

[0120] The present invention also provides a composition disclosed in any one of the above aspects for use in treating juvenile idiopathic arthritis (JIA).

[0121] The present invention also provides a composition as disclosed in any one of the above aspects for use in treating systemic juvenile-onset idiopathic arthritis (SoJIA).

[0122] The present invention also provides a composition disclosed in any one of the above aspects for use in treating systemic juvenile idiopathic arthritis (sJIA).

[0123] The present invention also provides a composition disclosed in any one of the above aspects for use in treating interstitial lung disease (ILD).

[0124] The present invention also provides a composition disclosed in any one of the above aspects for use in treating macrophage activation syndrome (MAS).

[0125] The present invention also provides a composition disclosed in any one of the above aspects for use in treating hemophagocytic lymphohistiocytosis (HLH).

[0126] The present invention also provides a composition disclosed in any one of the above aspects for use in treating familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with a genetic deficiency of perforin, munc 13-4.

[0127] The present invention also provides a composition disclosed in any one of the above aspects for use in the treatment of synthaxin 11.

[0128] The present invention also provides a composition disclosed in any one of the above aspects for use in treating an immune disorder.

[0129] The present invention also provides a composition disclosed in any one of the above aspects for use in treating Chediak-Higashi syndrome (CHS).

[0130] The present invention also provides a composition disclosed in any one of the above aspects for use in treating Griscelli Syndrome (GS).

[0131] The present invention also provides a composition disclosed in any one of the above aspects for use in treating X-linked lymphoproliferative syndrome (XLP).

[0132] The present invention also provides a composition as disclosed in any one of the above aspects for use in the treatment of acquired hemophagocytic lymphohistiocytosis, particularly associated with infectious conditions caused by herpes viruses, particularly EBV.

[0133] The present invention also provides a composition disclosed in any one of the above aspects for use in treating cryopyrin-associated periodic syndromes (CAPS).

[0134] The present invention also provides a composition disclosed in any one of the above aspects for use in treating familial cold autoinflammatory syndrome (FCAS).

[0135] The present invention also provides a composition disclosed in any one of the preceding aspects for use in treating Muckle-Wells Syndrome (MWS).

[0136] The present invention also provides a composition as disclosed in any one of the above aspects for use in treating neonatal-onset multisystem inflammatory disease (NOMID).

[0137] The present invention also provides a composition as disclosed in any one of the above aspects for use in treating an autoinflammatory syndrome associated with an NLRC4 mutation.

[0138] The present invention also provides a composition disclosed in any one of the above aspects for use in treating giant cell arteritis (GCA).

[0139] The present invention also provides a composition disclosed in any one of the above aspects for use in treating geographic atrophy.

[0140] The present invention also provides a composition disclosed in any one of the above aspects for use in the treatment of sarcoidosis, pulmonary sarcoidosis.

[0141] The present invention also provides a composition disclosed in any one of the preceding aspects for use in treating transfusion-associated lung injury.

[0142] The present invention also provides a composition disclosed in any one of the above aspects for use in treating bronchopulmonary dysplasia (BPD).

[0143] The present invention also provides a composition disclosed in any one of the above aspects for use in treating acute respiratory distress syndrome (ARDS).

[0144] The present invention also provides a composition disclosed in any one of the above aspects for use in treating interstitial lung disease (ILD).

[0145] The present invention also provides a composition disclosed in any one of the above aspects for use in treating idiopathic pulmonary fibrosis.

[0146] The present invention also provides a composition disclosed in any one of the above aspects for use in treating cystic fibrosis.

[0147] The present invention also provides a composition disclosed in any one of the above aspects for use in treating pulmonary arterial hypertension.

[0148] The present invention also provides a composition disclosed in any one of the above aspects for use in the treatment of asthma.

[0149] The present invention also provides a composition disclosed in any one of the above aspects for use in treating bronchiectasis.

[0150] The present invention also provides a composition disclosed in any one of the above aspects for use in treating heart failure.

[0151] The present invention also provides a composition disclosed in any one of the above aspects for use in treating ischemic heart disease.

[0152] The present invention also provides a composition disclosed in any one of the above aspects for use in treating atherosclerosis.

[0153] The present invention also provides a composition disclosed in any one of the above aspects for use in treating amyotrophic lateral sclerosis.

[0154] The present invention also provides a composition disclosed in any one of the above aspects for use in treating dry eye syndrome.

[0155] The present invention also provides a composition disclosed in any one of the above aspects for use in treating keratitis.

[0156] The present invention also provides a composition disclosed in any one of the above aspects for use in treating corneal ulcers and abrasions.

[0157] The present invention also provides a composition disclosed in any one of the above aspects for use in treating corneal neovascularization.

[0158] The present invention also provides a composition disclosed in any one of the above aspects for use in treating pathological intraocular neovascularization.

[0159] The present invention also provides a composition disclosed in any one of the above aspects for use in treating iritis.

[0160] The present invention also provides a composition disclosed in any one of the above aspects for use in treating glaucoma.

[0161] The present invention also provides a composition disclosed in any one of the above aspects for use in treating macular degeneration.

[0162] The present invention also provides a composition disclosed in any one of the above aspects for use in treating Sjogren's syndrome.

[0163] The present invention also provides a composition disclosed in any one of the above aspects for use in treating autoimmune uveitis.

[0164] The present invention also provides a composition disclosed in any one of the above aspects for use in treating Behcet's disease.

[0165] The present invention also provides a composition as disclosed in any one of the above aspects for use in treating conjunctivitis, particularly allergic conjunctivitis.

[0166] The present invention also provides a composition disclosed in any one of the above aspects for use in treating eyelid dermatitis.

[0167] The present invention also provides a composition disclosed in any one of the above aspects for use in treating non-alcoholic fatty liver disease (NAFLD).

[0168] The present invention also provides a composition disclosed in any one of the above aspects for use in treating steatohepatitis.

[0169] The present invention also provides a composition disclosed in any one of the above aspects for use in the treatment of solid organ and blood stem cell transplantation.

[0170] The present invention also provides a composition disclosed in any one of the above aspects for use in treating ischemia-reperfusion injury.

[0171] The present invention also provides a composition disclosed in any one of the above aspects for use in treating familial Mediterranean fever.

[0172] The present invention also provides a composition disclosed in any one of the above aspects for use in treating tumor necrosis factor receptor 1-associated periodic syndromes.

[0173] The present invention also provides a composition disclosed in any one of the above aspects for use in treating cryopyrin-associated periodic fever syndromes.

[0174] The present invention also provides a composition disclosed in any one of the above aspects for use in treating hyper-IgD syndrome.

[0175] The present invention also provides a composition disclosed in any one of the above aspects for use in treating gout.

[0176] The present invention also provides a composition disclosed in any one of the above aspects for use in treating Schnitzler's syndrome.

[0177] The present invention also provides a composition disclosed in any one of the above aspects for use in treating Wegener's granulomatosis.

[0178] The present invention also provides a composition disclosed in any one of the above aspects for use in treating Hashimoto's thyroiditis.

[0179] The present invention also provides a composition disclosed in any one of the above aspects for use in treating Crohn's disease.

[0180] The present invention also provides a composition disclosed in any one of the above aspects for use in treating ulcerative colitis.

[0181] The present invention also provides a composition disclosed in any one of the above aspects for use in treating an immunoglobulin-4 (IgG4)-related disease.

[0182] The present invention also provides a composition disclosed in any one of the above aspects for use in stem cell therapy treatment.

[0183] Treatment of any of the IL-18-related diseases or disorders according to any one of the preceding aspects with an IL-18 inhibitor of the invention, in particular an IL-18BP of the invention as defined herein, or a composition comprising an IL-18 inhibitor of the invention, in particular an IL-18BP of the invention as defined herein, includes preventing, arresting, alleviating or ameliorating symptoms associated with said disease or disorder.

[0184] In various further aspects, the present invention relates to an IL-18 inhibitor of the invention, in particular an IL-18BP of the invention as defined herein, or a composition comprising an IL-18 inhibitor of the invention, in particular an IL-18BP of the invention as defined herein, for use according to any one of the preceding aspects, wherein: - the increased expression of IFNγ, IL-13 or IL-17A is altered, in particular inhibited, compared to an untreated subject suffering from said disease or disorder; and / or Correcting the IL-18 / IL-18BP imbalance by scavenging and neutralizing excess free IL-18 in tissues and the circulation through binding of free IL-18 by IL-18BP; and / or IL-18BP inhibits neutrophil infiltration into the lungs, particularly through attenuation of G-CSF release in the pulmonary airways; and / or - the binding of IL-18, particularly the binding of free IL-18 to IL-18R, is limited or inhibited, and in particular the binding of free IL-18 to IL-18Rα is neutralized, limited or prevented; and / or the IL-18BP reduces the binding of IL-18 to the IL-18 receptor, in particular to IL-18Rα, by at least 5%, particularly at least 10%, particularly at least 15%, particularly at least 20%, particularly at least 25%, particularly at least 30%, particularly at least 40%, particularly at least 45%, particularly at least 50%, particularly at least 55%, particularly at least 60%, particularly at least 65%, particularly at least 70%, particularly at least 75%, particularly at least 80%, particularly at least 85%, particularly at least 90%, particularly at least 95%, particularly 100%; and / or IL-18BP neutralizes free IL-18 by limiting or preventing the binding of IL-18 to the IL-18 receptor (IL-18R), particularly IL-18Rα.

[0185] In various embodiments, the present invention provides new opportunities for treating pediatric autoinflammatory diseases associated with severe systemic inflammation (hereinafter referred to as MAS-like pediatric conditions) by combining true quantification of free IL-18 in the body fluids of the patient to be treated with therapeutic targeting of IL-18 by IL-18 binding proteins (IL-18BPs) or antibodies that specifically bind to free IL-18.

[0186] In particular, the present invention provides in one aspect an IL-18 inhibitor, in particular an IL-18BP as defined herein or an active fragment or variant thereof, or a composition comprising said IL-18 inhibitor, in particular an IL-18BP, or an active fragment or variant thereof as defined herein, for use in the treatment of a pediatric autoinflammatory disease or condition in a patient suffering from such a disease or disorder, in particular for use in the treatment of an MAS-like pediatric disease or condition and / or symptoms associated therewith.

[0187] In particular, said patient is a mammal, especially a human.

[0188] In one specific embodiment of the invention, the MAS-like pediatric disease or condition is an IL-18-associated autoinflammatory disease or condition in children involving severe systemic inflammation.

[0189] In particular, provided herein is an IL-18 inhibitor, in particular an IL-18BP as defined herein or an active fragment or variant thereof, or a composition comprising said IL-18 inhibitor, in particular an IL-18BP as defined herein or an active fragment or variant thereof, for use in the treatment of pediatric autoinflammatory diseases or conditions and / or symptoms associated therewith, which involve severe systemic inflammation caused by NLRC4 mutations.

[0190] NLRC4 mutations can result in increased NLRC4-inflammasome activation and NLRC4-mediated macrophage activation syndrome (MAS). A defining feature of this disease is high levels of IL-18 and other cytokines. Clinically, this condition is characterized by recurrent episodes of fever, fatigue, splenomegaly, vomiting, and loose stools involving the small intestine and colon.

[0191] In another specific embodiment, the present invention provides an IL-18 inhibitor, in particular an IL-18BP as defined herein or an active fragment or variant thereof, or a composition comprising said IL-18 inhibitor, in particular an IL-18BP as defined herein or an active fragment or variant thereof, for use in the treatment of a pediatric autoinflammatory disease or condition associated with severe systemic inflammation caused by XIAP deficiency.

[0192] In particular, the present invention provides an IL-18 inhibitor, in particular an IL-18BP as defined herein or an active fragment or variant thereof, or a composition comprising said IL-18 inhibitor, in particular an IL-18BP as defined herein or an active fragment or variant thereof, for use in the treatment of X-linked lymphoproliferative syndrome 2 (XLP2), which is caused by mutations in XIAP / BIRC4.

[0193] Mutations in XIAP can lead to XIAP deficiency.

[0194] XIAP deficiency is a childhood disorder that affects males and can manifest shortly after birth. The most common clinical manifestations are HLH (54%), recurrent splenomegaly (57%), and inflammatory bowel disease (IBD, 26%).

[0195] XIAP is a potent negative regulator of NLRP3 and the NLRC4 inflammasome in mice and possibly humans, and hyperactivation of NLRC4 leads to constitutive production of IL-18 by myeloid cells.

[0196] Loss-of-function mutations in XIAP deficiency and the various disease phenotypes are only partially described.

[0197] One of these phenotypes observed in XIAP-deficient patients is increased susceptibility to viral infections (EBV, CMV), and it has been hypothesized that XIAP may be required for the survival of virus-specific T cells.

[0198] Furthermore, XIAP deficiency has been found to increase susceptibility to HLH.

[0199] Patients with XIAP deficiency commonly develop hemophagocytic lymphohistiocytosis (HLH), a condition that is often recurrent. Patients with HLH present with fever, cytopenias, hepatosplenomegaly, liver dysfunction, coagulation abnormalities, and hemophagocytosis.

[0200] In contrast to FHL and XLP-1, EBV-induced HLH in XIAP deficiency is not accompanied by impaired NK cell and CD8+ T cell cytotoxic responses, which are apparently normal.

[0201] In addition, patients with XIAP deficiency often exhibit extremely severe enterocolitis, and approximately 20% of patients with XIAP deficiency who suffer from Crohn's-like refractory enterocolitis have been reported to respond poorly to corticosteroids, immunosuppressants, and anti-TNF agents.

[0202] A possible molecular explanation for the relationship between XIAP deficiency and Crohn's-like disease is based on the fact that NOD-induced NF-kB activation depends on XIAP through an indirect interaction between the BIR2 domain of XIAP and the NOD1 / 2-interacting protein RIP2. XIAP, in fact, contributes to NOD1 / 2 signaling by its ability to promote the ubiquitination of receptor-interacting protein kinase 2 (RIPK2) as an inducer of NF-kB activation.

[0203] Thus, loss of XIAP expression leads to defective NOD1 / 2 signaling, resulting in insufficient activation of NF-kB, which is thought to be associated with CD-like pathology due to impaired secretion of antibacterial responses in the intestine.

[0204] More recently, the role of XIAP in innate immunity was further expanded by the finding that XIAP is involved in the function of dectin-1, a pattern-recognition receptor implicated in the suppression of fungal infection. In this model, XIAP was shown to be required for NF-kB and MAPK activation, cytokine production, and phagocytosis following dectin-1 activation by its ligand.

[0205] In another aspect, there is provided herein an IL-18 inhibitor of the present invention, in particular an IL-18BP as defined herein or an active fragment or variant thereof, or a composition comprising said IL-18 inhibitor, in particular an IL-18BP as defined herein or an active fragment or variant thereof, for the treatment of early onset inflammatory bowel disease (EOIBD), particularly in the age groups defined herein.

[0206] The introduction of an age group between infantile IBD and A1a EOIBD is understandable given that several important subgroups of patients with monogenic IBD (e.g., those with XIAP deficiency, chronic granulomatous disease [CGD], or other neutrophil deficiencies) often have an age onset greater than 2 years. In contrast, the frequency of patients diagnosed with conventional polygenic IBD, particularly CD, increases significantly after age 7 years. This explains the relative prevalence of monogenic IBD in those with an age onset less than 6 years.

[0207] The location, progression and response to treatment of IBD are age-related characteristics. Age at onset can provide information about the type of IBD and its associated genetic traits. 1) Patients with defects in IL-10 signaling have very early-onset disease that usually occurs within the first few months of life. 2) Pediatric-onset IBD is the term reserved for patients whose disease began before the age of 17. 3) A further subgrouping of the pediatric population has led to the designation of patients with early-onset IBD (EOIBD), where the onset of the disease is before the age of 10 years. 4) Very early-onset IBD (VEOIBD) refers to patients under the age of 6. Very early-onset inflammatory bowel disease (VEOIBD), in which IBD is diagnosed before the age of 5, often presents with a more severe phenotype that is distinct from later-onset IBD. 5) Infantile IBD refers to patients whose disease began before the age of 2 years. 6) Neonatal IBD

[0208] The estimated incidence of VEOIBD is 4.37 per 100,000 children, with a prevalence of 14 per 100,000.

[0209] In most cases of IBD with onset after the age of 7–10 years, there is a polygenic contribution to genetic susceptibility.

[0210] Disorders termed monogenic IBD tend to present at an earlier age, and data suggest that the proportion of monogenic disorders with IBD-like symptoms among all IBD patients is inversely correlated with age of onset.

[0211] The underlying mechanisms of early-onset inflammatory bowel disease (EOIBD) are multiple distinct genetic defects, such as mutations / variants in IL-10, XIAP, NCF2, MEFV, LRBA, IL-10R, common variable immunodeficiency (CVID), CD19, MSH5, etc., and respond poorly to conventional treatments.

[0212] The most frequent mechanisms underlying VEOIBD are monogenic conditions that impair IL-10 signaling (IL-10, IL-10Ra, IL-10Rb) and XIAP deficiency due to loss-of-function mutations. As mentioned above, XIAP deficiency results in elevated levels of IL-18 in the serum and possibly also in the intestinal compartment.

[0213] Because these entities are practically refractory to first-line immunosuppressants and even to biologics such as anti-TNF, treatments to stabilize the disease remain an unmet medical need.

[0214] Thus, the present invention provides an option for the treatment of the above-mentioned conditions and / or symptoms associated therewith.

[0215] In one embodiment, the invention relates to an antibody of the invention, in particular a composition comprising an antibody according to the invention, for use in the treatment of an IL-18-associated disease or disorder in a subject suffering from such a disease.

[0216] In one embodiment, the present invention provides a method for determining the amount of free IL-18 in a sample or in situ, comprising detecting specific binding of an IL-18BP as defined herein or an antibody of the invention to free IL-18 protein in the sample or in situ, a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an IL-18BP or antibody of the invention as defined herein, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the IL-18BP or antibody to free IL-18; c) detecting binding of IL-18 to the IL-18BP or antibody to determine the amount of free IL-18 in the sample. The present invention relates to a method comprising:

[0217] In one embodiment, the present invention provides a method for diagnosing an IL-18-associated disease or disorder, in particular an IL-18-associated disease or disorder as defined herein, comprising detecting specific binding of an IL-18BP or antibody of the present invention as defined herein to free IL-18 protein in a sample or in situ, a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an IL-18BP or antibody of the invention as defined herein, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the IL-18BP or antibody to free IL-18; c) detecting binding of IL-18 to the IL-18BP or antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any one of the preceding embodiments with the amount in a sample from a healthy subject; The present invention relates to a method comprising:

[0218] In one embodiment, the present invention provides a method for diagnosing a predisposition to an IL-18 associated disease or disorder in a patient, in particular an IL-18 associated disease or disorder as defined in any one of the preceding embodiments, comprising detecting specific binding of an IL-18BP or antibody of the invention as defined herein to free IL-18 protein in a sample or in situ, a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an IL-18BP or antibody of the invention as defined herein, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the IL-18BP or antibody to free IL-18; c) detecting binding of IL-18 to the IL-18BP or antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any one of the preceding embodiments with the amount in a sample from a healthy patient; wherein an increased amount of said free IL-18 in the sample compared to a normal control value obtained from a healthy patient indicates that said patient is suffering from or at risk of developing a disease or disorder as defined in any one of the preceding aspects.

[0219] In one embodiment, the present invention provides a method for monitoring minimal residual disease in a patient following treatment with a composition as defined in any one of the previous embodiments, comprising: a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an IL-18BP or antibody of the invention as defined herein, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the IL-18BP or antibody to free IL-18; c) detecting binding of IL-18 to the IL-18BP or antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any one of the preceding embodiments with the amount in a sample from a healthy patient; wherein an increased amount of said free IL-18 in the sample compared to a normal control value obtained from a healthy patient indicates that said patient still suffers from minimal residual disease.

[0220] In one embodiment, the present invention provides a method for predicting a patient's responsiveness to treatment with a composition as defined in any one of the previous embodiments, comprising: a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an IL-18BP or antibody of the invention as defined herein, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the IL-18BP or antibody to free IL-18; c) detecting binding of IL-18 to the IL-18BP or antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any one of the preceding embodiments with the amount in a sample from a healthy patient; wherein a low level of said free IL-18 in the sample indicates that said patient is likely to respond to treatment.

[0221] In one embodiment, the invention relates to a method according to any one of the preceding embodiments, wherein the IL-18BP is isoform a, b, c or d of IL-18BP, particularly isoform a, particularly isoform c, particularly isoform a, b, c or d as set forth in SEQ ID NOs: 7 and 388-390, especially isoform a of IL-18BP as set forth in SEQ ID NO: 7, or isoform c as set forth in SEQ ID NO: 389.

[0222] Mixtures of the above isoforms may also be used in the compositions of the invention, particularly mixtures of isoform a and isoform c.

[0223] In one embodiment, the invention relates to the method of any one of the preceding embodiments, wherein in step a) the method comprises a further step of using an IL-18BP-specific binding molecule that binds to a site on IL-18BP that is different from the capture molecule, in particular one of these molecules binds to the IL-18 binding site on IL-18BP.

[0224] In one embodiment, the present invention relates to the method of any one of the preceding embodiments, comprising the further step of determining the presence of free IL-18BP in the sample in step a) by using an IL-18BP-specific capture molecule and an IL-18BP-specific detection molecule that binds to a site on IL-18BP that is different from the capture molecule, in particular one in which one of these IL-18BP-specific molecules binds to the IL-18-binding site on IL-18BP, by determining in step c) the amount of free and total IL-18 and the amount of free IL-18BP and total IL-18BP bound to the capture molecules in the sample; and in step d) by comparing the amount of free and / or total IL-18 and free and / or total IL-18BP in a sample from a patient suffering from a disease or disorder as defined in any one of the preceding embodiments with the amounts in a sample from a healthy patient.

[0225] In one embodiment, the capture molecule is a.lL-18BP, b. An IL-18-specific antibody of the invention as defined herein is.

[0226] In one embodiment, the present invention relates to a method according to any one of the previous embodiments, wherein said sample is selected from the group consisting of bronchoalveolar lavage fluid (BALF) circulating fluid, secretions, biopsies, and homogenized tissue, in particular serum, urine, tears, saliva, bile, sweat, exhaled or expired air, sputum, bronchoalveolar fluid, sebum, cellular, glandular, mucosal or tissue secretions.

[0227] In one embodiment, the invention relates to a method of any one of the preceding embodiments, wherein the amount of free IL-18 in isolated serum of a subject, particularly a human, suffering from said disease is equal to or greater than 5 pg / mL, and in particular up to 10000 pg / mL, whereas the amount of free IL-18 in serum of a healthy subject, particularly a healthy human, is equal to or less than 4 pg / mL.

[0228] The present invention further relates to a diagnostic kit for detecting free IL-18, comprising an antibody of the invention as defined herein as a capture molecule and a second IL-18-specific binding molecule as a detection molecule, and optionally a second IL-18-specific capture molecule, wherein the detection molecule binds to a site on IL-18 that is different from the capture molecule.

[0229] The IL-18BP for use in the method for detecting and quantifying free IL-18 in a probe or in a sample according to any one of the above embodiments is human IL-18BP, in particular recombinant human interleukin-18 binding protein (rhIL-18BP).

[0230] In particular, the IL-18BP is isoform a, b, c or d of IL-18BP, in particular isoform a, in particular isoform c, in particular isoform a, b, c or d as set forth in SEQ ID NOs: 7 and 388-390, among which isoform a of IL-18BP as set forth in SEQ ID NO: 7, or isoform c as set forth in SEQ ID NO: 389.

[0231] Mixtures of the above isoforms, particularly mixtures of isoform a and isoform c, may also be used in the compositions of the present invention.

[0232] Also included within the scope of the present invention are muteins, fragments, peptides, functional derivatives, functional fragments, portions, circularly permuted derivatives, fusion proteins comprising IL-18BP, isoforms, or salts thereof.

[0233] In one embodiment of the present invention, recombinant human interleukin-18 binding protein (rhIL-18BP) is used that is substantially free of N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP.

[0234] In various further embodiments of the invention, the deletion mutant comprises a deletion of 1 to 5 amino acid residues from the C-terminus of IL-18BP and / or 1 to 30 amino acid residues from the N-terminus of IL-18BP.

[0235] In particular, the proportion of deletion variants in an IL-18BP preparation used in a method for detecting and quantifying free IL-18 in a probe or in a sample according to any one of the above embodiments is less than 30%, particularly less than 20%, particularly less than 15%, particularly less than 10%, particularly less than 7.5%, particularly less than 5%, particularly less than 2.5%, particularly less than 1%, particularly less than 0.5%, particularly less than 0.25%, particularly less than 0.1%.

[0236] In various embodiments, any immunoassay format known to those skilled in the art can be used to determine the presence or absence of free IL-18 in a sample by the methods described herein, such as assay formats that utilize indirect detection methods using secondary reagents for detection, particularly ELISA assays, immunoprecipitation assays, and agglutination assays. Detailed descriptions of these assays are provided, for example, in Harlow and Lane, Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory, New York 1988 pp. 555-612; WO 96 / 13590 to Maertens and Stuyver; Zrein et al. (1998); and WO 96 / 29605.

[0237] The sample may be an undiluted or diluted biological fluid such as, but not limited to, serum, urine, tears, saliva, bile, sweat, exhaled or expired air, sputum, bronchoalveolar fluid, sebum, cellular, glandular, mucosal or tissue secretions, biopsies, homogenized tissue, etc.

[0238] For in situ diagnosis, the IL-18BP or antibody of the present invention or any active or functional part thereof can be administered to the organism to be diagnosed by methods known in the art, such as intravenous injection, intranasal injection, intraperitoneal injection, intracerebral injection, intra-arterial injection, etc., so that specific binding occurs between the antibody according to the present invention and the epitope region on the amyloid protein. The antibody / antigen complex can be conveniently detected by a label attached to the antibody or its functional fragment, or by any other detection method known in the art.

[0239] In another aspect of the present invention, the detection of free IL-18 described herein can be achieved by an immunoassay procedure. An immunoassay typically involves contacting a test sample with an antibody or IL-18BP of the present invention, as described herein in various embodiments, which specifically binds to free IL-18, and detecting the presence of an IL-18BP / free IL-18 complex or an antibody / free IL-18 complex in the sample. The immunoassay procedure can be selected from a wide variety of immunoassay procedures known to those skilled in the art, such as competitive or non-competitive enzyme-based immunoassays, enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and Western blotting. Furthermore, multiplexed assays, including arrays, can also be used, in which the IL-18BP or antibody of the present invention is placed on a support, such as glass beads or a plate, and reacted or otherwise contacted with the test sample.

[0240] The antibodies used in these assays may be monoclonal or polyclonal and may be of any type, including IgG, IgM, IgA, IgD, and IgE. Antibodies can be produced by immunizing animals such as rats, mice, and rabbits. Antigens used for immunization may be isolated from samples or synthesized by recombinant protein technology. Methods for producing antibodies and performing antibody-based assays are well known to those skilled in the art and are described in further detail, for example, in Antibodies: A Laboratory Manual (1988) by Harlow & Lane; Immunoassays: A Practical Approach, Oxford University Press, Gosling, JP (ed.) (2001); and / or in Current Protocols in Molecular Biology (Ausubel et al.), which are regularly and periodically updated.

[0241] Various chemical or biochemical derivatives of the IL-18BP or antibody or antibody fragment of the present invention can be produced using known methods. One type of derivative useful diagnostically as an immunoconjugate comprises an IL-18BP or antibody molecule of the present invention, or an antigen-binding fragment thereof, conjugated with a detectable label. However, in many embodiments, the IL-18BP or antibody is unlabeled during the assay, but is indirectly labeled by binding to or being bound by another molecule that is labeled. The present invention encompasses molecular complexes comprising an IL-18BP or antibody molecule of the present invention and a label.

[0242] Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, phycoerythrin, Alexa Fluor 647, Alexa Fluor 680, DilC, and the like. 19 (3), rhodamine Red-X, Alexa Fluor 660, Alexa Fluor 546, Texas Red, YOYO-1+DMA, tetramethylrhodamine, Alexa Fluor 594, BODIPY FL, Alexa Fluor 488, fluorescein, BODIPY TR, BODIPY TMR, carboxySNARF-1, FM 1-43, Fura-2, lndo-1, Cascade Blue, NBD, DAPI, Alexa Fluor 350, aminomethylcoumarin, lucifer yellow, propidium iodide, or dansylamide; an example of a luminescent material is luminol; examples of bioluminescent materials include green fluorescent protein, modified green fluorescent protein, luciferase, luciferin, and aequorin, and examples of suitable radioactive materials include fluorescein, ... 125 I, 131 I, 35 S or 3 Contains H.

[0243] Immunoassays typically involve incubating a sample, such as a biological fluid, tissue extract, freshly harvested cells, or cell lysate, in the presence of a detectably labeled IL-18BP or antibody according to the present invention, or a peptide fragment thereof, and detecting the bound IL-18BP or antibody by any of several techniques well known in the art. One method for measuring the level of free IL-18 using the IL-18BP or antibody of the present invention is by enzyme immunoassay (EIA), such as enzyme-linked immunosorbent assay (ELISA) (Voller, A. et al., J. Clin. Pathol. 37:507-520 (1978); Butler, J. E., Meth. Enzymol. 73:482-523 (1981); Maggto, E. (ed.), Enzyme Immunoassay, CRC Press, Boca Raton, FL, 1980). The enzyme conjugated to either an IL-18BP or antibody of the present invention, or a binding partner of an IL-18BP or antibody, when subsequently exposed to an appropriate substrate, will react with the substrate in such a manner as to produce a chemical moiety that can be detected, for example, by spectrophotometric or fluorometric means.

[0244] In one specific embodiment of the present invention, the IL-18BP used in any of the above formats, especially in the ELISA format, is IL-18BP isoform a, b, c or d or a derivative thereof, especially an isoform, especially isoform c or a derivative thereof, especially isoforms a, b, c or d as set forth in SEQ ID NOs: 7 and 388-390, especially isoform a of IL-18BP as set forth in SEQ ID NO: 7 or isoform c as set forth in SEQ ID NO: 389.

[0245] Mixtures of the above isoforms, particularly mixtures of isoform a and isoform c, may also be used in the compositions of the present invention.

[0246] The biological sample can be contacted with and immobilized on a solid support or carrier such as nitrocellulose, or other solid support capable of immobilizing cells, cell particles, or soluble proteins. The support can then be washed with a suitable buffer, followed by treatment with a detectably labeled IL-18BP or antibody of the present invention. The solid support can then be washed a second time with a buffer to remove unbound IL-18BP or antibody. The amount of label bound to the solid support can then be detected by conventional means. One well-known example of such a technique is Western blotting.

[0247] In various embodiments, the present invention includes compositions comprising a labeled IL-18BP or a labeled antibody according to the invention described herein.

[0248] In yet another aspect, the present invention provides a method for treating an IL-18 associated disease or disorder in a subject as defined herein, comprising: a. quantifying the amount of free IL-18 in the body fluid of said subject using a method according to the invention, as described herein in various embodiments; b. administering a therapeutically or prophylactically effective amount of a composition as defined in any one of embodiments 1-37 and 41 to a subject having an abnormal level of free IL-18 in a body fluid, determined to be 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% greater than the level of free IL-18 in the body fluid of a healthy control subject, in particular by systemic, intranasal, buccal, oral, transmucosal, intratracheal, intravenous, subcutaneous, intraurinary, intravaginal, sublingual, intrabronchial, intrapulmonary, transdermal or intramuscular administration, in particular bronchopulmonary administration. The present invention relates to a method comprising:

[0249] The compositions of the present invention may contain additional medicinal agents, pharmaceutical agents, carriers, buffers, dispersants, diluents, co-therapeutic agents, such as anti-inflammatory agents, bronchodilators, antihistamines, decongestant or antitussive substances, depending on the intended use and application.

[0250] In one embodiment of the invention, the pharmaceutical compositions of the invention and disclosed in various embodiments herein are administered prophylactically.

[0251] In another embodiment of the invention, the pharmaceutical compositions of the invention and disclosed in various embodiments herein are administered therapeutically.

[0252] In one embodiment of the invention, the pharmaceutical compositions of the invention and disclosed in various embodiments herein are administered to a subject suffering from or predisposed to developing an IL-18-associated disease or disorder by systemic, intranasal, intraocular, intravitreal, ophthalmic, buccal, oral, transmucosal, intratracheal, intravenous, subcutaneous, urinary, rectal, vaginal, sublingual, intrabronchial, pulmonary, transdermal, or intramuscular administration. In particular, the pharmaceutical compositions of the invention and disclosed in various embodiments herein are administered by bronchopulmonary administration.

[0253] The pharmaceutical compositions of the present invention, and as disclosed in various embodiments herein, may be provided as liquids, sprayable liquids, microspheres, semisolids, gels, or powders for transmucosal administration, such as intranasal, buccal, oral transmucosal, intratracheal, intraurinary, intravaginal, sublingual, intrabronchial, pulmonary, and / or transdermal administration. Additionally, the compositions may be in solid dosage forms for buccal, oral transmucosal, and / or sublingual administration. Intranasal, buccal, oral intratracheal, intraurinary, intravaginal, transmucosal, and sublingual administration result in the disintegration of the compositions described herein in the oral cavity at body temperature, and, optionally, adhesion to the body tissues of the oral cavity. Additionally, the compositions disclosed herein may further comprise one or more additives, diluents, binders, lubricants, glidants, disintegrants, desensitizing agents, emulsifiers, mucoadhesives, solubilizing agents, suspending agents, viscosity modifiers, ionic tonicity agents, buffers, carriers, surfactants, flavoring agents, or mixtures thereof.

[0254] In one specific aspect of the invention, the composition is formulated as a parenteral, intravenous, tablet, pill, bioadhesive patch, drop, sponge, film, lozenge, hard candy, wafer, sphere, lollipop, disc, suppository or spray.

[0255] Transmucosal administration is generally rapid because of the rich vascular supply of mucous membranes and the absence of the stratum corneum of the epidermis.Such drug transport typically results in a rapid rise in blood concentration, and also avoids the enterohepatic circulation and immediate destruction by gastric acid or partial first-pass effect due to intestinal wall and hepatic metabolism.Drugs typically require prolonged exposure to the mucosal surface for meaningful drug absorption to occur.

[0256] The mucosal route may also be more effective than the oral route because these routes result in relatively rapid absorption and onset of therapeutic action. Furthermore, the mucosal route may be preferable for use in treating patients who have difficulty swallowing tablets, capsules, or other oral solids, or who have impaired intestinal absorption due to disease. Thus, there are many advantages to transmucosal administration of IL-18BP, or a pharmaceutical composition comprising IL-18BP and a pharmaceutically acceptable carrier and / or excipient.

[0257] With either the intranasal or buccal route, drug absorption can be delayed or sustained, or uptake can be nearly as rapid as when an intravenous bolus is administered. Due to its high permeability and abundant blood supply, the sublingual route can provide a rapid onset of action.

[0258] Intranasal compositions can be administered by any suitable method depending on the dosage form. Compositions containing microspheres or powders can be administered using an intranasal inhaler device. Examples of these devices are well known to those skilled in the art and include commercially available powder systems such as the Fisons Lomudal System. The inhaler generates a fine cloud of dry powder or microspheres. Preferably, the inhaler is equipped with a mechanism to ensure a substantially consistent dose of the composition is administered. The powder or microspheres can be administered directly through an inhaler equipped with a vial or container for the powder or microspheres. Alternatively, the powder or microspheres can be loaded into a capsule, such as a gelatin capsule, or other single-dose device adapted for intranasal administration. Preferably, the inhaler has a mechanism for breaking open the capsule or other device. Furthermore, the composition can provide an initial rapid release of the active ingredient followed by a sustained release of the active ingredient, for example, by providing multiple types of microspheres or powders. Furthermore, alternative methods suitable for administering compositions to the nasal cavity will be well known to those skilled in the art. Any suitable method can be used. For a more detailed description of suitable methods, see EP2112923, EP1635783, EP1648406, EP2112923, the contents of all of which are incorporated herein by reference.

[0259] In one embodiment of the present invention, the pharmaceutical compositions of the present invention and disclosed in various embodiments herein may also be administered intranasally, i.e., by inhalation, and therefore may be formulated in a form suitable for intranasal administration, i.e., as an aerosol, dry powder formulation, or liquid preparation.

[0260] Examples of suitable pharmaceutical carriers, excipients and / or diluents are well known in the art and include, but are not limited to, gums, starches (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, dextrose), cellulosic materials (e.g., microcrystalline cellulose), acrylates (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.

[0261] Pharmaceutically acceptable carriers for liquid preparations include aqueous or non-aqueous solutions, suspensions, dry powder preparations, emulsions, or oils. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate. Examples of oils include oils of animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, olive oil, sunflower oil, fish liver oil, other fish oils, or fats derived from milk or eggs.

[0262] The present invention also relates to the pulmonary administration of the pharmaceutical compositions of the present invention and disclosed in various embodiments herein in the form of dry powder, gaseous or volatile formulations via the respiratory tract into the systemic circulation by inhalation.Absorption is virtually as rapid as the formulation can be delivered into the alveoli of the lungs, because the alveoli and vascular epithelial membranes are highly permeable, have abundant blood flow, and have a large adsorption area.For example, aerosols can be delivered from pressure-filled metered dose inhalers (MDIs).

[0263] The pharmaceutical compositions of the present invention, and as disclosed in various embodiments herein, will generally be administered in admixture with a suitable pharmaceutical excipient, diluent, or carrier, selected according to the chosen means of inhalation and standard pharmaceutical practice.

[0264] In another embodiment of the present invention, the formulation of IL-18BP or the pharmaceutical composition comprising IL-18BP is a dry powder, optionally together with at least one pharmaceutically acceptable particulate carrier, which may be one or more materials known as pharmaceutically acceptable carriers, preferably selected from materials known as carriers in dry powder inhalation compositions, such as sugars, including monosaccharides, disaccharides, and polysaccharides, and sugar alcohols, such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starch, dextran, mannitol, or sorbitol. A particularly preferred carrier is lactose, such as lactose monohydrate or anhydrous lactose. The dry powder can be contained as a unit dose in, for example, a gelatin or plastic capsule or in a blister (e.g., aluminum or plastic) for use in a dry powder inhaler device, which can be a single-dose or multi-dose device, preferably together with an amount of carrier such that the dosage unit contains 5 mg to 50 mg of total powder weight per capsule. Alternatively, the dry powder can be contained in a reservoir in a multiple-dose dry powder inhaler (MDDPI) device adapted for delivery.

[0265] Any other therapeutically effective route of administration can be used, such as absorption through epithelial or endothelial tissue, or by gene therapy in which a DNA molecule encoding the active agent is administered to the patient (e.g., via an expression vector) causing the active agent to be expressed and secreted in vivo.

[0266] The pharmaceutical compositions of the present invention and disclosed in various embodiments herein can be used in human and veterinary medicine to treat humans and animals, including birds, non-human primates, dogs, cats, pigs, goats, sheep, cattle, horses, mice, rats and rabbits, for the treatment of IL-18 associated diseases or disorders as described in various embodiments herein.

[0267] In one specific embodiment, the present invention provides a pharmaceutical composition of the invention as disclosed herein in its various embodiments for use in treating an IL-18 associated disease or disorder as described herein in its various embodiments, wherein the subject is a mammal, and particularly wherein the subject is a human.

[0268] In another specific embodiment, the pharmaceutical compositions of the invention disclosed in various embodiments herein are administered in a therapeutically effective amount together with a suitable dose of at least a second pro-inflammatory cytokine inhibitor, particularly said inhibitor being specific for IL-1, IL-6, IL-13, IL-17A, IFNγ or TNFα.

[0269] Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, saline and buffered media, e.g., phosphate buffered saline, water, emulsions, e.g., oil / water, emulsions, various types of wetting agents, sterile solutions, and other media. Compositions containing such carriers can be formulated by well-known conventional methods. Suitable carriers can include any material that retains biological activity when combined with the biologically active compounds of the present invention.

[0270] Efforts have been made in the art to chemically modify the barrier properties of the skin to allow penetration of certain agents, enhance the efficacy of the delivered agents, enhance the delivery time, reduce the delivered dose, reduce side effects from various delivery methods, reduce patient reactions, etc.

[0271] In this regard, penetration enhancers are used to increase the permeability of the skin surface to drugs, and are often proton-accepting solvents such as dimethyl sulfoxide (DMSO) and dimethylacetamide. Other penetration enhancers that have been investigated and reported to be effective include 2-pyrrolidine, N,N-diethyl-m-toluamide (Deet), 1-dodecyl-azacycloheptan-2-one, N,N-dimethylformamide, N-methyl-2-pyrrolidine, calcium thioglycolate, hexanol, fatty acids and esters, pyrrolidine derivatives, derivatives of 1,3-dioxane and 1,3-dioxolane, 1-N-dodecyl-2-pyrrolidine-5-carboxylic acid, 2-pentyl-2-oxo-pyrrolidineacetic acid, 2-dodecyl-2-oxo-1-pyrrolidineacetic acid, 1-azacycloheptan-2-one-2-dodecylacetic acid, and amino alcohol derivatives, including derivatives of 1,3-dioxane, among others.

[0272] Preparations for transmucosal administration may include sterile aqueous or non-aqueous solutions, suspensions, dry powder formulations, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. Transmucosal vehicles include sodium chloride solution, Ringer's dextrose, dextrose, and sodium chloride, lactated Ringer's, or fixed oils. Preservatives and other additives, such as antibacterial agents, antioxidants, chelating agents, and inert gases, may also be present. In addition, the pharmaceutical compositions of the present invention may include a proteinaceous carrier, such as serum albumin or immunoglobulin, preferably of human origin.

[0273] In various embodiments, the pharmaceutical compositions of the present invention disclosed herein may be administered topically to a body surface and therefore may be formulated in a dosage form suitable for topical administration. Suitable topical formulations include gels, ointments, creams, lotions, drops, and the like. For topical administration, the pharmaceutical compositions of the present invention disclosed herein in various embodiments are prepared and applied as a solution, suspension, or emulsion in a physiologically acceptable diluent, with or without a pharmaceutical carrier.

[0274] The pharmaceutical compositions of the present invention and disclosed in various embodiments herein can also be administered as controlled-release compositions, i.e., compositions in which the active ingredient is released over a period of time after administration. Controlled-release or sustained-release compositions include formulations in lipophilic depots (e.g., fatty acids, waxes, oils). In another embodiment, the composition is an immediate-release composition, i.e., a composition in which all active ingredients are released immediately after administration.

[0275] Further examples of suitable formulations are provided in WO 2006 / 085983, the entire contents of which are incorporated herein by reference. For example, the pharmaceutical compositions of the present invention and disclosed in various embodiments herein may be provided as liposomal formulations. Techniques for forming liposomal suspensions are well known in the art. The lipid layer used may be of any conventional composition and may contain or be cholesterol-free. Liposomes can be reduced in size through the use of standard sonication and homogenization techniques. In various embodiments, the liposomal formulations containing the pharmaceutical compositions of the present invention disclosed herein can be lyophilized to produce lyophilizates that can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate the liposomal suspension. In various embodiments, the pharmaceutical compositions of the present invention disclosed herein can be administered at a dose appropriate for the subject. The dosing regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, the dosage for any one subject will depend on many factors, including the subject's size, body surface area, age, the particular compound being administered, sex, time and route of administration, general health, and other drugs being administered concomitantly.

[0276] Furthermore, it is envisioned that the pharmaceutical composition of the present invention may contain additional biologically active substances depending on the intended use of the pharmaceutical composition.These additional biologically active substances may be, for example, antibodies, antibody fragments, hormones, growth factors, enzymes, binding molecules, cytokines, chemokines, nucleic acid molecules and drugs.In one preferred embodiment, the pharmaceutical composition of the present invention is co-administered with a long-acting beta-adrenergic receptor agonist (LABA), a long-acting muscarinic antagonist (LAMA), a phosphodiesterase inhibitor, a kinase inhibitor, a cytokine and chemokine inhibitor or antagonist, or a protease inhibitor, which is a steroid, a corticosteroid, a glucocorticoid and a glucocorticoid agonist, or a combination thereof.

[0277] In various embodiments, the dosage of the pharmaceutical compositions of the present invention disclosed herein will depend on the condition being treated, the particular composition used, and other clinical factors such as the subject's weight, size and condition, body surface area, the particular compound or composition being administered, other drugs administered concomitantly, and the route of administration.

[0278] In various embodiments, the pharmaceutical compositions of the present invention disclosed herein are useful in treating IL-18-associated diseases, such as chronic obstructive pulmonary disease (COPD), transfusion-associated lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), adult Still's disease, juvenile Still's disease, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension, asthma, bronchiectasis, heart failure, amyotrophic lateral sclerosis (ALS), xerophthalmia (DED), keratitis, corneal ulcers and abrasions, corneal neovascularization, pathological intraocular neovascularization, iritis, glaucoma, macular degeneration, Sjogren's syndrome, autoimmune uveitis, Behcet's disease, and the like. The composition may be administered in combination with other bioactive substances and procedures for the treatment of conditions associated with inflammatory bowel disease (IGF) and other conditions, such as conjunctivitis, allergic conjunctivitis, eyelid dermatitis, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), steatohepatitis, solid organ and blood transplants, ischemia-reperfusion injury, familial Mediterranean fever, tumor necrosis factor receptor 1-associated periodic syndrome, cryopyrin-associated periodic fever syndrome, hyper-IgD syndrome, gout, Schnitzler syndrome, Wegener's granulomatosis, also known as granulomatosis with polyangiitis (GPA), Hashimoto's thyroiditis, Crohn's disease, ulcerative colitis, immunoglobulin-4 (IgG4)-associated disease, and stem cell therapy. The other bioactive substance may be part of the same composition that already constitutes the composition of the present invention in the form of a mixture, where the composition of the present invention and the other bioactive substance may be mixed with each other in or with the same pharmaceutically acceptable solvent and / or carrier, or may be provided separately as part of separate compositions, or they may be supplied separately or together in a kit-of-parts format.

[0279] In various aspects, the pharmaceutical composition of the present invention disclosed herein can be administered simultaneously, intermittently, or sequentially with one or more other bioactive substances.For example, the composition of the present invention can be administered simultaneously with the first additional bioactive substance, or can be administered sequentially after or before the administration of the composition.When choosing the application scheme of administering multiple additional bioactive substances together with at least one composition of the present invention, compounds or substances can also be administered partially simultaneously, partially sequentially, and in various combinations.

[0280] Accordingly, another object of the present invention is to provide mixtures of the pharmaceutical compositions of the present invention as disclosed herein in various embodiments, optionally comprising one or more additional biologically active substances in therapeutically or prophylactically effective amounts, for the prevention and / or therapeutic treatment and / or alleviation of the effects of chronic obstructive pulmonary disease (COPD), heart disease and type 2 diabetes, and methods of using such compositions or mixtures thereof according to the present invention therefor.

[0281] Therefore, another object of the present invention is to provide a method for treating chronic obstructive pulmonary disease (COPD), transfusion-associated lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), adult Still's disease, juvenile Still's disease, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension, asthma, bronchiectasis, heart failure, amyotrophic lateral sclerosis (ALS), xerophthalmia (DED), keratitis, corneal ulcers and abrasions, corneal neovascularization, pathological intraocular neovascularization, iritis, glaucoma, macular degeneration, Sjogren's syndrome, autoimmune uveitis, Behcet's disease, conjunctivitis, allergic conjunctivitis, eyelid dermatitis, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, solid organ transplantation and blood transplantation, ischemia, and methods of using such compositions or mixtures thereof according to the present invention for the prevention and / or therapeutic treatment and / or amelioration of the effects of reperfusion injury, familial Mediterranean fever, tumor necrosis factor receptor 1-associated periodic syndrome, cryopyrin-associated periodic fever syndrome, hyper-IgD syndrome, gout, Schnitzler syndrome, Wegener's granulomatosis, also known as granulomatosis with polyangiitis (GPA), Hashimoto's thyroiditis, Crohn's disease, ulcerative colitis, immunoglobulin-4 (IgG4)-associated disease, and stem cell therapy.

[0282] The other biologically active substances or compounds may exert their biological effects by the same or similar mechanism as the compositions of the present invention, or by an unrelated mechanism of action, or by multiple related and / or unrelated mechanisms of action.

[0283] Generally, other biologically active compounds may include antibodies raised against and binding to INF-γ, IL-17A, IL-13, IL-1β, IL-6, IL-2, IL-4, IL-12, TNF-α. In particular, the mixture according to the invention may comprise IL-18BP (IL-18BP) or a pharmaceutical composition comprising IL-18BP (IL-18BP) and a pharmaceutically acceptable carrier and / or excipient according to the invention and as described herein.

[0284] In various embodiments, the appropriate dosage of the pharmaceutical compositions of the present invention disclosed herein will vary depending on the condition, age, and species of the subject, and can be easily determined by one skilled in the art. The total daily dosage for use in both veterinary and human medicine will preferably be in the range of 0.1 to 10 mg per kilogram.

[0285] Furthermore, functional derivatives of IL-18BP can be conjugated with polymers in order to improve protein properties, such as stability, half-life, bioavailability, tolerance by the human body, or immunogenicity. To achieve this goal, IL18BP can be linked to, for example, polyethylene glycol (PEG). PEGylation can be carried out by known methods, for example, as described in WO 92 / 13095.

[0286] Therefore, in another embodiment of the present invention, IL-18BP is PEGylated.

[0287] In yet another embodiment of the present invention, IL-18BP is a fusion protein in which all or part of IL-18BP is fused with all or part of an immunoglobulin, preferably with the constant region (Fc) of the immunoglobulin, and the fusion protein is still capable of binding to IL-18. More specifically, the immunoglobulin may be of the IgG1 or IgG2 isotype.

[0288] In a further embodiment of the present invention, IL-18BP is PEGylated and fused to all or part of an immunoglobulin, preferably the constant region (Fc) of an immunoglobulin, such that the fusion protein is still capable of binding to IL-18. More specifically, the immunoglobulin may be of the IgG1 or IgG2 isotype.

[0289] Those skilled in the art will understand that the resulting fusion protein retains the biological activity of IL-18BP, particularly its binding to IL-18. The fusion can be direct or via a short linker peptide, which can be as short as 1-3 amino acid residues or longer, e.g., 13 amino acid residues in length. The linker can be, for example, a 13-amino acid linker sequence containing the tripeptide sequence EFM (Glu-Phe-Met) or Glu-Phe-Gly-Ala-Gly-Leu-Val-Leu-Gly-Gly-Gln-Phe-Met, inserted between the IL-18BP sequence and the immunoglobulin sequence. The resulting fusion protein can have improved properties, such as a longer residence time in body fluids (half-life), increased specific activity, increased expression level, or easier purification of the fusion protein.

[0290] Preferably, it is fused to a heavy chain region, such as the CH2 and CH3 domains of human IgG1. The production of specific fusion proteins comprising IL-18BP and portions of immunoglobulins is described, for example, in Example 11 of WP99 / 09063. Other isoforms of Ig molecules, such as isoforms IgG2 or IgG4, or other Ig classes such as IgM or IgA, are also suitable for producing fusion proteins in the present invention. The fusion protein may be monomeric or multimeric, heteromultimeric, or homomultimeric.

[0291] definition Technical terms and expressions used within the scope of this application shall generally be given the meanings commonly applied to them in the relevant art, unless otherwise indicated hereinafter.

[0292] As used in this specification and the accompanying embodiments, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0293] The terms "treatment," "treating," and the like are used herein generally to mean obtaining a desired pharmacological and / or physiological effect. The effect may be preventative, in that a disease or its symptoms are completely or partially prevented, and / or therapeutic, in that a disease and / or adverse effects that may result from the disease are partially or completely stabilized or cured. As used herein, "treatment" encompasses any treatment of a disease in a subject, including: (a) preventing the occurrence of a disease, i.e., one associated with an unwanted immune response, in a subject who may be predisposed to the disease; (b) suppressing the disease, i.e., arresting its onset; or (c) palliating the disease, i.e., causing regression of the disease; or (d) reversing disease symptoms, i.e., leading to the recovery of damaged tissue.

[0294] As used herein, the term "IL-18 binding protein (IL-18BP)" includes full-length proteins, muteins, fragments, peptides, functional derivatives, functional fragments, portions, circularly permuted derivatives, fusion proteins comprising IL-18BP, isoforms, or salts thereof.

[0295] As used herein, the term "free IL-18" refers to monomeric, soluble, uncomplexed interleukin-18 protein.

[0296] The terms "functional" and "active" are used interchangeably herein and refer to modified IL-18BP or portions of IL-18BP that still have the same or essentially the same biological, pharmacological and therapeutic properties as unmodified or full-length IL-18BP, and therefore can be used in the present invention in the same manner as unmodified IL-18BP for the treatment of the diseases and disorders disclosed herein.

[0297] In various embodiments of the present invention, the term "IL-18BP" refers to human IL-18BP, in particular recombinant human IL-18BP, in particular isoform a, b, c or d of IL-18BP, in particular isoform a, isoform c, in particular isoforms a, b, c or d as shown in Figure 12 as SEQ ID NO 7 and SEQ ID NOs:388-390, among which isoform a of IL-18BP as shown in Figure 12 as SEQ ID NO:7, or isoform c as shown in Figure 12 as SEQ ID NO:389.

[0298] Mutants or functional fragments of IL-18BP "Immunoglobulins" are tetrameric molecules. In naturally occurring immunoglobulins, each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" chain (approximately 25 kDa) and one "heavy" chain (approximately 50-70 kDa). The amino-terminal portion of each chain contains a variable region of approximately 100-110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Human light chains are classified as [κ] and [λ] light chains. Heavy chains are classified as [μ], [δ], [γ], [α], or [ε], and define the antibody isotype as IgM, IgD, IgG, IgA, or IgE, respectively. Within the light and heavy chains, the variable and constant regions are connected by a "J" region of approximately 122 or more amino acids, and heavy chains also contain a "D" region of approximately 10 or more amino acids. For a review, see Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989)), which is incorporated by reference in its entirety for all purposes. The variable regions of each light / heavy chain pair form the antibody binding site, such that an intact immunoglobulin has two binding sites.

[0299] Immunoglobulin chains share the same overall structure, with relatively conserved framework regions (FRs) linked by three hypervariable regions, also called complementarity-determining regions or CDRs. The CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. Both light and heavy chains contain, from N- to C-terminal, the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to each domain follows the definition of the Kabat Sequences of Proteins of Immunological Interest. The Kabat complementarity-determining regions are based on sequence diversity and are the most commonly used (National Institutes of Health, Bethesda, Md. (1987 and 1991) or Chothia & Lesk J. Mol. Biol., 196:901-917 (1987)).

[0300] Chothia instead refers to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987), Chothia et al. Nature 342:878-883 (1989)).

[0301] An alternative system for assigning amino acids to each domain is the IMGT system (http: / / www.imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html). As used herein, the term "antibody" or "antibodies" is an art-recognized term and is intended to refer to molecules or active fragments of molecules that bind to known antigens, particularly immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain a binding site that immunospecifically binds to an antigen. Immunoglobulins according to the present invention can be immunoglobulin molecules of any type (IgG, IgM, IgD, IgE, IgA, and IgY) or class (IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass.

[0302] The term "antibody," as used herein, refers to an intact immunoglobulin or an antigen-binding fragment thereof that competes with the intact antibody for specific binding. In particular, within the scope of the present invention, "antibody" is intended to mean monoclonal antibodies, polyclonal antibodies, chimeric antibodies, single-chain antibodies, bispecific or bi-effective antibodies, simian antibodies, human antibodies, and humanized antibodies.

[0303] Examples of antigen-binding portions include Fab, Fab', F(ab')2, scFv, dAb, and Fv fragments, among others, including the products of a Fab immunoglobulin expression library, as well as epitope-binding fragments of any of the antibodies and fragments described above. Further examples of antigen-binding portions include complementarity-determining region (CDR) fragments, diabodies, and polypeptides comprising at least a portion of an immunoglobulin sufficient to confer specific binding to the polypeptide.

[0304] Such active fragments can be derived from the antibodies of the present invention by several techniques known in the art. For example, purified monoclonal antibodies can be cleaved with an enzyme such as pepsin and subjected to HPLC gel filtration. Appropriate fractions containing Fab fragments can then be collected and concentrated by membrane filtration or the like. For further description of general techniques for isolating active fragments of antibodies, see, for example, Khaw, BA et al., J. Nucl. Med. 23:1011-1019 (1982); Rousseaux et al., Methods Enzymology, 121:663-69, Academic Press, 1986.

[0305] "Humanized antibody" refers to a type of engineered antibody that has CDRs derived from immunoglobulins of non-human donors. In one embodiment, specific amino acids in the framework and constant domains of the heavy and light chains are mutated to avoid or suppress an immune response in humans. In an alternative embodiment, a humanized antibody can be made by fusing the constant domains from a human antibody with the variable domains of a non-human species. Examples of methods for making humanized antibodies can be found in U.S. Patent Nos. 6,054,297, 5,886,152, and 5,877,293.

[0306] In yet another embodiment of the present invention, a "humanized antibody" refers to a type of modified antibody having CDRs derived from a non-human donor immunoglobulin inserted between a human antibody "scaffold" derived from one or more human immunoglobulins. In addition, framework support residues can be modified to retain binding affinity. Methods for obtaining "humanized antibodies" are well known to those skilled in the art (see, for example, Queen et al., Proc. Natl Acad Sci USA, 86:10029-10032 (1989), Hodgson et al., Bio / Technology, 9:421(1991)).

[0307] "Humanized antibodies" can also be obtained by novel genetic engineering approaches that allow the production of affinity-matured, human-like polyclonal antibodies in large animals, such as rabbits (see, e.g., U.S. Pat. No. 7,129,084).

[0308] The term "monoclonal antibody" is also well recognized in the art and refers to an antibody that is mass-produced in the laboratory from a single clone and recognizes only one antigen. Monoclonal antibodies are typically produced by fusing normal, short-lived, antibody-producing B cells with rapidly proliferating cells such as cancer cells (sometimes called "immortal" cells). The resulting hybrid cells, or hybridomas, grow rapidly to create clones that produce large amounts of antibody. In the present invention, "monoclonal antibody" should be interpreted to include antibodies produced by maternal clones that have not yet achieved complete monoclonality.

[0309] The term "CDR" refers to the hypervariable region of an antibody. As used herein, the terms "hypervariable region," "HVR," or "HV" refer to the region of an antibody variable domain that is hypervariable in sequence and / or forms a structurally defined loop. Generally, antibodies contain six hypervariable regions: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Several delineations of hypervariable regions are used and are included within the scope of this specification. The Kabat complementarity determining region is based on sequence diversity and is the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)).

[0310] The letters "HC" and "LC" preceding the term "CDR" refer to the heavy and light chain CDRs, respectively. Chothia instead refers to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The AbM hypervariable regions represent a compromise between the Kabat CDRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. The "contact" hypervariable regions are based on an analysis of available complex crystal structures.

[0311] The terms "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat", and variations thereof, refer to the numbering system used for heavy or light chain variable domains of a collection of antibodies in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991).

[0312] Within the scope of the present invention, the term "functionally equivalent antibody" is understood to refer to an antibody that substantially shares at least one major functional property with a given antibody, for example, the functional properties described herein, including, but not limited to, binding specificity for free IL-18 protein. The antibody may be of any class, such as IgG, IgM, or IgA, or any subclass, such as IgG1, IgG2a, and other subclasses described herein or known in the art, particularly the IgG4 class. Furthermore, antibodies can be produced by any method, such as phage display, or in any organism or cell line, including bacterial, insect, mammalian, or other types of cells or cell lines, that produce antibodies with desired properties, such as humanized antibodies. Antibodies can also be formed by combining Fab portions and Fc regions from different species.

[0313] Antibody fragments or analogs can be easily prepared by those skilled in the art following the teachings of this specification. Preferred amino and carboxy termini of fragments or analogs occur near the boundaries of functional domains. Structural and functional domains can be identified by comparing nucleotide and / or amino acid sequence data with public or proprietary sequence databases. Computerized comparison methods are preferably used to identify sequence motifs or predicted protein conformation domains present in other proteins with known structure and / or function. Methods for identifying protein sequences that fold into known three-dimensional structures are known. See, e.g., Bowie et al., 1991, Science 253:164.

[0314] The term "human antibody" includes all antibodies having one or more variable and constant regions derived from human immunoglobulin sequences. In a preferred embodiment, all variable and constant domains are derived from human immunoglobulin sequences (fully human antibodies). These antibodies can be prepared in a variety of host cells, such as prokaryotic cells, e.g., E. coli. In another embodiment, the host cell is a eukaryotic cell, e.g., a protist cell, an animal cell, a plant cell, a plant, or a fungal cell. In one embodiment, the host cell is a mammalian cell, including, but not limited to, a CHO cell, a COS cell, an NS0 cell, a SP2 cell, or a PER.C6 cell, or a fungal cell, e.g., a Saccharomyces cerevisiae cell, or an insect cell, e.g., an Sf9 cell. In another embodiment, cells producing human antibodies can be grown in bioreactors, or in the case of plants, in greenhouses and fields (see, e.g., Riechmann L, et al (1988). Nature 332 (6162): 332-323; Queen C, et al. (Dec 1989). Proc Natl Acad Sci US A. 86 (24): 10029-33; Kashmiri SV, et al. (May 2005). Methods 36 (1): 25-34; Hou S, et al (July 2008). J Biochem 144 (1): 115-20).

[0315] "Patient" or "subject" are used interchangeably in the present invention and include both humans and other animals, particularly mammals, as well as other organisms. Thus, the present method is applicable to both human therapy and veterinary use. In a preferred embodiment, the patient or subject is a mammal, and in a most preferred embodiment, the patient or subject is a human.

[0316] The expressions "pharmaceutical composition" and "therapeutic composition" are used interchangeably in the broadest sense herein and refer to a therapeutically effective amount of the active ingredient, i.e., IL-18BP, in the context of the present invention, and, optionally, a pharmaceutically acceptable carrier or diluent.

[0317] It includes compositions suitable for the curative treatment, control, amelioration, amelioration, or prevention of a disease or disorder in humans or non-human animals. Thus, it includes pharmaceutical compositions for use in the fields of human or veterinary medicine. Such a "therapeutic composition" is characterized in that it comprises at least one IL-18BP compound or a physiologically acceptable salt thereof, and optionally a carrier or excipient, wherein the salt and carrier and excipient are tolerated by the target organism to be treated therewith.

[0318] A "therapeutically effective amount" is an amount that produces a therapeutic effect for a given condition and administration regimen. In particular, a "therapeutically effective amount" refers to an amount effective to prevent, reverse, alleviate, or ameliorate symptoms of disease or to prolong the survival of the treated subject, which may be a human or non-human animal. Determining a therapeutically effective amount is within the skill of one of ordinary skill in the art. In particular, in the present case, a "therapeutically or prophylactically effective amount" refers to the amount of a protein or peptide, mutein, functional derivative, portion, circularly permuted derivative, fusion protein, isoform, or salt thereof, and compound or pharmaceutical composition that, when administered to a human or animal, induces a therapeutic or prophylactic effect in said human or animal. Effective amounts can be readily determined by those skilled in the art using routine procedures. The therapeutically effective amount or dosage of the compound according to the present invention can vary within a wide range and can be determined in a manner known in the relevant art. The dosage can vary within a wide range and, of course, must be adjusted to the individual requirements in each particular case.

[0319] "Transmucosal" administration refers to various routes of administration in which a compound is absorbed by the mucous membranes of any part of the body, including, but not limited to, intranasal, buccal, oral transmucosal, intratracheal, intraurinary, rectal, intravaginal, sublingual, intrabronchial, pulmonary, and transdermal administration.

[0320] The definition of "pharmaceutically acceptable" is meant to encompass any carrier, excipient, diluent, or vehicle that does not interfere with the effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which it is administered.

[0321] The term "fusion protein" refers to a polypeptide comprising an IL-18BP or a viral IL-18BP, or a mutein or fragment thereof, fused with another protein, e.g., which has an extended residence time in body fluids. The IL-18BP or viral IL-18BP can thus be fused to another protein, polypeptide, etc., e.g., an immunoglobulin or a fragment thereof.

[0322] These isoforms, muteins, fusion proteins, or functional derivatives retain the biological activity of IL-18BP, particularly its ability to bind to IL-18, and preferably have essentially at least the same activity as IL-18BP. Ideally, such proteins will have even increased biological activity compared to unmodified IL-18BP. Preferred active moieties have activity that is superior to that of IL-18BP, or activity that has additional advantages, such as greater stability or lower toxicity or immunogenicity, or they are easier to produce in large quantities or to purify.

[0323] The term "interleukin-18 binding protein" also includes muteins, functional derivatives, portions, biologically active peptides, circularly permuted derivatives, fusion proteins, isoforms and salts thereof of IL-18BP.

[0324] As used herein, the term "mutein" refers to an analog of IL-18BP or a viral IL-18BP in which one or more amino acid residues of a native IL-18BP or a viral IL-18BP have been replaced by a different amino acid residue or deleted, or one or more amino acid residues have been added to the native sequence of IL-18BP or a viral IL-18BP, such that the activity of the resulting product is not significantly altered compared to that of wild-type IL-18BP or a viral IL-18BP. These muteins are prepared by known synthetic and / or site-directed mutagenesis techniques, high-throughput mutagenesis, DNA shuffling, protein evolution techniques, or any other known technique suitable for this purpose.

[0325] Any such mutein preferably has an amino acid sequence sufficiently similar to that of IL-18BP or sufficiently similar to that of viral IL-18BP so as to have substantially similar activity to IL-18BP. One activity of IL-18BP is the ability to bind to IL-18. As long as a mutein has substantial binding ability to IL-18, it can be used to purify IL-18, such as by affinity chromatography, and therefore can be considered to have substantially similar activity to IL-18BP. Therefore, whether any given mutein has substantially the same activity as IL-18BP can be determined by routine experimentation, including, for example, subjecting such a mutein to a simple sandwich competition assay, such as a radioimmunoassay or ELISA assay, to determine whether it binds to appropriately labeled IL-18.

[0326] Muteins of IL-18BP polypeptides or muteins of viral IL-18BPs, or the nucleic acids encoding them, that can be used in accordance with the present invention include a finite set of sequences that substantially correspond to replacement peptides or polynucleotides that can be routinely obtained by one of ordinary skill in the art without undue experimentation, based on the teachings and guidance provided herein.

[0327] Preferred changes for muteins according to the present invention are what are known as "conservative" substitutions. Conservative amino acid substitutions in IL-18BP polypeptides or proteins or viral IL-18BPs may include synonymous amino acids within a group having substantially similar physicochemical properties, such that substitutions between members of the group are expected to retain the biological function of the molecule (Grantham, 1974). It is clear that amino acid insertions and deletions can be made within the above-defined sequences without altering their function, particularly when the insertions or deletions involve only a few amino acids, e.g., fewer than 30, preferably fewer than 10, and when amino acids important for functional conformation, such as cysteine ​​residues, are not removed or replaced. Proteins and muteins produced by such deletions and / or insertions are within the scope of the present invention.

[0328] As used herein, "functional derivatives" include derivatives of IL-18BP or viral IL-18BP, as well as muteins and fusion proteins thereof, which can be prepared from functional groups present in side chains on residues or as N- or C-terminal groups by means well known in the art, and are included in the present invention so long as they are pharmaceutically acceptable, i.e., do not destroy the activity of the protein substantially similar to the activity of IL-18BP or viral IL-18BP, and do not impart toxicity to compositions containing them.

[0329] These derivatives may include, for example, polyethylene glycol side chains, which may mask antigenic sites and extend the residence of IL-18BP or viral IL-18BP in body fluids. Other derivatives include aliphatic esters of the carboxyl group, amides of the carboxyl group by reaction with ammonia or primary or secondary amines, N-acyl derivatives of free amino groups of amino acid residues formed with acyl moieties (e.g., alkanol or carbocyclic aroyl groups), and O-acyl derivatives of free hydroxyl groups (e.g., of seryl or threonyl residues) formed with acyl moieties.

[0330] By "active fragment" of IL-18BP or viral IL-18BP, muteins and fusion proteins, the present invention encompasses any fragment or precursor of the polypeptide chain of the IL-18BP protein molecule alone, or to which a molecule or residue, e.g., a sugar or phosphate residue, or a collection of protein molecules or sugar residues itself, is linked, provided that said portion has substantially similar activity to IL-18BP.

[0331] The term "salt" herein refers to both salts of carboxyl groups and acid addition salts of amino groups of IL-18BP molecules or analogs thereof. Salts of carboxyl groups can be formed by means known in the art, including inorganic salts such as sodium salts, calcium salts, ammonium salts, ferric salts, or zinc salts, and salts with organic bases, such as amines such as triethanolamine, arginine or lysine, piperidine, and procaine. Acid addition salts include salts with mineral acids such as hydrochloric acid or sulfuric acid, and salts with organic acids such as acetic acid or oxalic acid. Of course, any such salts must retain the biological activity of IL-18BP, such as the ability to bind to IL-18.

[0332] An "isoform" of IL-18BP refers to a protein that can be produced by alternative splicing and that can bind to IL-18 or a fragment thereof.

[0333] As used herein, the term "circularly permuted derivative" refers to a linear molecule whose termini are linked together, either directly or via a linker, to form a circular molecule, which is then cleaved at a different location to form a new linear molecule with termini different from those of the original molecule. Circularly permuted molecules include molecules whose structure is equivalent to a molecule that has been circularized and then cleaved. Thus, circularly permuted molecules may be synthesized de novo as linear molecules, bypassing the cyclization and cleavage steps. The preparation of circularly permuted derivatives is described in WO 95 / 27732.

[0334] The expression "abnormal levels of free IL-18" refers to increased or decreased levels of IL-18 compared to the values ​​detected in the body fluids of healthy control subjects. In particular, these abnormal levels refer to increased IL-18 values. In particular, said abnormal levels of free IL-18 in body fluids are 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the levels in the body fluids of healthy control subjects. In one embodiment of the present invention, the reference or control value is a normal, non-pathological standard value of free IL-18 determined in the patient to be treated.

[0335] The expression "abnormal ratio of free IL-18 / IL-18BP" refers to an increased ratio of IL-18 to IL-18BP compared to the value found in the body fluid of a healthy control subject. In particular, said abnormal ratio of free IL-18 to IL-18BP in body fluid is 1%, 2.5%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the ratio in the body fluid of a healthy control subject. In one embodiment of the present invention, the reference value or control value is a normal, non-pathological standard value of free IL-18 determined in the patient to be treated.

[0336] The terms "gene silencing" and "post-transcriptional gene silencing" refer to the downregulation of gene expression by mechanisms other than genetic modification. Silencing occurs at the post-transcriptional level by mRNA neutralization, which prevents mRNA translation and prevents the formation of an active gene product, most often a protein.

[0337] The term "predisposition" refers to a subject's increased susceptibility to developing a particular disease. In this case, a subject is classified as predisposed if, for example, elevated levels of IL-18 are found in the lungs, serum, sputum, bronchoalveolar lavage fluid (BALF), or bloodstream.

[0338] "Smoke / Smoking," "smoking-induced," "tobacco smoke," or "tobacco smoke-induced" refers to tobacco smoke.

[0339] "Alveolar macrophages" are a subtype of macrophage found in the alveoli. They often contain granules of exogenous material that they have captured from respiratory surfaces. Such black granules are particularly common in people with long-term exposure to fine dust and particulate matter, such as smokers or long-time city dwellers.

[0340] A "Th2 cytokine response" is mediated by IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, and / or IL-17A, particularly IL-4 and / or IL-8 and / or IL-17A, while a "Th1 cytokine response" is mediated by interferon-γ (IFN-γ), IL-2, and tumor necrosis factor-α (TNF-α).

[0341] The expression "IL-18 / IL-18BP imbalance" refers to the dysregulation of the interaction between IL-18 and IL-18BP, ultimately leading to elevated levels of unbound IL-18.

[0342] A "disease" is a state of health in an animal in which the animal is unable to maintain homeostasis and in which the animal's health continues to deteriorate unless the disease is ameliorated. In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but the animal's health is less favorable than would be the case in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further decline in the animal's health.

[0343] A disease or disorder is "improved" if the severity of the symptoms of the disease or disorder, the frequency with which the subject experiences such symptoms, or both, are reduced.

[0344] The terms "dysregulated" or "dysregulated," as used herein, refer to an impaired biological process that can result in adverse physiological consequences or abnormal expression of a gene, nucleic acid, protein, peptide, or other biomolecule. When expression of a gene, nucleic acid, protein, peptide, or other biomolecule is dysregulated, the gene, nucleic acid, protein, peptide, or other biomolecule is expressed, processed, or maintained at levels that exceed what is considered the normal range for that gene, nucleic acid, protein, peptide, or other biomolecule, as determined by one of skill in the art. Dysregulation of a gene, nucleic acid, protein, peptide, or other biomolecule in a mammal can be determined by measuring the level of the gene, nucleic acid, protein, peptide, or other biomolecule in the mammal and comparing the measured level with the level measured in a matched population known not to be dysregulated by that gene, nucleic acid, protein, peptide, or other biomolecule. Alternatively, the level can be compared to that measured in the same individual at a different time.

[0345] As used herein, the term "heart disease" or "cardiovascular disease" includes diseases and disorders that affect the heart and the body's myocardium or blood vessels. Heart disease can lead to heart failure, which ultimately becomes one of the most frequent causes of death in industrialized society. Examples of heart disease induced by IL-18 / IL-18BP imbalance include, but are not limited to, obstructive heart disease, thrombolytic dysfunction, alcoholic cardiomyopathy, aortic valve prolapse, aortic valve stenosis, arrhythmia, cardiogenic shock, congenital heart disease, dilated cardiomyopathy, heart attack, heart failure, cardiac tumor, valvular pulmonary stenosis, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, ischemic heart disease, ischemic cardiomyopathy, mitral valve regurgitation, mitral valve prolapse, peripartum cardiomyopathy, and stable angina.

[0346] As used herein, the term "type 2 diabetes" refers to the most common type of diabetes. This disease or disorder is characterized by either the body not producing or producing insufficient amounts of the enzyme insulin, or by a defect in the cellular response to insulin. Such defects are believed to be related to the insulin receptor.

[0347] As used herein, "endogenous" refers to any substance that originates or is produced within an organism, cell, tissue, or system. The term "exogenous" refers to any substance that originates or is produced outside an organism, cell, tissue, or system.

[0348] As used herein, the term "expression" is defined as the transcription and / or translation of a specific nucleotide sequence driven by a promoter. As used herein, the term "expression vector" refers to a vector containing a nucleic acid sequence encoding at least a portion of a gene product that can be transcribed. In some cases, the RNA molecule is subsequently translated into a protein, polypeptide, or peptide. In other cases, such as in the production of antisense molecules, siRNA, and ribozymes, these sequences are not translated. Expression vectors can contain various regulatory sequences, which refer to nucleic acid sequences necessary for the transcription, and possibly translation, of an operably linked coding sequence in a particular host organism. In addition to regulatory sequences governing transcription and translation, vectors and expression vectors can also contain nucleic acid sequences that perform other functions. The expression vectors of the present invention can be used in gene therapy for the treatment of diseases or disorders disclosed herein. In particular, the expression vector is a viral vector. Viruses that can be used as vehicles for delivering expression vectors are selected from the group consisting of retroviruses, adenoviruses, lentiviruses, herpes simplex viruses, vaccinia viruses, poxviruses, and adeno-associated viruses.

[0349] As used herein, the terms "inhibit," "neutralize," or "block" should be taken as synonyms meaning to measurably reduce or completely prevent the expression, stability, function, or activity of a molecule, reaction, interaction, gene expression, mRNA, and / or protein. Inhibitors are compounds, e.g., antagonists, that bind to proteins, genes, and mRNAs, partially or completely block their activation, reduce, prevent, delay their activation, inactivate, desensitize, or downregulate their stability, expression, function, and activity.

[0350] "Antisense expression vector" refers to an expression vector that encodes a single-stranded or double-stranded RNA that is complementary to a messenger RNA (mRNA) strand and inhibits the translation of the mRNA into amino acids. The term antisense RNA includes asRNA, siRNA, shRNA, and microRNA.

[0351] As used herein, the term "gene therapy" refers to the use of DNA, such as an expression vector, as a pharmaceutical agent to treat the diseases disclosed herein.

[0352] Summary of aspects of the invention 1. A composition comprising IL-18BP or an active fragment thereof for use in treating an IL-18-related disease or disorder in a subject, wherein the subject is suffering from such a disease or disorder, and the subject's body fluid has been determined to have an abnormal level of free IL-18 using an assay capable of detecting free IL-18 in body fluids, which is in particular 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the level of free IL-18 in the body fluid of a healthy control subject, and the assay is a portion thereof, wherein the antibody or active portion thereof binds to IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and the composition is substantially free of N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP, wherein these mutants are present in an amount particularly less than 30%, particularly less than 20%, particularly less than 15%, particularly less than 10%, particularly less than 7.5%, particularly less than 5%, particularly less than 2.5%, particularly less than 1%, particularly less than 0.5%, particularly less than 0.25%, and particularly less than 0.1%. 2. A composition comprising an IL-18 inhibitor or an active fragment thereof for use in treating an IL-18-related disease or disorder in a subject, wherein the subject suffers from such a disease, and the subject's body fluid has been determined to have an abnormal level of free IL-18, in particular 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the level of free IL-18 in the body fluid of a healthy control subject, using an assay capable of detecting free IL-18 in the body fluid comprising an IL-18BP or antibody or a functional portion thereof, and A composition comprising an IL-18 inhibitor or an active fragment thereof, wherein the antibody or an active portion thereof binds to IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, the inhibitor is IL-18BP or an antibody or a functional portion thereof, the antibody or an active portion thereof binds to IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and the composition comprises sodium chloride, and / or sodium hydroxide and / or sodium phosphate. 3. A composition comprising an IL-18 inhibitor or an active fragment thereof for use in treating an IL-18-related disease or disorder in a subject, wherein the subject is suffering from such a disease, and the subject's body fluid has been determined to have an abnormal level of free IL-18, in particular 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the level of free IL-18 in the body fluid of a healthy control subject, using an assay capable of detecting free IL-18 in a body fluid comprising an IL-18BP or antibody or a functional portion thereof, and a composition comprising an IL-18 inhibitor or an active fragment thereof, wherein the active portion binds to IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, the inhibitor is an IL-18BP or an antibody or a functional portion thereof, the antibody or an active portion thereof binds to IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and the composition is administered to a subject to be treated in multiple doses per day, multiple doses per week, or multiple doses per month. 4. A composition for use according to any one of aspects 1 to 3, wherein the level of free IL-18 in body fluids has been determined to be equal to or greater than 5 pg / mL, in particular up to 10,000 pg / mL, compared to equal to or less than 4 pg / mL in healthy controls. 5. Assays for quantifying levels of free IL-18 in body fluids a) contacting a sample of a body fluid suspected of containing free IL-18 with an IL-18BP or an antibody or an active fragment thereof that specifically binds to free IL-18 but not to IL-18 bound in a complex and that functions as a capture molecule for free IL-18; b) binding the IL-18BP or antibody to free IL-18; c) detecting binding of IL-18 to the IL-18BP or antibody to determine the amount of free IL-18 in the sample. 5. A composition for use according to any one of aspects 1 to 4, comprising: 6. A composition for use according to any one of aspects 1 to 5, wherein the antibody used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is an antibody comprising any functionally equivalent antibody or a functional portion thereof, which antibody or a functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP, but does not bind to the IL-18 / IL-18BP complex, and which comprises CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region which are comprised in or essentially consist of the corresponding heavy chain CDR region of an antibody having the sequence identified in Table 8 and set out in column 5 of Table 8, and CDR1, CDR2 and CDR3 of the light chain variable (VK) region which are comprised in or essentially consist of the corresponding light chain CDR region of an antibody identified in Table 8 and set out in column 5 of Table 8. 7. A composition for use according to any one of aspects 1 to 6, wherein the antibody used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is an antibody, including any functionally equivalent antibody or functional portion thereof, which antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and which antibody comprises CDR1, CDR2, and CDR3 of the heavy chain variable (VH) region of an antibody identified in Table 8 and having the sequence set out in Table 8, and CDR1, CDR2, and CDR3 of the light chain variable (VK) region of an antibody identified in Table 8 and having the sequence set out in Table 8. 8. The composition for use according to any one of aspects 1 to 7, wherein the antibody used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is an antibody selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a single-chain antibody, a bispecific or dual-effect antibody, a simianized antibody, a human antibody, and a humanized antibody. 9. A composition for use according to any one of aspects 1 to 6, wherein the antibody used as an inhibitor of IL-18 or as a capture molecule in an assay for quantifying free IL-18 in body fluids is a human antibody or a humanized antibody. 10. The composition for use according to any one of aspects 1 and 4 to 9, wherein said deletion mutant comprises a deletion of 1 to 5 amino acid residues at the C-terminus of IL-18BP and / or 1 to 30 amino acid residues at the N-terminus of IL-18BP. 11. A composition for use according to aspect 10, wherein the proportion of deletion mutants in the composition is less than 30%, particularly less than 20%, particularly less than 15%, particularly less than 10%, particularly less than 7.5%, particularly less than 5%, particularly less than 2.5%, particularly less than 1%, particularly less than 0.5%, particularly less than 0.25%, particularly less than 0.1%. 12. The composition for use according to any one of aspects 1, 2, and 4-11, wherein the composition is administered to the subject to be treated in multiple doses per day, multiple doses per week, or multiple doses per month. 13. The composition for use according to any one of aspects 1-12, wherein the composition is administered in two doses per week, three doses per week, or four doses per week. 14. The composition for use according to aspect 13, wherein a single dose comprises between 10 mg and 600 mg of IL-18BP. 15. The composition for use according to aspect 14, wherein a single dose comprises 10 to 20 mg, 20 to 40 mg, 40 to 80 mg, 80 to 160 mg, 160 mg to 320 mg, or 320 mg to 600 mg of IL-18BP. 16. A composition for use according to any one of aspects 1 to 15, wherein the treatment is continued until the treated subject exhibits at least a therapeutic response. 17. The therapeutic response is (a) Normalization of body temperature (normal range: 36.3–37.4°C measured in the axilla in the absence of NSAIDs in the 24 hours prior to measurement) (b) Improvement in joint swelling and tenderness (20% or more); and (c) ≥70% decrease in CRP or normalization of CRP and ferritin to baseline; 17. The composition for use according to embodiment 16, characterized by: 18. A composition for use according to any one of aspects 1 to 17, wherein the IL18 BP is human IL-18BP, in particular recombinant human interleukin-18 binding protein (rhIL-18BP). 19. The composition for use according to any one of aspects 1 to 18, wherein the IL-18BP is isoform a or isoform c of IL-18BP. 20. The composition for use according to any one of aspects 1 to 19, wherein the IL-18BP is isoform a of IL-18BP as set forth in SEQ ID NO:7. 21. The disease or disorder associated with IL-18 is chronic obstructive pulmonary disease (COPD), transfusion-related lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), Still's disease, particularly adult Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic juvenile-onset idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS) including primary, secondary, and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH), perforin, munc 13-4 and 18-2, synthaxin Familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with 11 genetic defects; immunodeficiencies such as Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP); acquired hemophagocytic lymphohistiocytosis associated with infectious conditions, particularly herpesviruses such as EBV and other pathogens; cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID); autoinflammatory syndromes associated with NLRC4 mutations; giant cell arteritis (GCA); geographic atrophy; pulmonary sarcoidosis.sarcoidis), idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension, asthma, bronchiectasis, heart failure, ischemic heart disease, amyotrophic lateral sclerosis (ALS), atherosclerosis, xerophthalmia (DED), keratitis, corneal ulcers and abrasions, corneal neovascularization, pathological intraocular neovascularization, iritis, glaucoma, macular degeneration, Sjögren's syndrome, autoimmune uveitis, Behçet's disease, conjunctivitis, allergic conjunctivitis, eyelid dermatitis, type 1 diabetes, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, parenchymal organ and blood stem cell transplantation, ischemia-reperfusion 21. The composition for use according to any one of aspects 1 to 20, wherein the inflammatory bowel disease (IGD) is selected from the group consisting of: inflammatory bowel disease (IGD), inflammatory bowel disease (IGF ... 22. The composition for use according to any one of the preceding aspects, wherein said subject has been diagnosed with Still's disease based on the presence of at least two of the major items of the Yamaguchi criteria. 23. At least two of the major items in the Yamaguchi Criteria are met. i. Fever above 39°C lasting more than one week ii. 10,000 / mm3 with more than 80% polymorphonuclear neutrophils 3 Leukocytosis above iii. Typical skin rash iv. joint pain lasting more than 2 weeks; and optionally, elevated inflammatory markers. 24. The composition for use according to any one of aspects 22-23, wherein the subject to be treated has been exposed to a non-steroidal anti-inflammatory drug (NSAID), prednisone and / or a synthetic disease-modifying antirheumatic drug (sDMARD) but has not responded to the treatment or has only responded incompletely to the treatment. 25. The composition for use according to aspect 24, wherein the subject to be treated has been exposed to a non-steroidal anti-inflammatory drug (NSAID), in particular at a dose of at least 5 mg / day for more than one month, prednisone, and / or a synthetic disease-modifying antirheumatic drug (sDMARD), in particular at a dose of at least 10 mg / day for more than three months. 26. The composition for use according to any one of the preceding embodiments, wherein said IL-18-associated disease or disorder is part of a chronic obstructive pulmonary disease (COPD) syndrome induced by smoking, exposure to secondhand smoke, or air pollutants in general, and is characterized by the presence of poorly reversible airflow limitation. 27. The composition for use according to any one of the preceding embodiments, wherein said IL-18-associated disease or disorder involves multiple components of heterogeneous COPD disease and COPD exacerbations induced by viral or bacterial infections. 28. The composition for use according to any one of the preceding embodiments, wherein said IL-18-associated disease or disorder is systemic manifestations of IL-18-induced inflammation and accompanying comorbidities selected from the group consisting of emphysema, tissue inflammation, tissue destruction, lung resection, loss of vasculature, endothelial cell apoptosis, mucosal metaplasia, cardiac hypertrophy, decreased VEGF in lung tissue, pulmonary vascular loss, vascular muscularization, vascular remodeling, collagen deposition, abnormal elastin layers in the lungs, fibrotic airway remodeling, alveolar enlargement, chronic remodeling of airways and pulmonary vessels, and decreased lung function. 29. The composition for use according to any one of the preceding embodiments, wherein treatment comprises preventing, arresting, reducing or reversing symptoms associated with said disease or disorder. 30. The composition for use according to any one of the preceding aspects, wherein the increased expression of IFNγ, IL-13 or IL-17A is altered, in particular inhibited, compared to an untreated subject suffering from said disease or disorder. 31. A composition for use according to any one of the previous embodiments, which corrects the IL-18 / IL-18BP imbalance by scavenging and neutralizing excess free IL-18 in tissues and circulation through binding of free IL-18 by IL-18BP. 32. A composition for use according to any one of the previous aspects, wherein IL-18BP inhibits neutrophil infiltration into the lungs, particularly through attenuation of G-CSF release within the pulmonary airways. 33. The composition for use according to any one of the preceding embodiments for the treatment of chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), heart disease, amyotrophic lateral sclerosis (ALS), xerophthalmia and / or type II diabetes. 34. A composition for use according to any one of the previous embodiments for the treatment of chronic obstructive pulmonary disease (COPD). 35. A composition for use according to any one of the previous embodiments for the treatment of cardiac disease. 36. A composition for use according to any one of the preceding embodiments for the treatment of amyotrophic lateral sclerosis (ALS). 37. A composition for use according to any one of the previous embodiments for the treatment of dry eye syndrome. 38. A composition for use according to any one of the previous embodiments for the treatment of type II diabetes. 39. A composition for use according to any one of the previous aspects, wherein the binding of IL-18, in particular the binding of free IL-18 to IL-18R, especially the binding of free IL-18 to IL-18Rα, is limited or inhibited. 40. The composition for use according to any one of the previous aspects, wherein IL-18BP reduces binding of IL-18 to the IL-18 receptor, in particular to IL-18Rα, by at least 5%, particularly at least 10%, particularly at least 15%, particularly at least 20%, particularly at least 25%, particularly at least 30%, particularly at least 40%, particularly at least 45%, particularly at least 50%, particularly at least 55%, particularly at least 60%, particularly at least 65%, particularly at least 70%, particularly at least 75%, particularly at least 80%, particularly at least 85%, particularly at least 90%, particularly at least 95%, particularly 100%. 41. The composition for use according to any one of the previous aspects, wherein the IL-18BP neutralizes free IL-18 by limiting or preventing the binding of IL-18 to the IL-18 receptor (IL-18R), in particular the binding of free IL-18 to IL-18Rα. 42. A human or humanized antibody, including any functionally equivalent antibody or portion thereof, which antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and which comprises CDR1, CDR2 and CDR3 of a heavy chain variable (VH) region that are comprised in or essentially consist of the corresponding heavy chain CDR regions of an antibody having the sequence identified in Table 8 and set out in column 5 of Table 8, and CDR1, CDR2 and CDR3 of a light chain variable (VK) region that are comprised in or essentially consist of the corresponding light chain CDR regions of an antibody having the sequence identified in Table 8 and set out in column 5 of Table 8. 43. A human or humanized antibody according to embodiment 42, including any functionally equivalent antibody or portion thereof, wherein the antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP, but does not bind to the IL-18 / IL-18BP complex, and wherein the antibody comprises CDR1, CDR2 and CDR3 of a heavy chain variable region having the sequence set out in Table 8, and CDR1, CDR2 and CDR3 of a light chain variable region having the sequence set out in Table 8. 44. An antibody, including any functionally equivalent antibody or portion thereof, which antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and which comprises CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region which are comprised in or essentially consist of the CDRs of the corresponding heavy chain CDR regions of an antibody identified in Table 8 and having the sequence set out in column 5 of Table 8, and CDR1, CDR2 and CDR3 of the light chain variable (VK) region which are comprised in or essentially consist of the CDRs of the corresponding light chain CDR regions of an antibody identified in Table 8 and having the sequence set out in column 5 of Table 8, and which is not antibodies 107C6, 108F8, 109A6, 111A6, 131B4, 131E8, 131H1, 132H4, 133A6 identified in the Sequence Listing based on the VH and VK sequences. 45. A composition comprising the antibody according to any one of aspects 42 to 44. 46. ​​The composition according to aspect 45, which is a pharmaceutical composition comprising a pharmaceutically acceptable carrier. 47. A composition according to embodiment 45 or 46, comprising an antibody according to any one of embodiments 42 to 44, for use in treating an IL-18 associated disease or disorder in a subject suffering from a disease as defined in any one of embodiments 1 to 41. 48. A method for determining the amount of free IL-18 in a sample or in situ, comprising detecting specific binding of an antibody as defined in any one of aspects 42 to 44 to free IL-18 protein in the sample or in situ, a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any one of aspects 42 to 44, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample. A method comprising: 49. A method for diagnosing an IL-18-associated disease or disorder in a patient, in particular an IL-18-associated disease or disorder as defined in any one of the preceding aspects, comprising detecting specific binding of an antibody as defined in any one of aspects 42 to 44 to free IL-18 protein in a sample or in situ, a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any one of aspects 42 to 44, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any one of the preceding embodiments with the amount in a sample from a healthy subject. A method comprising: 50. A method for diagnosing a predisposition to an IL-18-associated disease or disorder in a patient, in particular an IL-18-associated disease or disorder as defined in any one of the preceding aspects, comprising detecting specific binding of an antibody as defined in any one of aspects 42 to 44 to free IL-18 protein in a sample or in situ, a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any one of aspects 42 to 44, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any one of the preceding embodiments with the amount in a sample from a healthy patient. wherein a higher amount of free IL-18 in the sample compared to a normal control value obtained from a healthy patient indicates that said patient is suffering from or is at risk of developing a disease or disorder as defined in any one of the preceding aspects. 51. A method for monitoring minimal residual disease in a patient following treatment with a composition as defined in any one of aspects 1 to 41 and 45 to 47, comprising: a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any one of aspects 42 to 44, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a subject suffering from a disease or disorder as defined in any one of the preceding embodiments with the amount in a sample from a healthy patient. wherein an increased amount of free IL-18 in the sample compared to a normal control value obtained from a healthy patient indicates that the patient is still suffering from minimal residual disease. 52. A method for predicting a patient's responsiveness to treatment with a composition as defined in any one of embodiments 1 to 41 and 45 to 47, comprising: a) contacting a sample or a specific body part or body site suspected of containing free IL-18 with an antibody as defined in any one of aspects 42 to 44, which specifically binds to free IL-18 but does not bind to IL-18 bound in a complex, and which acts as a capture molecule for free IL-18; b) binding the antibody to free IL-18; c) detecting binding of IL-18 to the antibody to determine the amount of free IL-18 in the sample; d) comparing the amount of free IL-18 in a sample from a patient suffering from a disease or disorder as defined in any one of the preceding embodiments with the amount in a sample from a healthy patient. wherein a low amount of free IL-18 in the sample indicates that the patient is likely to respond to treatment. 53. The method according to any one of aspects 48 to 52, comprising in step a) the further step of using an IL-18BP-specific binding molecule that binds to a site on IL-18BP that is different from the capture molecule, in particular one of these molecules binds to the IL-18 binding site on IL-18BP. 54. The method according to any one of embodiments 48 to 53, comprising the further step of determining the presence of free IL-18BP in the sample in step a) by using an IL-18BP-specific capture molecule and an IL-18BP-specific detection molecule that binds to a site on IL-18BP that is different from the capture molecule, in particular one of these IL-18BP-specific molecules that binds to the IL-18-binding site on IL-18BP, and by determining in step c) the amount of free and total IL-18 and free IL-18BP and total IL-18BP that is bound to the capture molecules in the sample; and in step d) by comparing the amount of free and / or total IL-18 and free and / or total IL-18BP in a sample from a patient suffering from a disease or disorder as defined in any one of the preceding embodiments with the amounts in a sample from a healthy patient. 55. The capture molecule is a.IL-18BP, b. An IL-18-specific antibody as defined in any one of aspects 42 to 44. 55. The method of any one of aspects 48 to 54, wherein 56. The method according to any one of aspects 48 to 55, wherein the sample is selected from the group consisting of bronchoalveolar lavage fluid (BALF) circulating fluid, secretions, biopsies, and homogenized tissue, in particular serum, urine, tears, saliva, bile, sweat, exhaled or expired air, sputum, bronchoalveolar fluid, sebum, cellular, glandular, mucosal or tissue secretions. 57. A method according to any one of aspects 48 to 56, wherein the amount of free IL-18 in isolated serum of a subject, particularly a human, suffering from said disease is equal to or greater than 5 pg / mL, and in particular up to 10,000 pg / mL, while the amount of free IL-18 in serum of a healthy subject, particularly a healthy human, is equal to or less than 4 pg / mL. 58. A diagnostic kit for detecting free IL-18, comprising an antibody as defined in any one of aspects 42 to 44 as a capture molecule, a second IL-18-specific binding molecule as a detection molecule, and optionally a second IL-18-specific capture molecule, wherein the detection molecule binds to a site on IL-18 that is different from the capture molecule. 59. A method for treating an IL-18-associated disease or disorder in a subject, comprising: a. quantifying the amount of free IL-18 in the subject's body fluid using a method described in embodiment 48; b. administering a therapeutically or prophylactically effective amount of a composition as defined in any one of embodiments 1-37 and 41 to a subject having an abnormal level of free IL-18 in a body fluid, determined to be 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% greater than the level of free IL-18 in the body fluid of a healthy control subject, in particular by systemic, intranasal, buccal, oral, transmucosal, intratracheal, intravenous, subcutaneous, intraurinary, intravaginal, sublingual, intrabronchial, intrapulmonary, transdermal or intramuscular administration, in particular bronchopulmonary administration. A method comprising: 60. Binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; a) CDR1, CDR2 and CDR3 of a heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:309, SEQ ID NO:310 and SEQ ID NO:311, and CDR1, CDR2 and CDR3 of a light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:312, SEQ ID NO:313 and SEQ ID NO:314; b) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:315, SEQ ID NO:316 and SEQ ID NO:317, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:318, SEQ ID NO:319 and SEQ ID NO:320; c) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:321, SEQ ID NO:322 and SEQ ID NO:323, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:324, SEQ ID NO:325 and SEQ ID NO:326; d) CDR1, CDR2 and CDR3 of a heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, and CDR1, CDR2 and CDR3 of a light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 330, SEQ ID NO: 331 and SEQ ID NO: 332; e) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 327, SEQ ID NO: 328 and SEQ ID NO: 329, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 333, SEQ ID NO: 334 and SEQ ID NO: 335; f) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:336, SEQ ID NO:337 and SEQ ID NO:338, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:345, SEQ ID NO:346 and SEQ ID NO:347; g) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 339, SEQ ID NO: 340 and SEQ ID NO: 341, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 345, SEQ ID NO: 346 and SEQ ID NO: 347; h) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 342, SEQ ID NO: 343 and SEQ ID NO: 344, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 345, SEQ ID NO: 346 and SEQ ID NO: 347; i) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:348, SEQ ID NO:349 and SEQ ID NO:350, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:357, SEQ ID NO:358 and SEQ ID NO:359; j) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:351, SEQ ID NO:352 and SEQ ID NO:353, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:357, SEQ ID NO:358 and SEQ ID NO:359; k) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region comprised within or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 354, SEQ ID NO: 355 and SEQ ID NO: 356, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region comprised within or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 357, SEQ ID NO: 358 and SEQ ID NO: 359; l) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 360, SEQ ID NO: 361 and SEQ ID NO: 362, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 363, SEQ ID NO: 364 and SEQ ID NO: 365; m) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 360, SEQ ID NO: 361 and SEQ ID NO: 362, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 366, SEQ ID NO: 367 and SEQ ID NO: 368; n) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 369, SEQ ID NO: 370 and SEQ ID NO: 371, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 372, SEQ ID NO: 373 and SEQ ID NO: 374; o) CDR1, CDR2 and CDR3 of a heavy chain variable (VH) region comprised in or consisting essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:375, SEQ ID NO:376 and SEQ ID NO:377, and CDR1, CDR2 and CDR3 of a light chain variable (VH) region comprised in or consisting essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO:378, SEQ ID NO:379 and SEQ ID NO:380; or p) CDR1, CDR2 and CDR3 of the heavy chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding heavy chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 381, SEQ ID NO: 382 and SEQ ID NO: 383, and CDR1, CDR2 and CDR3 of the light chain variable (VH) region, which CDRs are comprised in or consist essentially of the corresponding light chain CDR1, CDR2 and CDR3 regions set forth in SEQ ID NO: 384, SEQ ID NO: 385 and SEQ ID NO: 386. 45. The antibody of embodiment 42 or embodiment 44, including any functionally equivalent antibody or functional part thereof, comprising: 61. An antibody comprising any functionally equivalent antibody or portion thereof, wherein the antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and wherein the antibody comprises CDR1, CDR2 and CDR3 of a heavy chain variable region having the sequence determined according to Chothia as set out in Table 8, and CDR1, CDR2 and CDR3 of a corresponding light chain variable region having the sequence determined according to Chothia as set out in Table 8. 62. binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO: 153, SEQ ID NO: 154 and SEQ ID NO: 155, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO: 156, SEQ ID NO: 157 and SEQ ID NO: 158; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:159, SEQ ID NO:160 and SEQ ID NO:161, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:162, SEQ ID NO:163 and SEQ ID NO:164; c) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 165, SEQ ID NO: 166 and SEQ ID NO: 167, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 168, SEQ ID NO: 169 and SEQ ID NO: 170; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:171, SEQ ID NO:172 and SEQ ID NO:173, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:174, SEQ ID NO:175 and SEQ ID NO:176; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:171, SEQ ID NO:172 and SEQ ID NO:173, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:177, SEQ ID NO:178 and SEQ ID NO:179; f) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:180, SEQ ID NO:181 and SEQ ID NO:182, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:189, SEQ ID NO:190 and SEQ ID NO:191; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:183, SEQ ID NO:184 and SEQ ID NO:185, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:189, SEQ ID NO:190 and SEQ ID NO:191; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:186, SEQ ID NO:187 and SEQ ID NO:188, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:189, SEQ ID NO:190 and SEQ ID NO:191; i) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:192, SEQ ID NO:193 and SEQ ID NO:194, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:201, SEQ ID NO:202 and SEQ ID NO:203; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:195, SEQ ID NO:196 and SEQ ID NO:197, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:201, SEQ ID NO:202 and SEQ ID NO:203; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:198, SEQ ID NO:199 and SEQ ID NO:200, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:201, SEQ ID NO:202 and SEQ ID NO:203; l) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:204, SEQ ID NO:205 and SEQ ID NO:206, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:207, SEQ ID NO:208 and SEQ ID NO:209; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:204, SEQ ID NO:205 and SEQ ID NO:206, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:210, SEQ ID NO:211 and SEQ ID NO:212; n) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 213, SEQ ID NO: 214 and SEQ ID NO: 215, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 216, SEQ ID NO: 217 and SEQ ID NO: 218; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:219, SEQ ID NO:220 and SEQ ID NO:221, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:222, SEQ ID NO:223 and SEQ ID NO:224; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 225, SEQ ID NO: 226 and SEQ ID NO: 227, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 228, SEQ ID NO: 229 and SEQ ID NO: 230 62. The antibody of embodiment 61, including any functionally equivalent antibody or functional part thereof, comprising: 63. An antibody comprising any functionally equivalent antibody or portion thereof, wherein the antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and wherein the antibody comprises CDR1, CDR2 and CDR3 of a heavy chain variable region having the sequence determined according to Kabat as set out in Table 8, and CDR1, CDR2 and CDR3 of a corresponding light chain variable region having the sequence determined according to Kabat as set out in Table 8. 64. Binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:231, SEQ ID NO:232 and SEQ ID NO:233, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:234, SEQ ID NO:235 and SEQ ID NO:236; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:237, SEQ ID NO:238 and SEQ ID NO:239, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:240, SEQ ID NO:241 and SEQ ID NO:242; c) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:243, SEQ ID NO:244 and SEQ ID NO:245, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:246, SEQ ID NO:247 and SEQ ID NO:248; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:249, SEQ ID NO:250 and SEQ ID NO:251, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:252, SEQ ID NO:253 and SEQ ID NO:254; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:249, SEQ ID NO:250 and SEQ ID NO:251, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:255, SEQ ID NO:256 and SEQ ID NO:257; f) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:258, SEQ ID NO:259 and SEQ ID NO:260, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:267, SEQ ID NO:268 and SEQ ID NO:269; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:261, SEQ ID NO:262 and SEQ ID NO:263, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:267, SEQ ID NO:268 and SEQ ID NO:269; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:264, SEQ ID NO:265 and SEQ ID NO:266, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:267, SEQ ID NO:268 and SEQ ID NO:269; i) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:270, SEQ ID NO:271 and SEQ ID NO:272, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:279, SEQ ID NO:280 and SEQ ID NO:281; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:273, SEQ ID NO:274 and SEQ ID NO:275, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:279, SEQ ID NO:280 and SEQ ID NO:281; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:276, SEQ ID NO:277 and SEQ ID NO:278, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:279, SEQ ID NO:280 and SEQ ID NO:281; l) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:282, SEQ ID NO:283 and SEQ ID NO:284, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:285, SEQ ID NO:286 and SEQ ID NO:287; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 282, SEQ ID NO: 283 and SEQ ID NO: 284, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 288, SEQ ID NO: 289 and SEQ ID NO: 290; n) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 291, SEQ ID NO: 292 and SEQ ID NO: 293, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 294, SEQ ID NO: 295 and SEQ ID NO: 296; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:297, SEQ ID NO:298 and SEQ ID NO:299, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:300, SEQ ID NO:301 and SEQ ID NO:302; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 303, SEQ ID NO: 304 and SEQ ID NO: 305, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 306, SEQ ID NO: 307 and SEQ ID NO: 308 64. The antibody of embodiment 63, including any functionally equivalent antibody or functional part thereof, comprising: 65. An antibody comprising any functionally equivalent antibody or portion thereof, wherein the antibody or functional portion thereof binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex, and wherein the antibody comprises CDR1, CDR2 and CDR3 of a heavy chain variable region having the sequence determined according to IMGT as set out in Table 8, and CDR1, CDR2 and CDR3 of a corresponding light chain variable region having the sequence determined according to IMGT as set out in Table 8. 66. Binds to free IL-18 at or near the binding site of IL-18BP but does not bind to the IL-18 / IL-18BP complex; a) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:27, SEQ ID NO:28 and SEQ ID NO:29, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:30, SEQ ID NO:31 and SEQ ID NO:32; b) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:33, SEQ ID NO:34 and SEQ ID NO:35, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:36, SEQ ID NO:37 and SEQ ID NO:38; c) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:39, SEQ ID NO:40 and SEQ ID NO:41, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:42, SEQ ID NO:43 and SEQ ID NO:44; d) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:45, SEQ ID NO:46 and SEQ ID NO:47, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:48, SEQ ID NO:49 and SEQ ID NO:50; e) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:45, SEQ ID NO:46 and SEQ ID NO:47, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:51, SEQ ID NO:52 and SEQ ID NO:53; f) CDR1, CDR2 and CDR3 of the heavy chain variable region as set forth in SEQ ID NO:54, SEQ ID NO:55 and SEQ ID NO:56, and CDR1, CDR2 and CDR3 of the light chain variable region as set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; g) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:104, SEQ ID NO:105 and SEQ ID NO:106, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; h) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:110, SEQ ID NO:111 and SEQ ID NO:112, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59; i) CDR1, CDR2 and CDR3 of the heavy chain variable region as shown in SEQ ID NO:60, SEQ ID NO:61 and SEQ ID NO:62, and CDR1, CDR2 and CDR3 of the light chain variable region as shown in SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68; j) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:63, SEQ ID NO:64 and SEQ ID NO:65, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:66, SEQ ID NO:67 and SEQ ID NO:68; k) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 122, SEQ ID NO: 123 and SEQ ID NO: 124, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 66, SEQ ID NO: 67 and SEQ ID NO: 68; I) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 130, SEQ ID NO: 131 and SEQ ID NO: 132, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 136, SEQ ID NO: 137 and SEQ ID NO: 138; m) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO: 130, SEQ ID NO: 131 and SEQ ID NO: 132, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO: 142, SEQ ID NO: 143 and SEQ ID NO: 144; n) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO:69, SEQ ID NO:70 and SEQ ID NO:71, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO:72, SEQ ID NO:73 and SEQ ID NO:74; o) CDR1, CDR2 and CDR3 of the heavy chain variable region set forth in SEQ ID NO:75, SEQ ID NO:76 and SEQ ID NO:77, and CDR1, CDR2 and CDR3 of the light chain variable region set forth in SEQ ID NO:78, SEQ ID NO:79 and SEQ ID NO:80; or p) CDR1, CDR2 and CDR3 of the heavy chain variable region shown in SEQ ID NO: 54, SEQ ID NO: 55 and SEQ ID NO: 56, and CDR1, CDR2 and CDR3 of the light chain variable region shown in SEQ ID NO: 57, SEQ ID NO: 58 and SEQ ID NO: 59 66. The antibody of embodiment 65, including any functionally equivalent antibody or functional part thereof, comprising: 67. The antibody of any one of aspects 60 to 66, which is not antibody 107C6, 108F8, 109A6, 111A6, 131B4, 131E8, 131H1, 132H4, 133A6, as identified in the Sequence Listing based on their VH and VK sequences. 68. An antibody comprising the VH amino acid sequence of SEQ ID NO:387. 69. The antibody of any one of aspects 60 to 67, which is a fully human antibody or a humanized antibody. 70. A composition comprising the antibody according to any one of aspects 60 to 67. 71. The composition according to aspect 69, which is a pharmaceutical composition comprising a pharmaceutically acceptable carrier. 72. A composition according to embodiment 69 or 70, comprising an antibody according to any one of embodiments 60 to 66, for use in treating an IL-18 associated disease or disorder in a subject suffering from a disease as defined in any one of embodiments 1 to 41. 73. The antibody according to any one of aspects 60 to 67 for use in a method according to any one of aspects 48 to 57. 74. The antibody according to embodiment 73, which is used as a capture molecule and / or a detection molecule. 75. An IL-18 inhibitor or a composition comprising said IL-18 inhibitor for use in the treatment of a pediatric autoinflammatory disease or condition and / or symptoms associated with said disease or condition. 76. An IL-18 inhibitor or composition for use according to aspect 75, wherein the IL-18 inhibitor is an IL-18BP or an active fragment or variant thereof, and the composition comprises said IL-18BP or an active fragment or variant thereof. 77. An IL-18 inhibitor or composition for use according to embodiment 75 or embodiment 76, wherein the pediatric autoinflammatory disease or condition is an MAS-like pediatric disease or condition. 78. An IL-18 inhibitor or composition for use according to aspect 77, wherein the MAS-like pediatric disease or condition is an IL-18-associated pediatric autoinflammatory disease or condition accompanied by severe systemic inflammation. 79. The IL-18 inhibitor or composition for use according to aspect 78, wherein said autoinflammatory disease or condition accompanied by severe systemic inflammation is caused by an NLRC4 mutation. 80. The IL-18 inhibitor or composition for use according to aspect 78, wherein said autoinflammatory disease or condition associated with severe systemic inflammation is associated with XIAP deficiency. 81. The IL-18 inhibitor or composition for use according to aspect 80, wherein said XIAP deficiency is caused by a mutation in XIAP / BIRC4. 82. An IL-18 inhibitor or composition for use according to embodiment 80 or embodiment 81 for the treatment of X-linked lymphoproliferative syndrome 2 (XLP2), which is caused by mutations in XIAP / BIRC4. 83. An IL-18 inhibitor or composition for use according to embodiment 82 for the treatment of severe early-onset hemophagocytic lymphohistiocytosis / MAS (HLH / MAS) with monogenic XIAP deficiency caused by mutations in XIAP / BIRC4. 84. An IL-18 inhibitor or composition for use according to embodiment 80 for the treatment of enteritis, in particular Crohn's-like enteritis, caused by or associated with XIAP deficiency. 85. An IL-18 inhibitor or composition for use according to embodiment 80 for reducing the susceptibility of a patient suffering from XIAP deficiency to viral infection, in particular EBV and / or CMV infection, before the viral infection occurs or after viral clearance through treatment with an antiviral drug. 86. The IL-18 inhibitor or composition for use according to any one of aspects 75 to 85, wherein said autoinflammatory disease or condition involving severe systemic inflammation is accompanied by high levels of IL-18 and free IL-18. 87. The IL-18 inhibitor or composition for use according to any one of aspects 75 to 82, wherein the subject to be treated has been exposed to one or more compounds selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), prednisone; synthetic disease-modifying antirheumatic drugs (sDMARDs), immunosuppressants and biological immunosuppressants, but has not responded to the treatment or has only responded incompletely to the treatment. 88. The IL-18 inhibitor or composition for use according to any one of the preceding embodiments, wherein said composition is substantially free of N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP. 89. An IL-18 inhibitor or a composition for use according to any one of the preceding embodiments, for treatment in a mammal, in particular a human. 90. The IL-18 inhibitor or composition for use according to any one of the preceding aspects, wherein said IL-18 inhibitor or composition is administered to a subject in need thereof in multiple doses per day, multiple doses per week, or multiple doses per month. 91. The IL-18 inhibitor or composition for use according to any one of the preceding embodiments, wherein said IL-18 inhibitor or composition is administered in one dose per week, two doses per week, three doses per week, or four doses per week. 92. The IL-18 inhibitor or composition for use according to any one of the previous embodiments, wherein said IL-18 inhibitor or composition is administered every 24 hours to every 48 hours. 93. The IL-18 inhibitor, particularly an IL-18BP, for use according to any one of the preceding embodiments, or the composition, wherein a single dose comprises between 0.5 mg IL-18 inhibitor / kg body weight and 10 mg IL-18 inhibitor / kg body weight, particularly between 1 mg IL-18 inhibitor / kg body weight and 8 mg IL-18 inhibitor / kg body weight, particularly between 2 mg IL-18 inhibitor / kg body weight and 6 mg IL-18 inhibitor / kg body weight, particularly between 1 mg IL-18 inhibitor / kg body weight and 5 mg IL-18 inhibitor / kg body weight. 94. The IL-18 inhibitor, particularly IL-18BP, or composition for use according to any one of the preceding embodiments, wherein a single dose of 0.5 mg IL-18 inhibitor / kg body weight to 5 mg IL-18 inhibitor / kg body weight is administered every 24 hours or every 48 hours. 10. The IL-18 inhibitor, particularly IL-18BP, or composition for use according to any one of the preceding embodiments, wherein a single dose of 95.1 mg IL-18 inhibitor / kg body weight is administered every 48 hours. 96. The IL-18 inhibitor or composition for use according to any one of the previous aspects, wherein said IL-18 inhibitor is IL-18BP, particularly human IL-18BP, in particular recombinant human interleukin-18 binding protein (rhIL-18BP). 97. The IL-18 inhibitor or composition for use according to any one of the preceding embodiments, wherein said human IL-18BP is selected from isoforms a, b, c and d of human IL-18BP, particularly isoform a, particularly isoform c, particularly isoforms a, b, c or d as depicted in Figure 12, especially isoform a of IL-18BP as depicted as SEQ ID NO:7 in Figure 12, or isoform c as depicted as SEQ ID NO:389 in Figure 12. 98. The IL-18 inhibitor, particularly IL-18BP, or composition for use according to any one of the previous embodiments, wherein human IL-18BP isoform a or a composition comprising human IL-18BP isoform a is administered every 48 hours in a single dose of 1 mg IL-18BP / kg body weight. 99. A method for the treatment of a pediatric autoinflammatory disease or condition, particularly a MAS-like pediatric disease or condition, and / or symptoms associated with said disease or condition, comprising the step of administering to a subject suffering from such a disease or condition an IL-18 inhibitor or a composition comprising an IL-18 inhibitor. 100. The method of embodiment 99, wherein said IL-18 inhibitor is IL-18BP or an active fragment or variant thereof, and wherein the composition comprises said IL-18BP or an active fragment or variant thereof. 101. A method according to embodiment 98 or embodiment 100, wherein the pediatric autoinflammatory disease or condition is one of the diseases or conditions listed in any one of embodiments 77 to 86. 102. A method according to any one of embodiments 99 to 101, wherein the IL-18 inhibitor, in particular IL-18BP or an active fragment or variant thereof, and a composition comprising an IL-18 inhibitor, in particular IL-18BP or an active fragment or variant thereof, is administered at a frequency and / or in a dosage as indicated in any one of embodiments 90 to 94. 103. A method according to any one of aspects 99-101, wherein the subject to be treated is a mammal or a human. 104. The method according to any one of embodiments 99 to 101, wherein the IL-18 inhibitor listed in any one of the preceding embodiments is IL-18BP, particularly human IL-18BP, and in particular selected from isoforms a, b, c and d of human IL-18BP, particularly isoform a, particularly isoform c, particularly isoforms a, b, c or d as depicted in Figure 12, especially isoform a of IL-18BP as depicted in Figure 12 as SEQ ID NO:7, or isoform c as depicted in Figure 12 as SEQ ID NO:389. 105. A method according to any one of aspects 99-101, wherein human IL-18BP isoform a or a composition comprising human IL-18BP isoform a is administered in a single dose of 1 mg IL-18BP / kg body weight every 48 hours. 106. The method of any one of aspects 99 to 101, wherein the subject to be treated has been exposed to one or more compounds selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), prednisone; synthetic disease-modifying antirheumatic drugs (sDMARDs), immunosuppressants, and biological immunosuppressants, but has not responded to the treatment or has only responded incompletely to the treatment. [Brief explanation of the drawings]

[0353] [Figure 1] Comparison of total and free IL-18 in individual sepsis patients. Adapted from Novick et al. (2001). The level of free IL-18 (●) in the serum of sepsis patients at admission was calculated based on the concentrations of total IL-18 (○) and IL-18BPa, taking into account that IL-18 and IL-18BPa form a 1:1 complex and a calculated KD of 400 pM. Each vertical line connects the total and free IL-18 in an individual serum sample. The above ELISA assay was performed using the antibody pair developed by Taniguchi et al. (1997). Antibody 125-2H was used as the primary / capture antibody, and antibody 159-12B was used as the secondary / developing antibody. [Figure 2] Detection of total IL-18 by antibodies 125-2H and 159-12B. The data demonstrate that both antibodies can quantify total IL-18. [Figure 3] Titration of 400 pg / ml IL-18 as a function of IL-18BP levels. [Figure 4] Induction of murine IL-18 in the lung airway lumen on day 5 after 1) air exposure, 2) cigarette smoke (TS), 3) p[I:C] alone, and 4) p[I:C] combined with cigarette smoke on day 4 (induction of exacerbation). The dotted line indicates the lower limit of detection. All statistical analyses were performed using unpaired t-tests. [Figure 5]Inhibition of total cell infiltration in the lung airway lumen of mice on day 5 after 1) air exposure, 2) cigarette smoke (TS), 3) p[I:C] alone, 4) p[I:C] combined with cigarette smoke on day 4 (induction of exacerbation), 5-7) p[I:C] combined with cigarette smoke on day 4 in the presence of IL-18BP at either 1, 3, or 10 mg / kg, and 8) dexamethasone at 10 mg / kg. All statistical analyses were performed using unpaired t-tests. [Figure 6] Inhibition of total cell infiltration in the airway lumen of mice on day 5 after 1) air exposure, 2) cigarette smoke (TS), 3) p[I:C] alone, 4) p[I:C] combined with cigarette smoke on day 4 (induction of exacerbation), 5) p[I:C] combined with cigarette smoke on day 4 in the presence of IL-18BP at 10 mg / kg, and 6) dexamethasone at 10 mg / kg. Statistical analysis was performed using ANOVA with Sidak's post-hoc test. [Figure 7] Inhibition of neutrophil infiltration by IL-18BP. Neutrophil infiltration in the airway lumen of mice was monitored on day 5 after 1) air exposure, 2) cigarette smoke (TS), 3) p[I:C] alone, 4) p[I:C] combined with cigarette smoke on day 4 (induction of exacerbation), 5-7) p[I:C] combined with cigarette smoke on day 4 in the presence of IL-18BP at either 1, 3, or 10 mg / kg, and 8) dexamethasone at 10 mg / kg. Statistical analysis was performed using ANOVA with Sidak's post-hoc test. [Figure 8] Inhibition of neutrophil infiltration by IL-18BP. Neutrophil infiltration in the airway lumen of mice was monitored on day 5 after 1) air exposure, 2) cigarette smoke (TS), 3) p[I:C] alone, 4) p[I:C] combined with cigarette smoke on day 4 (induction of exacerbation), 5) p[I:C] combined with IL-18BP at 10 mg / kg and cigarette smoke on day 4, and 6) dexamethasone at 10 mg / kg. Statistical analysis was performed using ANOVA with Sidak's post-hoc test. [Figure 9]Inhibition of the G-CSF pathway by IL-18BP. The presence of G-CSF (pg / ml) in the lung airway lumen of mice was monitored by ELISA on day 5 after 1) air exposure, 2) cigarette smoke (TS), 3) p[I:C] a...

Claims

1. 1. A pharmaceutical composition for use in treating an IL-18-associated disease or disorder in a subject, comprising IL-18BP, the subject suffers from such a disease or disorder, and the subject belongs to a group of patients with abnormal levels of free IL-18, in particular 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the levels of free IL-18 in the body fluids of healthy control subjects, the pharmaceutical composition comprises N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP, which mutants are present in an amount of less than 40%, and the deletion mutants comprise deletion of 1 to 5 amino acid residues at the C-terminus of IL-18BP and / or deletion of 1 to 30 amino acid residues at the N-terminus of IL-18BP, and the IL-18BP is selected from isoform a of human IL-18BP shown in Figure 12 as SEQ ID NO: 7 or isoform c shown in Figure 12 as SEQ ID NO: 389, and The disease or disorder associated with IL-18 is chronic obstructive pulmonary disease (COPD), transfusion-associated lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), pediatric autoinflammatory diseases or conditions, Still's disease, particularly adult Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic juvenile-onset idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS), including primary, secondary, and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH); perforin, munc 13-4 and 18-2, or synthaxin Familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with 11 genetic defects; acquired hemophagocytic lymphohistiocytosis associated with immunodeficiency, e.g., Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP); acquired hemophagocytic lymphohistiocytosis associated with infectious conditions, especially herpes viruses such as EBV and other pathogens; autoinflammatory syndromes associated with NLRC4 mutations; giant cell arteritis (GCA); septic arthritis, pyoderma gangrenosum, and acne (PAPA); pulmonary sarcoidosis (pulmonary sarcoidosis); sarcoidis), heart failure, ischemic heart disease, dry eye disease (DED), keratitis, corneal ulcers and abrasions, iritis, glaucoma, Sjogren's syndrome, autoimmune uveitis, Behcet's disease, conjunctivitis, allergic conjunctivitis, type 2 diabetes, parenchymal organ and blood stem cell transplantation, ischemia-reperfusion injury, familial Mediterranean fever (FMF), tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS), hyper-IgD syndrome (mevalonate kinase gene mutation), gout, Schnitzler syndrome, Wegener's granulomatosis also known as granulomatosis with polyangiitis (GPA), Hashimoto's thyroiditis, Crohn's disease, early-onset inflammatory bowel disease (EOIBD), extreme EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis, and Blau syndrome (NOD-2 mutation), The pharmaceutical composition.

2. A pharmaceutical composition for use as described in claim 1, wherein the level of free IL-18 in the body fluids of the patient group has been determined to be 5 pg / mL or more, in particular up to 10,000 pg / mL, compared to 4 pg / mL or less in healthy controls.

3. 3. The pharmaceutical composition for use according to claim 1 or 2 for reducing susceptibility to viral infections.

4. 4. A pharmaceutical composition according to any one of claims 1 to 3 for use in the treatment of a pediatric autoinflammatory disease or condition and / or symptoms associated with said disease or condition.

5. 5. The pharmaceutical composition for use according to claim 4, wherein the pediatric autoinflammatory disease or condition is a pediatric MAS-like disease or condition, including primary, secondary and recurrent MAS, particularly the MAS-like pediatric disease or condition is a pediatric IL-18-associated autoinflammatory disease or condition accompanied by severe systemic inflammation, particularly the autoinflammatory disease or condition accompanied by severe systemic inflammation is caused by an NLRC4 mutation, particularly the autoinflammatory disease or condition accompanied by severe systemic inflammation is accompanied by XIAP deficiency, particularly the XIAP deficiency is caused by a mutation in XIAP / BIRC4.

6. 6. The pharmaceutical composition for use according to claim 5, for the treatment of X-linked inhibitor of apoptosis protein deficiency (XIAP) and / or X-linked lymphoproliferative syndrome 2 (XLP2), in particular when caused by mutations in XIAP / BIRC4.

7. 7. The pharmaceutical composition for use according to claim 6, for the treatment of severe early-onset hemophagocytic lymphohistiocytosis / MAS (HLH / MAS) with monogenic XIAP deficiency caused by mutations in XIAP / BIRC4.

8. 8. The pharmaceutical composition for use according to claim 7 for the treatment of enteritis, in particular Crohn's-like enteritis, caused by or associated with XIAP deficiency.

9. 9. The pharmaceutical composition for use according to claim 8, for reducing the susceptibility of a patient suffering from XIAP deficiency to viral infection, particularly EBV and / or CMV infection, before the viral infection occurs or after viral clearance through treatment with an antiviral drug.

10. 10. The pharmaceutical composition for use according to any one of claims 4 to 9, wherein the autoinflammatory disease or condition involving severe systemic inflammation is accompanied by high levels of IL-18 and free IL-18.

11. 4. The pharmaceutical composition according to any one of claims 1 to 3 for the treatment of early onset severe septic arthritis, pyoderma gangrenosum and acne (PAPA).

12. 4. The pharmaceutical composition according to any one of claims 1 to 3 for the treatment of early onset inflammatory bowel disease (EOIBD), very EOIBD (VEOIBD), infantile IBD and neonatal IBD.

13. 13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein the subject to be treated has been exposed to one or more compounds selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDS), prednisone, synthetic disease-modifying anti-rheumatic drugs (sDMARDs), immunosuppressants and biological immunosuppressants, but has not responded to the treatment, in particular to non-steroidal anti-inflammatory drugs (NSAIDs) and prednisone at a dose of at least 5 mg / day for more than one month, and / or to synthetic disease-modifying anti-rheumatic drugs (sDMARDs) at a dose of at least 10 mg / day for more than three months, or has only responded incompletely to the treatment.

14. 14. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein the composition is administered in multiple doses per day, multiple doses per week, or multiple doses per month to a subject in need thereof.

15. 15. The pharmaceutical composition for use according to any one of claims 1 to 14, administered in one dose per week, two doses per week, three doses per week, or four doses per week.

16. 16. The pharmaceutical composition for use according to any one of claims 1 to 15, which is administered every 24 to 48 hours.

17. 17. The pharmaceutical composition for use according to any one of claims 1 to 16, wherein a single dose comprises between 0.5 mg and 600 mg of IL-18BP, in particular between 10 mg and 600 mg of IL-18BP, in particular between 10 and 20 mg, in particular between 20 and 40 mg, in particular between 40 and 80 mg, in particular between 80 and 160 mg, in particular between 160 mg and 320 mg, or in particular between 320 mg and 600 mg of IL-18BP.

18. 18. The pharmaceutical composition for use according to claim 17, wherein a single dose comprises between 0.5 mg IL-18BP / kg body weight and 10 mg IL-18BP / kg body weight, in particular between 1 mg IL-18BP / kg body weight and 8 mg IL-18BP / kg body weight, in particular between 2 mg IL-18BP / kg body weight and 6 mg IL-18BP / kg body weight, in particular between 1 mg IL-18BP / kg body weight and 5 mg IL-18BP / kg body weight.

19. 19. The pharmaceutical composition for use according to any one of claims 1 to 18, wherein a single dose of 0.5 mg IL-18BP / kg body weight to 5 mg IL-18BP / kg body weight is administered every 24 hours or every 48 hours, in particular a single dose of 1 mg IL-18BP / kg body weight is administered every 48 hours.

20. wherein the disease or disorder is adult Still's disease, and the treated subject exhibits at least a therapeutic response, particularly (a) normalization of body temperature (normal range is 36.3–37.4°C measured in the axilla in the absence of NSAIDs for the 24 hours prior to measurement); (b) improvement in joint swelling and tenderness (20% or more); and (c) ≥70% reduction in CRP or normalization of CRP and ferritin to baseline levels 20. The pharmaceutical composition for use according to any one of claims 1 to 3 and 13 to 19, wherein treatment is continued until the patient shows a therapeutic response characterized by:

21. 21. The pharmaceutical composition for use according to any one of claims 1 to 3 and 13 to 20, wherein the N-terminal deletion mutants and / or C-terminal deletion mutants of IL-18BP are present in an amount of less than 30%, particularly less than 20%, particularly less than 15%, particularly less than 10%, particularly less than 7.5%, particularly less than 5%, particularly less than 2.5%, particularly less than 1%, particularly less than 0.5%, particularly less than 0.25%, particularly less than 0.1%, particularly less than 0.05%, particularly less than 0.01%.

22. 22. The pharmaceutical composition for use according to any one of claims 1 to 3 and 13 to 21, wherein the disease or disorder associated with IL-18 is adult Still's disease.

Images