IL-18 binding protein (IL-18BP) in the treatment of VEXAS

Abstract

The present invention provides an IL-18 inhibitor for use in treating VEXAS syndrome or a condition associated with VEXAS syndrome in a subject.

Description

[Technical field]

[0001] The present invention provides an IL-18 inhibitor for use in treating VEXAS syndrome or a condition associated with VEXAS syndrome in a subject. [Background technology]

[0002] VEXAS syndrome (vacuole, E1 enzyme, X-linked, autoinflammatory, somatic) is a monogenic, adult-onset autoinflammatory disease predominantly seen in men, caused by mutations in the UBA1 gene in hematopoietic progenitor cells; see Grayson et al. (2021) Blood 137(26):3591-4. The syndrome was first reported by Beck et al., who wrote: "Using a genotype-driven approach, we identified a disorder that links multiple, seemingly unrelated, adult-onset inflammatory syndromes."; see Beck DB, Ferrada MA, Sikora KA, et al. (2020) N. Engl. J. Med. 383(27):2628-2638. An autoinflammatory response driven by myeloid cells and progressive bone marrow failure are central features of the disease.

[0003] This newly identified disorder was now surprisingly correlated with elevated levels of cytokines, particularly IL-18. The inventors therefore predicted that a therapeutic approach using IL-18BP could be adopted, optionally combined with the quantification of free IL-18 in the body fluids and / or tissues of the patient to be treated by using a quantitative assay as described in WO 2015 / 032932 (Patent Document 1) and WO 2016 / 139297 (Patent Document 2), respectively (the disclosures of which are incorporated herein by reference). Bourbon et al. (2021) Blood 137, No. 26 (Non-Patent Document 3) describes possible treatment options for VEXAS syndrome. Kirino et al. (2021) Annals of Rheumatic Diseases 80, no.11 (Non-Patent Document 4) describes the use of the IL-6 receptor antibody tocilizumab in VEXAS. Finally, Wiesik-Szewczyk (2021) Reumatologica 59, no. 6 (Non-Patent Document 5) describes IL-1 inhibitors and their uses. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO 2015 / 032932 [Patent Document 2] WO 2016 / 139297 [Non-patent literature]

[0005] [Non-Patent Document 1] Grayson et al. (2021) Blood 137(26):3591-4 [Non-Patent Document 2] Beck DB, Ferrada MA, Sikora KA, et al. (2020) N. Engl. J. Med. 383(27):2628-2638 [Non-Patent Document 3] Bourbon et al. (2021) Blood 137, No. 26 [Non-Patent Document 4] Kirino et al. (2021) Annals of Rheumatic Diseases 80, no.11 [Non-Patent Document 5] Wiesik-Szewczyk (2021) Reumatologica 59, no.6 Summary of the Invention

[0006] Thus, the present invention solves the problem of a lack of effective treatment options for VEXAS patients.

[0007] That is, the present invention relates to, inter alia, the following aspects: 1. An IL-18 inhibitor for use in treating VEXAS syndrome or a symptom associated with VEXAS syndrome in a subject. 2. An IL-18 inhibitor for use in embodiment 1, wherein the symptoms associated with VEXAS syndrome are characterized by signs of autoinflammation, particularly signs of severe autoinflammation, and / or hyperinflammation, particularly hyperinflammation characterized by known inflammatory markers, particularly hyperinflammation characterized by elevated levels of known inflammatory markers such as CRP. 3. An IL-18 inhibitor for use according to embodiment 1, wherein said subject has one or more mutations in the UBA1 gene on the X chromosome, in particular at locus p11.3. 4. An IL-18 inhibitor for use in embodiment 3, wherein said mutation results in an alternative isoform of the UBA-1 gene product, in particular a shorter isoform. 5. An IL-18 inhibitor for use in embodiment 4, wherein said mutation results in an M41T, M41V, or M41L substitution. 6. An IL-18 inhibitor for use according to any one of aspects 1 to 5, wherein said treatment is achieved and / or supported by blocking the pro-inflammatory activity of IL-18. 7. Any functional equivalent or functional portion of IL-18 binding protein (IL-18BP) that retains the ability to block the proinflammatory activity of IL-18. 7. The IL-18 inhibitor for use in any one of aspects 1 to 6, which is an IL-18 binding protein (IL-18BP) comprising: 8. Any functional equivalent or functional portion of human IL-18BP (hIL-18 BP) that retains the blocking of the proinflammatory activity of IL-18. 8. The IL-18 inhibitor for use in embodiment 7, which is the human IL-18BP (hIL-18 BP) comprising: 9. Any functional equivalent or functional portion of recombinant human IL-18BP (rhIL-18 BP) that retains the ability to block the proinflammatory activity of IL-18. 9. The IL-18 inhibitor for use in embodiment 8, which is the recombinant human IL-18BP (rhIL-18 BP) comprising: 10. An IL-18 inhibitor for use in embodiment 8 or embodiment 9, wherein said human IL-18BP is selected from: Any functional equivalent or functional portion of isoforms a, b, c, and / or d that retains the ability to block the proinflammatory activity of IL-18. isoforms a, b, c and d of human IL-18BP, in particular isoform a as shown in SEQ ID NO: 2, isoform b as shown in SEQ ID NO: 3, isoform c as shown in SEQ ID NO: 4, or isoform d as shown in SEQ ID NO: 5. 11. Any functional equivalent or functional portion of IL-18BP as set forth in SEQ ID NO: 2 that retains the ability to block the proinflammatory activity of IL-18. 10. The IL-18 inhibitor for use in embodiment 8 or embodiment 9, which is an IL-18BP as shown in SEQ ID NO: 2 comprising: 12. An IL-18 inhibitor for use in embodiment 11, wherein said functional equivalent has 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the sequence shown in SEQ ID NO: 2 and retains the ability to block the pro-inflammatory activity of IL-18. 13. The functional equivalent or functional part is Muteins, fragments, peptides, functional derivatives, functional fragments, fractions, circularly permuted derivatives, fusion proteins comprising IL-18BP, isoforms, or salts thereof, which retain the ability to block the proinflammatory activity of IL-18. 13. An IL-18 inhibitor for use in any one of aspects 7 to 12, comprising: 14. An IL-18 inhibitor for use according to any one of aspects 7 to 13, comprising in addition to said IL-18 binding protein (IL-18BP) an N-terminal and / or C-terminal deletion variant of IL-18BP in an amount of up to 40%, particularly up to 30%, particularly up to 20%, particularly up to 15%, particularly up to 10%, particularly up to 7.5%, particularly up to 5%, particularly up to 2.5%, particularly up to 1%, particularly up to 0.5%, particularly up to 0.25%, particularly up to 0.1%, particularly up to 0.05%, particularly up to 0.01%. 15. An IL-18 inhibitor for use according to embodiment 14, wherein said deletion variant comprises a deletion of 1 to 5 amino acid residues at the C-terminus of said IL-18BP and / or a deletion of 1 to 30 amino acid residues at the N-terminus of said IL-18BP. 16. An IL-18 inhibitor for use according to embodiment 14 or embodiment 15, wherein said N-terminal and / or C-terminal deletion variants of IL-18BP are present in an amount of up to 40%, in particular in an amount of between 2% and 35%. 17. The IL-18 inhibitor for use according to any one of aspects 1 to 16, wherein the body fluids and / or body tissues of said subject to be treated have been quantified as having an abnormal level of free IL-18 using an assay capable of detecting free IL-18 in body fluids and / or body tissues, said abnormal level of free IL-18 being 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 fluids and / or body tissues of a healthy control subject. 18. An IL-18 inhibitor for use in embodiment 17, wherein the subject to be treated has a level of free IL-18 greater than about 2.7 pg / ml, in particular greater than about 8 pg / ml, or the body fluids and / or body tissues of the subject to be treated have been quantified to have a level of free IL-18 greater than about 2.7 pg / ml, in particular greater than about 8 pg / ml. 19. The IL-18 inhibitor for use according to any one of aspects 1 to 18, wherein said subject has an abnormally elevated level of total IL-18. 20. An IL-18 inhibitor for use in embodiment 19, wherein IFN-γ-mediated IL-18BP induction is impaired. 21. An IL-18 inhibitor for use according to any one of aspects 17 to 20, wherein the level of total IL-18 is greater than about 250 pg / ml, in particular greater than about 1000 pg / ml, in particular greater than about 3000 pg / ml, or the body fluids and / or body tissues of said subject to be treated have been quantified as having a level of total IL-18 greater than about 250 pg / ml, in particular greater than about 1000 pg / ml, in particular greater than about 3000 pg / ml. 22. An IL-18 inhibitor for use according to any one of aspects 17 to 21, wherein the subject has a level of ferritin greater than 400 ng / ml, preferably greater than 1000 ng / ml, or the body fluids and / or body tissues of the subject to be treated have been quantified to have a level of ferritin greater than 400 ng / ml, preferably greater than 1000 ng / ml. 23. Quantifying the level of free IL-18 in said body fluids and / or body tissues comprises the steps of: (a) contacting a sample of a body fluid and / or a body tissue suspected of containing free IL-18 with an IL-18 inhibitory substance as defined in any one of embodiments 7 to 16 as a capture molecule for free IL-18; (b) binding the IL-18 inhibitor to free IL-18; (c) detecting binding of the IL-18 inhibitor and determining the amount of free IL-18 in the sample. 23. An IL-18 inhibitor for use in any one of aspects 17 to 22, comprising: 24. The IL-18 inhibitor for use according to any one of aspects 17 to 23, wherein said body fluids and / or body tissues are selected from the group consisting of bronchoalveolar lavage fluid (BALF) circulating fluid, secretions, biopsies, and homogenized tissues, in particular serum, urine, tears, saliva, bile, sweat, expired or exhaled air, sputum, bronchoalveolar fluid, sebum, cells, glands, mucosa, bone marrow, or tissue secretions. 25. A composition for use in the treatment of VEXAS syndrome or a symptom associated therewith, comprising an IL-18 inhibitor as defined in any one of aspects 7 to 16 and a pharma- ceutically acceptable carrier and / or excipient. 26. The IL-18 inhibitor for use of any one of embodiments 1 to 24 or composition for use of embodiment 25, wherein said IL-18 inhibitor or composition is administered to a subject in need thereof in a single dose per day, multiple doses per day, multiple doses per week, or multiple doses per month. 27. An IL-18 inhibitor for use according to any one of embodiments 1 to 24 or a composition for use according to embodiment 25 or embodiment 26, wherein said IL-18 inhibitor or composition is administered in 1 dose per week, 2 doses per week, 3 doses per week, 4 doses per week, 5 doses per week, 6 doses per week, in particular 7 doses per week, preferably 3 or 4 doses per week. 28. An IL-18 inhibitor for use according to any one of aspects 1 to 24 or a composition for use according to aspect 25 or aspect 26, wherein said IL-18 inhibitor or composition is administered every 24 hours to 48 hours, preferably every 48 hours. 29. The IL-18 inhibitor for use of any one of embodiments 1 to 24 or the composition for use of embodiment 25 or embodiment 26, wherein said IL-18 inhibitor or composition is administered in a single dose every other day, such as for three weeks. 30. An IL-18 inhibitor for use according to any one of embodiments 1 to 24 and 26 to 29 or a composition for use according to any one of embodiments 25 to 29, wherein a single dose comprises between 0.5 mg IL-18 inhibitor / kg body weight and 10 mg IL-18 inhibitor / kg body weight, in particular between 1 mg IL-18 inhibitor / kg body weight and 8 mg IL-18 inhibitor / kg body weight, in particular between 1.5 mg IL-18 inhibitor / kg body weight and 6 mg IL-18 inhibitor / kg body weight, in particular between 2 mg IL-18 inhibitor / kg body weight and 4 mg IL-18 inhibitor / kg body weight. 31. An IL-18 inhibitor for use according to any one of embodiments 1 to 24 and 26 to 30 or a composition for use according to any one of embodiments 24 to 30, 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 or 48 hours, in particular a single dose of 2 mg IL-18 inhibitor / kg body weight is administered every 48 hours. 32. An IL-18 inhibitor for use according to any one of embodiments 1 to 24 and 26 to 31 or a composition for use according to any one of embodiments 25 to 31, wherein said subject to be treated is a mammal. 33. The IL-18 inhibitor for use or composition for use of embodiment 32, wherein the subject to be treated is a human. 34. Recombinant human IL-18BP (rhIL-18 BP) or a composition comprising said recombinant human IL-18BP (rhIL-18 BP), including any functional equivalent or functional portion thereof that retains the ability to block the pro-inflammatory activity of IL-18, for use in the treatment of VEXAS syndrome or a condition associated therewith in a human, wherein said recombinant human IL-18BP (rhIL-18 BP) or a composition comprising said recombinant human IL-18BP (rhIL-18 BP), preferably wherein said human has detectable levels of free IL-18, in particular wherein said recombinant human IL-18BP (rhIL-18 BP) or a composition comprising said recombinant human IL-18BP (rhIL-18 BP), is administered to said human in a single dose of 2 mg / kg body weight every 48 hours. 36. A composition comprising said recombinant human IL-18BP or said recombinant human IL-18BP (rhIL-18BP), including any functional equivalent or functional portion thereof, for use according to embodiment 35, wherein human patients suffering from VEXAS syndrome or a condition associated therewith exhibit an uncontrolled systemic inflammatory response and have abnormally elevated levels of total IL-18. 37. A composition comprising said recombinant human IL-18BP or said recombinant human IL-18BP (rhIL-18BP), including any functional equivalent or functional part thereof, for use according to embodiment 36, wherein the level of free IL-18 in the body fluids or tissues of said human patient is greater than 2.7 pg / mL. 38. A composition comprising said recombinant human IL-18BP or said recombinant human IL-18BP (rhIL-18BP), including any functional equivalent or functional part thereof, for use according to embodiment 37, wherein the level of total IL-18 is greater than about 250 pg / ml, in particular greater than about 1000 pg / ml, in particular greater than about 3000 pg / ml, or the body fluids and / or body tissues of the subject to be treated have been quantified as having a level of total IL-18 greater than about 250 pg / ml, in particular greater than about 1000 pg / ml, in particular greater than about 3000 pg / ml. 39. Recombinant human IL-18BP (rhIL-18 BP) or a composition comprising said recombinant human IL-18BP (rhIL-18 BP), including any functional equivalent or functional portion thereof that retains the ability to block the pro-inflammatory activity of IL-18, for use in the treatment of VEXAS syndrome or a symptom associated therewith in a human, optionally a human with confirmed VEXAS syndrome and a human with a level of ferritin greater than 400 ng / mL, preferably greater than 1000 ng / ml. 40. A composition comprising said recombinant human IL-18BP or said recombinant human IL-18BP (rhIL-18BP), including any functional equivalent or functional part thereof, for use according to embodiment 39, wherein the level of total IL-18 is greater than about 250 pg / ml, in particular greater than about 1000 pg / ml, in particular greater than about 3000 pg / ml, or wherein the bodily fluids and / or bodily tissues of the subject to be treated have been quantified as having a level of total IL-18 greater than about 250 pg / ml, in particular greater than about 1000 pg / ml, in particular greater than about 3000 pg / ml. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Thus, in its broadest aspect, the present invention relates to an IL-18 inhibitor for use in treating VEXAS syndrome or symptoms associated with VEXAS syndrome in a subject. The treatment of VEXAS syndrome itself is a preferred embodiment of the present invention herein. However, it is also provided herein to treat, prevent and / or alleviate symptoms associated with VEXAS, particularly via the treatment of VEXAS itself.

[0009] Clinical signs of VEXAS syndrome may show various phenotypes, among which the most frequently observed signs / symptoms are fever, fatigue, weight loss, lymphadenopathy, arthralgia / arthritis, and skin nodular lesions. In addition, frequent findings on laboratory tests include anemia, neutropenia, thrombocytopenia, and / or elevated blood markers such as CRP and ferritin. Vacuolization of myeloid cells is a characteristic sign of VEXAS. Hemophagocytosis is frequently observed in the bone marrow, and the bone marrow may also show signs of myelofibrosis. Recurrent skin rash and symmetric polyarthritis are also known signs / symptoms. Inflammatory markers are usually elevated, at least during the active phase of the disease, i.e., when symptoms are observed (Staels, F., et al. (2021). Frontiers in Immunology 12). Thus, in some aspects, the present invention relates to an IL-18 inhibitor for use in alleviating symptoms associated with VEXAS syndrome, particularly one or more of fever, fatigue, weight loss, lymphadenopathy, joint pain / arthritis, skin nodular lesions, preferably in patients diagnosed with VEXAS syndrome.

[0010] Within the scope of the present invention, the treatment of VEXAS syndrome or symptoms associated with VEXAS syndrome is preferably achieved and / or supported by blocking the proinflammatory activity of IL-18.

[0011] Thus, the IL-18 inhibitor is preferably an IL-18 binding protein (IL-18BP), which is an IL-18BP including any functional equivalents or functional portions thereof that retain the ability to block the proinflammatory activity of IL-18.

[0012] In a particular embodiment, said IL-18 inhibitor is an IL-18 binding protein (IL-18BP), in particular human IL-18BP (hIL-18BP), in particular recombinant human IL-18BP (rhIL-18BP), including any functional equivalents or functional portions thereof that retain the ability to block the pro-inflammatory activity of IL-18.

[0013] In another particular embodiment, the IL-18BP is selected from isoforms a, b, c and d of IL-18BP, in particular isoform a, in particular isoform c, in particular SEQ ID NO: 2, and isoforms a, b, c or d as depicted in SEQ ID NO: 3, 4 and 5, but in particular isoform a of IL-18BP as depicted in SEQ ID NO: 2, or isoform c of IL-18BP as depicted in SEQ ID NO: 4, including any functional equivalents or functional parts thereof that retain the ability to block the pro-inflammatory activity of IL-18.

[0014] The present invention also contemplates the use of mixtures of different combinations of the above isoforms, in particular mixtures of isoform a and isoform c, including any functional equivalents or functional portions thereof that retain the ability to block the proinflammatory activity of IL-18.

[0015] Thus, compositions comprising an IL-18BP as defined above are also provided for the uses described herein.

[0016] Within the scope of the present invention, the term "functional" is meant to refer to equivalents or portions that still retain the IL-18 blocking activity of the IL-18 inhibitor in the subject's body and are therefore capable of blocking the pro-inflammatory activity of IL-18 and therefore interrupting the immunopathological cascade responsible for VEXAS-associated symptoms.

[0017] Also included within the scope of the present invention are functional muteins, functional fragments, functional peptides, functional derivatives, functional fractions, functional circularly permuted derivatives, functional fusion proteins comprising IL-18BP, functional isoforms or functional salts thereof, which retain the ability to block the pro-inflammatory activity of IL-18, and preferably retain the IL-18 blocking activity of IL-18BP in a subject, and thus are able to block the pro-inflammatory activity of free IL-18, and therefore interrupt the immunopathological cascade responsible for VEXAS-associated symptoms.

[0018] In one embodiment, the present invention relates to IL-18BP, which is a fusion protein comprising all or a part of IL-18BP fused to all or a part of an immunoglobulin, preferably to a constant region of an immunoglobulin; this fusion protein is still capable of binding to IL-18 and retains the ability to block the proinflammatory activity of free IL-18, preferably retains the IL-18 blocking activity of IL-18BP, and thus can block the proinflammatory activity of free IL-18, thus interrupting the immunopathological cascade responsible for VEXAS-associated symptoms. More specifically, the immunoglobulin can be of IgG1 or IgG2 isotype for use in the composition according to any one of the embodiments described herein.

[0019] In another aspect, the present invention relates to IL-18BP, which is a fusion protein comprising all or a portion of IL-18BP fused to all or a portion of a small molecule, in particular to all or a portion of a small molecule drug; this fusion protein retains the ability to block the pro-inflammatory activity of free IL-18, and preferably is still able to block the activity of IL-18, thus blocking the pro-inflammatory activity of IL-18 and therefore interrupting the immunopathological cascade responsible for VEXAS-associated symptoms.

[0020] In one embodiment, the present invention provides an IL-18 inhibitor for use as disclosed in any one of the embodiments described herein; the inhibitor is an IL-18 binding protein (IL-18BP) having 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence shown in SEQ ID NO: 2 and SEQ ID NO: 3, 4 and 5, in particular to the sequence shown in SEQ ID NO: 2 and SEQ ID NO: 4, and retains the IL-18 blocking activity of the IL-18 inhibitor, and thus is capable of blocking the pro-inflammatory activity of IL-18 and therefore interrupting the immunopathological cascade responsible for VEXAS-associated symptoms.

[0021] In another embodiment of the invention, IL-18BP or a composition comprising IL-18BP may further comprise an N-terminal and / or C-terminal deletion variant of IL-18BP in an amount of up to 40%, particularly up to 30%, particularly up to 20%, particularly up to 15%, particularly up to 10%, particularly up to 7.5%, particularly up to 5%, particularly up to 2.5%, particularly up to 1%, particularly up to 0.5%, particularly up to 0.25%, particularly up to 0.1%, particularly up to 0.05%, particularly up to 0.01%.

[0022] In a particular embodiment, said N-terminal and / or C-terminal deletion variants of IL-18BP are present in an amount of up to 40%, in particular in an amount of between 2% and 35%.

[0023] In particular, said deletion variants comprise a deletion of 1 to 5 amino acid residues at the C-terminus of IL-18BP and / or a deletion of 1 to 30 amino acid residues at the N-terminus of IL-18BP.

[0024] In one aspect, the present invention relates to a composition for use in the treatment of VEXAS or a VEXAS-associated condition as defined in any one of the aspects disclosed herein, comprising an IL-18 inhibitor as defined in any one of the aspects disclosed herein and a pharma- ceutically acceptable carrier and / or excipient.

[0025] In various aspects of the present invention, an IL-18 inhibitor, in particular an IL-18BP of the present invention as described herein (including any functional equivalents or functional portions thereof), or a composition comprising said IL-18 inhibitor, in particular an IL-18BP of the present invention (including any functional equivalents or functional portions thereof), is used for the treatment of VEXAS or a VEXAS-associated condition.

[0026] An IL-18 inhibitor, particularly an IL-18BP of the present invention (including any functional equivalent or functional portion thereof), or a composition comprising said IL-18 inhibitor, particularly an IL-18BP of the present invention (including any functional equivalent or functional portion thereof), is used for the treatment of VEXAS or a VEXAS-associated condition.

[0027] Treatment of VEXAS or a VEXAS-associated condition according to any one of the preceding aspects with an IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein (including any functional equivalents or functional portions thereof), or a composition comprising an IL-18 inhibitor of the present invention, in particular an IL-18BP of the present invention as defined herein (including any functional equivalents or functional portions thereof), includes prevention, arrest, alleviation or reversal (amelioration) of symptoms associated with VEXAS.

[0028] In another particular embodiment, an IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalents or functional portions thereof), or a composition comprising an IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalents or functional portions thereof), is administered to a subject to be treated at least until the treated subject exhibits a therapeutic response, particularly an alleviation of at least one of the symptoms associated with VEXAS.

[0029] 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 modified, and in particular inhibited, increased expression of IFN-γ, IL-13 or IL-17A compared to untreated subjects suffering from VEXAS or a VEXAS-associated condition; and / or Binding of free IL-18 by IL-18BP corrects the IL-18 / IL-18BP imbalance by capturing and neutralizing excess free IL-18 in tissues and the circulation; and / or limited or inhibited binding of IL-18, in particular the binding of free IL-18 to the IL-18 receptor (IL-18R), especially the binding of free IL-18 to IL-18Rα; and / or 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 at least 100%; and / or · IL-18BP neutralizes free IL-18 by limiting or preventing IL-18 binding to the IL-18 receptor (IL-18R), particularly IL-18Rα.

[0030] In one embodiment, an IL-18 inhibitor is provided for use in any one of the embodiments provided herein, wherein the subject has been diagnosed with an abnormal level of ferritin (FERR), particularly a FERR level of greater than 400 ng / mL, preferably greater than 1000 ng / mL, greater than 1500 ng / mL, greater than 2000 ng / mL, greater than 2500 ng / mL, greater than 3000 ng / mL, or greater than 3500 ng / mL.

[0031] In one aspect, the present invention relates to an IL-18 inhibitor of the present invention, in particular IL-18BP (including any functional equivalent or functional portion thereof), or a composition comprising an IL-18 inhibitor of the present invention, in particular IL-18BP (including any functional equivalent or functional portion thereof), for use according to any one of the preceding aspects, wherein the level of free IL-18 in body fluids and / or tissues has been determined to be greater than or equal to 2.7 pg / ml, in particular greater than about 8 pg / ml.

[0032] In certain embodiments of the invention, the levels of free IL-18 in body fluids and / or tissues are above the limit of quantification (>8 pg / ml).

[0033] In another particular embodiment of the invention, the levels of free IL-18 in body fluids and / or tissues are above the limit of detection (>2.7 pg / ml).

[0034] In yet another particular embodiment, the level of total IL-18 in body fluids and / or body tissues is abnormal, particularly greater than about 250 pg / ml, particularly greater than about 1000 pg / ml, and especially greater than about 3000 pg / ml.

[0035] The measurement of free IL-18 in body fluids and / or body tissues can be achieved by using an assay for quantifying the level of free IL-18 in body fluids and / or body tissues in a biological sample or in situ, which assay comprises the following steps: (a) contacting a sample of a body fluid and / or body tissue or body part or region suspected of containing free IL-18 with an IL-18BP or an antibody that specifically binds to free IL-18 but not to IL-18 bound in a complex and that acts as a capture molecule for free IL-18; (b) binding an IL-18BP or antibody to free IL-18; (c) detecting binding of IL-18 to the IL-18BP or antibody and determining the amount of free IL-18 in the sample or in situ. Includes.

[0036] In one aspect, the invention relates to a method according to any one of the previous aspects, 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, expired or exhaled air, sputum, bronchoalveolar fluid, sebum, cells, glands, mucosa, bone marrow, or tissue secretions.

[0037] In order to confirm the presence or absence of free IL-18 in a sample according to the method described in various embodiments herein, any immunoassay format known to those skilled in the art can be used, such as an assay format that utilizes indirect detection using a secondary reagent for detection.In particular, ELISA and immunoprecipitation and agglutination assays can be used.Detailed descriptions of these assays can be found, for example, in Harlow and Lane, Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory, New York 1988) 555-612; Maertens and Stuyver's WO96 / 13590; Zrein et al. (1998) and WO96 / 29605.

[0038] A sample may be an undiluted or diluted biological fluid, such as, but not limited to, serum, urine, tears, saliva, bile, sweat, exhaled or expired breath, sputum, bronchoalveolar fluid, sebum, cellular, glandular, mucosal or tissue secretions, biopsies, homogenized tissues, and the like.

[0039] For in situ diagnosis, IL-18BP or antibody or active and functional parts thereof can be administered to the organism to be diagnosed by methods known in the art, such as, for example, intravenous, intranasal, intraperitoneal, intracerebral, intra-arterial injection, so that specific binding of IL-18BP or antibody to free IL-18 can occur. The antibody / antigen complex can be conveniently detected via a label attached to the antibody or functional fragment thereof, or by other detection methods known in the art.

[0040] In another aspect of the present invention, the detection of free IL-18 as described herein can be achieved by immunoassay techniques. Immunoassays typically include contacting a test sample with an IL-18BP or antibody as described herein in various embodiments that 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 method can be selected from a wide variety of immunoassay methods known to those skilled in the art, such as competitive or non-competitive enzyme-based immunoassays, enzyme-linked immunosorbent assays (ELISA), radioimmunoassays (RIA), Western blots, and the like. In addition, multiplex assays can be used, such as arrays, in which IL-18BP or antibodies are placed on a support such as glass beads or plates and reacted or otherwise contacted with the test sample.

[0041] The antibodies used in these assays may be monoclonal or polyclonal and may be of any type, such as IgG, IgM, IgA, IgD, IgE, etc. Antibodies may be produced by immunizing animals such as rats, mice, rabbits, etc. The antigens used for immunization may be isolated from the sample or may be 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 detail, for example, in Antibodies: A Laboratory Manual by Harlow & Lane (1988); Immunoassays: A Practical Approach, Oxford University Press, Gosling, JP (ed.) (2001) and / or in the regularly updated Current Protocols in Molecular Biology (Ausubel et al.).

[0042] Various chemical or biochemical derivatives of IL-18BP or antibody or antibody fragment can be made using known methods. One type of derivative useful diagnostically as an immunoconjugate comprises IL-18BP or antibody molecule or its antigen-binding fragment bound to a detectable label. However, in many embodiments, IL-18BP or antibody is unlabeled, but becomes indirectly labeled during the course of the assay by binding or being bound to another labeled molecule. The present invention encompasses molecular complexes comprising IL-18BP or antibody molecule and a label.

[0043] Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials.

[0044] 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 substances 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 + DNA, tetramethylrhodamine, Alexa Fluor 594, BODIPY FL, Alexa Fluor 488, fluorescein, BODIPY TR, BODIPY TMR, carboxy SNARF-1, FM 1-43, Fura-2, Indo-1, Cascade Blue, NBD, DAPI, Alexa Fluor 350, aminomethylcoumarin, lucifer yellow, propidium iodide, or dansylamide; an example of a luminescent material includes luminol; examples of bioluminescent materials include green fluorescent protein, modified green fluorescent protein, luciferase, luciferin, and aequorin; examples of suitable radioactive materials include, 125 I, 131 I, 35 S or 3 Examples include H.

[0045] Immunoassays typically involve incubating a sample, such as a biological fluid, tissue extract, freshly harvested cells, or cell lysate, in the presence of detectably labeled IL-18BP or antibody or a peptide fragment thereof, and detecting bound IL-18BP or antibody by any of a number of techniques well known in the art.One method of measuring the level of free IL-18 using IL-18BP or antibody is by enzyme immunoassay (EIA), such as enzyme-linked immunosorbent assay (ELISA) (Voller, A. et al., J. Clin. Pathol. 31:507-520 (1978); Butler, JE, Meth. Enzymol. 73:482-523 (1981); Maggio, E. (ed.), Enzyme Immunoassay, CRC Press, Boca Raton, FL, 1980). The enzyme coupled to an IL-18BP or antibody, or to a binding partner of an IL-18BP or antibody, when later exposed to an appropriate substrate, will react with the substrate in such a manner as to produce a chemical moiety which can be detected, for example, by spectrophotometric or fluorometric means.

[0046] In a particular embodiment of the invention, the IL-18BP used in any of the above formats, in particular in the ELISA format, is IL-18BP isoform a, b, c or d, or a functional equivalent or derivative thereof, or a functional fragment thereof, in particular isoform a, in particular isoform c, or a derivative thereof, in particular isoform a, b, c or d as depicted in SEQ ID NO: 2, as well as in SEQ ID NOs: 3, 4 and 5, but especially isoform a of IL-18BP as depicted in SEQ ID NO: 2 or isoform c as depicted in SEQ ID NO: 4.

[0047] Mixtures of the above isoforms may also be used in the compositions of the invention, particularly mixtures of isoform a and isoform c.

[0048] The biological sample can be contacted with a solid support or carrier, such as nitrocellulose, or other solid support capable of immobilizing cells, cell particles, or soluble proteins, and immobilized on the support. The support can then be washed with a suitable buffer, and then treated with detectably labeled IL-18BP or antibody. The solid support is then washed again with a buffer to remove unbound IL-18BP or antibody. The amount of label bound to the solid support can be detected by conventional means. A well-known example of such a technique is Western blotting.

[0049] In various aspects, the present invention provides compositions comprising a labeled IL-18BP or a labeled antibody according to the invention as described herein.

[0050] In yet another aspect, the present invention relates to a method for treating VEXAS or a VEXAS-associated condition as defined in any one of the preceding aspects, the method comprising the steps of: a. in a first optional step, determining the amount of free IL-18 in the body fluids and / or body tissues of said subject using the methods according to the invention as described herein in various embodiments; b. administering a therapeutically or prophylactically effective amount of an IL-18 inhibitor as defined in any one of the preceding embodiments or a composition comprising said IL-18 inhibitor, particularly by systemic, intranasal, buccal, oral, transmucosal, intratracheal, intravenous, subcutaneous, intraurinary, vaginal, sublingual, intrabronchial, intrapulmonary, transdermal, or intramuscular administration, particularly bronchopulmonary administration, to a subject suffering from VEXAS or a VEXAS-associated condition as defined in any one of the preceding embodiments and having abnormal levels of free IL-18 in body fluids and / or body tissues, wherein the abnormal levels of free IL-18 are 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 and / or body tissues of a healthy control subject.

[0051] In a particular embodiment, the IL-18 inhibitor is an IL-18BP as defined in the previous embodiments herein.

[0052] The IL-18 inhibitors of the present invention or pharmaceutical compositions comprising an IL-18 inhibitor as disclosed in various embodiments herein are administered in an appropriate dosage form and dosage unit and dosing interval to a subject suffering from VEXAS or a VEXAS-associated condition as defined in any of the preceding embodiments herein.

[0053] In a particular embodiment, the IL-18 inhibitor of the invention as defined herein, in particular IL-18BP (including any functional equivalents or functional parts thereof), is formulated as a pharmaceutical composition comprising a sterile injectable solution and further sodium chloride and / or sodium hydroxide and / or sodium phosphate buffer, in particular in a concentration of 0.01M to 0.1M, in particular 0.01M to 0.05M, especially 0.01M.

[0054] In particular, the composition of the present invention comprises sodium chloride, sodium hydroxide and sodium phosphate buffer at a concentration of 0.01M.

[0055] The IL-18 inhibitors of the present invention, particularly IL-18BP (including any functional equivalents or functional portions thereof), or compositions comprising the IL-18 inhibitors of the present invention, particularly IL-18BP (including any functional equivalents or functional portions thereof), can be administered to a patient in need thereof in a single dose or dosage unit per day, multiple doses or dosage units per day, multiple doses or dosage units per week, or multiple doses or dosage units per month. A single dose or dosage unit can also be divided into several doses or dosage units and administered to the subject over the course of several hours or a full day.

[0056] In one embodiment, the IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), or a composition comprising an IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), is administered in 1 dose per week, 2 doses per week, 3 doses per week, 4 doses per week, 5 doses per week, 6 doses per week, in particular 7 doses per week.

[0057] In another embodiment, an IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), or a composition comprising an IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), is administered every 24 to 48 hours.

[0058] In yet another embodiment, the IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), or a composition comprising an IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), is administered every other day, three or four times per week.

[0059] In one embodiment, the composition according to the invention is administered by subcutaneous (sc) injection. In particular, the site of the sc injections alternates, in particular the injection sites are in different quadrants of the lateral thigh and anterior abdominal wall. The individual injections constituting a single dose of the composition of the invention are in particular administered in the same body region, but not at exactly the same injection site.

[0060] In one embodiment, the composition is allowed to return to room temperature, particularly 18-25° C., prior to administration.

[0061] In a particular embodiment, a single dose of the composition of the invention, in particular a composition for the use according to any one of the preceding embodiments, comprises between 10 mg and 600 mg of IL-18BP.

[0062] In particular, a single dose comprises 10 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 160 mg, 160 mg to 320 mg, or 320 mg to 600 mg of IL-18BP.

[0063] In various embodiments of the invention, 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 1.5 mg IL-18 inhibitor / kg body weight and 6 mg IL-18 inhibitor / kg body weight, particularly between 2 mg IL-18 inhibitor / kg body weight and 4 mg IL-18 inhibitor / kg body weight.

[0064] In a particular embodiment of the invention, a single dose comprises between 2 mg IL-18BP / kg body weight and 3 mg IL-18BP / kg body weight, in particular 2 mg IL-18BP / kg body weight.

[0065] In a particular embodiment, the IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), or a composition comprising an IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), is administered at a dose of 0.5 mg IL-18 inhibitor / kg body weight to 5 mg IL-18 inhibitor / kg body weight every 24 or 48 hours, in particular a single dose of 2 mg IL-18 inhibitor / kg body weight administered every 48 hours.

[0066] In another particular embodiment, a composition comprising human IL-18BP (rhIL-18 BP) (including any functional equivalent or functional portion thereof), or recombinant human IL-18BP (rhIL-18 BP) (including any functional equivalent or functional portion thereof), which retains the ability to block the pro-inflammatory activity of IL-18, is used for the treatment of VEXAS or a VEXAS-associated condition as described herein in various embodiments; wherein recombinant human IL-18BP (rhIL-18 BP) or a composition comprising recombinant human IL-18BP (rhIL-18 BP) is administered in a single dose of 2 mg / kg body weight every other day, for example for 3 weeks.

[0067] In yet another particular embodiment, recombinant human IL-18BP (rhIL-18 BP) or a composition comprising recombinant human IL-18BP (rhIL-18 BP), including any functional equivalent or functional portion thereof that retains the ability to block the proinflammatory activity of IL-18, is used for the treatment of VEXAS or a VEXAS-associated condition in a human patient suffering from VEXAS or a VEXAS-associated condition and having levels of free IL-18 that are 2-3 times higher than the levels in healthy control subjects; wherein recombinant human IL-18BP (rhIL-18 BP) or a composition comprising recombinant human IL-18BP (rhIL-18 BP) is administered to said patient in a single dose of 2 mg / kg body weight every other day, 3 or 4 times a week, for example for 3 weeks.

[0068] The compositions of the present invention may include additional medicinal agents, pharmaceutical substances, carriers, buffers, dispersing agents, diluents, co-therapeutic agents, such as anti-inflammatory agents, bronchodilators, antihistamines, decongestants, antitussives, antivirals and / or immunosuppressants, depending on the intended use and application.

[0069] In one embodiment of the invention, an inventive IL-18 inhibitor or a pharmaceutical composition comprising an inventive IL-18 inhibitor, as disclosed in various embodiments herein, is administered prophylactically.

[0070] In another embodiment of the present invention, an inventive IL-18 inhibitor or a pharmaceutical composition comprising an inventive IL-18 inhibitor, as disclosed in various embodiments herein, is administered therapeutically.

[0071] In one embodiment, the IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), or a composition comprising the IL-18 inhibitor of the present invention, particularly IL-18BP (including any functional equivalent or functional portion thereof), is used in co-medication. The co-medication may include known medicaments that treat or prevent one or more VEXAS-related symptoms, either concomitantly or separately. Symptoms include, but are not limited to, fever, fatigue, weight loss, lymphadenopathy, joint pain / arthritis, skin nodular lesions, and the like. Symptoms observed in laboratory tests may be anemia, neutropenia, thrombocytopenia, and / or elevated blood markers such as CRP and ferritin. Vacuolization of myeloid cells is also a characteristic sign of VEXAS. Hemophagocytosis is frequently observed in the bone marrow, and may also show signs of myelofibrosis. Recurrent skin rashes and symmetric polyarthritis are also known signs / manifestations. Inflammatory markers are usually elevated at least during the active phase of the disease, i.e., when symptoms are observed.Therefore, medicines known to be effective in one or more of the above symptoms are envisaged as co-medication for VEXAS or VEXAS-related symptoms.Such medications can include corticosteroids, tocilizumab and / or anakinra, cyclosporine, JAK inhibitors, rituximab, siltuximab, sirolimus, methotrexate, each as a single co-medication or in combination.

[0072] In one embodiment of the present invention, an IL-18 inhibitor of the present invention or a pharmaceutical composition comprising an IL-18 inhibitor of the present invention as disclosed in various embodiments herein is administered to a subject suffering from VEXAS or a VEXAS-associated condition as defined in any of the preceding embodiments herein by systemic, intranasal, intraocular, intravitreal, ophthalmic, buccal, oral, transmucosal, intratracheal, intravenous, subcutaneous, intraurinary, rectal, intravaginal, sublingual, intrabronchial, intrapulmonary, transdermal or intramuscular administration.

[0073] The IL-18 inhibitor of the present invention or pharmaceutical composition comprising an IL-18 inhibitor as disclosed in various embodiments herein may be provided as a liquid, liquid spray, microsphere, semi-solid, gel, or powder for transmucosal administration, for example, for intranasal, buccal, oral mucosal, intratracheal, urinary, vaginal, sublingual, intrabronchial, pulmonary, and / or transdermal administration.Furthermore, the composition may be in a solid dosage form for buccal, oral mucosal, and / or sublingual administration.Intranasal, buccal, oral mucosal, intraurinary, vaginal, transmucosal, and sublingual administration may result in the disintegration of the composition described herein in the oral cavity at body temperature, and in some cases, may adhere to the body tissue of the oral cavity. In addition, the compositions disclosed herein may further comprise one or more excipients, diluents, binders, lubricants, glidants, disintegrants, desensitizing agents, emulsifiers, mucoadhesives, solubilizing agents, suspending agents, viscosity modifiers, ionic tonicity agents, buffers, carriers, surfactants, flavorings, or mixtures thereof.

[0074] In certain aspects of the invention, an IL-18 inhibitor or a pharmaceutical composition comprising an IL-18 inhibitor is formulated as a solution, suspension, emulsion, tablet, pill, bioadhesive patch, drop, sponge, film, lozenge, hard candy, wafer, sphere, lollipop, disk shape, suppository or spray for parenteral or intravenous administration.

[0075] Transmucosal administration is generally rapid because of the rich vascular supply of the mucosa and the lack of a stratum corneum in the epidermis. Such drug delivery usually results in a rapid rise in blood concentration and similarly avoids the enterohepatic circulation and immediate destruction by gastric acid or partial first-pass effect of the intestinal wall and hepatic metabolism. For significant drug absorption to occur, a prolonged exposure of the drug to the mucosal surface is usually required.

[0076] Mucosal routes may also be more effective than oral routes in that these routes can provide relatively rapid absorption and onset of therapeutic effect.Furthermore, mucosal routes may be preferred for use in treating patients who have difficulty swallowing tablets, capsules, or other oral solids, or who have impaired intestinal absorption due to illness.Therefore, mucosal administration of IL-18 inhibitors, particularly IL-18BP, or pharmaceutical compositions comprising IL-18 inhibitors, particularly IL-18BP, and pharma- ceutical acceptable carriers and / or excipients, offers many advantages.

[0077] By either the intranasal or buccal route, drug absorption may be delayed or prolonged, but it may also be taken up almost as rapidly as if it were administered as an intravenous bolus. The sublingual route may provide a rapid onset of action because of the high permeability of the abundant blood supply.

[0078] Compositions for intranasal administration can be administered in a suitable manner depending on their form. Compositions containing microspheres or powders can be administered using a nasal insufflation device. Examples of such devices are well known to those skilled in the art and include commercially available systems for powders such as the Fisons Lomudal System. The insufflator generates a fine cloud of dry powder or microspheres. The insufflator is preferably equipped with a mechanism to ensure administration of a substantially constant amount of the composition. The powder or microspheres can be directly applied using an insufflator equipped with a bottle or container for the powder or microspheres. Alternatively, the powder or microspheres can be filled into a capsule, such as a gelatin capsule, or into other single-dose devices suitable for intranasal administration. The insufflator is preferably equipped with a mechanism to break open the capsule or other device. Additionally, 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. Additionally, alternative methods suitable for administering the composition to the nasal cavity are well known to those skilled in the art. Any suitable method may be used. For a more detailed description of suitable methods see EP2112923, EP1635783, EP1648406, EP2112923 (the entire contents of which are incorporated herein by reference).

[0079] In one embodiment of the present invention, the IL-18 inhibitors of the present invention or pharmaceutical compositions comprising an IL-18 inhibitor, as disclosed in various embodiments herein, may further 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.

[0080] 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.

[0081] Pharmaceutically acceptable carriers for liquid preparations are aqueous or non-aqueous solutions, suspensions, dry powder preparations, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.Examples of oils are oils of animal, vegetable, and synthetic origin, such as peanut oil, soybean oil, olive oil, sunflower oil, fish liver oil, other marine oils, or fats derived from milk or eggs.

[0082] The present invention also relates to pulmonary administration of the IL-18 inhibitors of the present invention or pharmaceutical compositions comprising IL-18 inhibitors, as disclosed herein in various embodiments, by inhalation through the respiratory tract as a dry powder, gaseous formulation or volatile formulation and delivery to the systemic circulation. Absorption is virtually as rapid as the formulation is delivered to the alveoli; because the alveoli and vascular epithelial membranes are fairly permeable, there is a rich blood flow, and there is a very large surface area for adsorption. For example, aerosols can be delivered from a pressurized metered-dose inhaler (MDI).

[0083] The IL-18 inhibitors of the present invention or pharmaceutical compositions comprising an IL-18 inhibitor, as disclosed in various embodiments herein, may generally be administered as a mixture with a suitable pharmaceutical excipient, diluent or carrier selected having regard to the intended means of inhalation and standard pharmaceutical practice.

[0084] In another embodiment of the present invention, the formulation of an IL-18 inhibitor, in particular a formulation of IL-18BP, or a pharmaceutical composition comprising an IL-18 inhibitor, in particular IL-18BP, is a dry powder and may optionally contain at least one pharma- ceutically acceptable particulate carrier; the carrier is one or more materials known as pharma- ceutically acceptable carriers, preferably selected from materials known as carriers in dry powder inhalation compositions, such as sugars, such as monosaccharides, disaccharides, 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, for example lactose monohydrate or anhydrous lactose. The dry powder may be packaged as a unit dose, e.g., in gelatin or plastic capsules or blisters (e.g., aluminum or plastic), for use in single or multi-dose dry powder inhalation devices, preferably in a dosage unit with a carrier in an amount to give a total weight of 5 mg to 50 mg of powder per capsule. Alternatively, the dry powder may be contained within a reservoir of a multi-dose dry powder inhalation (MDDPI) device adapted for delivery.

[0085] Any other therapeutically effective route of administration can be used, such as absorption through epithelial or endothelial tissue, or by gene therapy, a DNA molecule encoding an active agent can be administered to the patient (e.g., via an expression vector) such that the active agent is expressed and secreted in vivo.

[0086] The IL-18 inhibitors of the present invention or pharmaceutical compositions comprising an IL-18 inhibitor as disclosed in various embodiments herein can be used in human and veterinary medicine to treat humans and animals (e.g., birds, non-human primates, dogs, cats, pigs, goats, sheep, cows, horses, mice, rats, rabbits, etc.) to treat VEXAS or VEXAS-related conditions as described in various embodiments herein.

[0087] In certain embodiments, the present invention provides an IL-18 inhibitor or a pharmaceutical composition comprising an IL-18 inhibitor of the present invention as disclosed in various embodiments herein for use in the treatment of VEXAS or a VEXAS-associated condition as described in various embodiments herein, wherein the subject is a mammal, in particular the subject is a human.

[0088] In another particular embodiment, the pharmaceutical composition of the invention disclosed in various embodiments herein is administered in a therapeutically effective amount together with an appropriate dose of at least a second proinflammatory cytokine inhibitor, particularly said inhibitor being specific for IL-1, IL-6, IL-13, IL-17A, IFN-γ or TNFα.

[0089] Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, buffered media such as saline and phosphate buffered saline, water, emulsions such as oil / water emulsions, various wetting agents, sterile liquids, etc. Compositions containing such carriers can be formulated by well-known conventional methods. Suitable carriers include any material that, when combined with the biologically active compound of the present invention, causes the compound to retain its biological activity.

[0090] Efforts have been made in the art to chemically modify the barrier properties of the skin to allow penetration of certain agents, increase the efficacy of the delivered agents, shorten the delivery time, reduce the delivered dose, reduce side effects from various delivery methods, reduce patient reactions, etc.

[0091] In this regard, penetration enhancers are used to increase the permeability of the skin surface to drugs, and these are often proton-accepting solvents such as dimethylsulfoxide (DMSO) or 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, pyrrolidone derivatives, derivatives of 1,3-dioxane and 1,3-dioxolane, 1-N-dodecyl-2-pyrrolidone-5-carboxylic acid, 2-pentyl-2-oxo-pyrrolidine acetic acid, 2-dodecyl-2-oxo-1-pyrrolidine acetic acid, 1-azacycloheptan-2-one-2-dodecyl acetic acid, and amino alcohol derivatives including derivatives of 1,3-dioxane, among others.

[0092] Preparations for transmucosal administration include sterile aqueous or non-aqueous solutions, suspensions, dry powder formulations, and emulsions. Examples of non-aqueous solvents are 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, suspensions, such as 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, inert gases, and the like, may also be present. In addition, the pharmaceutical compositions of the present invention may include proteinaceous carriers, preferably of human origin, such as serum albumin or immunoglobulin.

[0093] The IL-18 inhibitors of the present invention or pharmaceutical compositions comprising IL-18 inhibitors disclosed in various embodiments herein can be administered locally to body surfaces and therefore can be formulated in a 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 in various embodiments herein are prepared and applied as solutions, suspensions, or emulsions in physiologically acceptable diluents with or without a pharmaceutical carrier.

[0094] The IL-18 inhibitor of the present invention or the pharmaceutical composition comprising an IL-18 inhibitor, as disclosed in various embodiments herein, can also be administered as a controlled release composition, i.e., a composition 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.

[0095] Further examples of suitable formulations are described in WO 2006 / 085983, the entire contents of which are incorporated herein by reference. For example, the IL-18 inhibitor of the present invention or pharmaceutical composition comprising an IL-18 inhibitor disclosed in various embodiments herein may be provided as a liposomal formulation. 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 not contain cholesterol. Liposomes may be reduced in size through the use of standard sonication and homogenization techniques. The liposomal formulation containing the pharmaceutical composition of the present invention disclosed in various embodiments herein may be lyophilized to a lyophilizate, which may be reconstituted with a pharma- ceutically acceptable carrier, such as water, to regenerate the liposomal suspension. The pharmaceutical composition of the present invention disclosed in various embodiments herein may be administered to a subject at an appropriate dose. The dosing regimen will be determined by the attending physician and clinical factors. As is well known in the medical art, the dosage administered to a given 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.

[0096] Furthermore, it is envisaged that the IL-18 inhibitor of the present invention or the pharmaceutical composition comprising the IL-18 inhibitor may contain additional biologically active substances depending on the intended use of the pharmaceutical composition. Such 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 a preferred embodiment, the pharmaceutical composition of the present invention may be co-administered with long-acting beta-adrenergic receptor agonists (LABA), long-acting muscarinic antagonists (LAMA), steroids, corticosteroids, glucocorticoids and glucocorticoid agonists, phosphodiesterase inhibitors, kinase inhibitors, cytokine and chemokine inhibitors, antibiotics, antagonists or protease inhibitors, antiviral and / or anti-inflammatory drugs, or combinations thereof.

[0097] The dosage of the IL-18 inhibitors or pharmaceutical compositions comprising an IL-18 inhibitor of the present invention disclosed in various embodiments herein will depend on the VEXAS-associated 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 being co-administered, and the route of administration.

[0098] The IL-18 inhibitors of the present invention or pharmaceutical compositions comprising IL-18 inhibitors as disclosed in various embodiments herein can be administered in combination with other biologically active substances and treatments for treating VEXAS-associated conditions. The other biologically active substances may be part of the same composition already comprising the composition according to the present invention, in the form of a mixture, where the composition of the present invention and the other biologically active substances are mixed in or with the same pharma- ceutically acceptable solvents and / or carriers, or may be provided separately as part of separate compositions, which compositions may be provided separately or together in the form of a kit of parts.

[0099] The IL-18 inhibitor of the present invention or the pharmaceutical composition comprising an IL-18 inhibitor, as disclosed in various embodiments herein, may be administered simultaneously, intermittently or sequentially with one other biologically active substance or multiple other biologically active substances. For example, the composition according to the present invention may be administered simultaneously with a first additional biologically active substance, or sequentially after or before administration of the composition. When an application scheme is selected in which multiple additional biologically active substances and at least one composition according to the present invention are administered, the compounds or substances may be administered in various combinations, partly simultaneously and partly sequentially.

[0100] Therefore, another object of the present invention is to provide mixtures comprising an IL-18 inhibitor of the present invention or a pharmaceutical composition comprising an IL-18 inhibitor as disclosed in various embodiments herein, and, optionally, a therapeutically or prophylactically effective amount of one or more further biologically active substances, as well as methods of using such mixtures for prophylactic and / or therapeutic treatment.

[0101] The other biologically active substances or compounds may exert their biological effects through the same or a similar mechanism of action as the compositions according to the invention, or through an unrelated mechanism of action, or through multiple related and / or unrelated mechanisms of action.

[0102] In general, other biologically active compounds include antibodies raised against and binding to IFN-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) according to the invention as described herein, or a pharmaceutical composition comprising IL-18BP (IL-18BP) and a pharma- ceutically acceptable carrier and / or excipient.

[0103] The appropriate dosage of the pharmaceutical composition of the present invention disclosed in various embodiments herein varies 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 employed in both veterinary and human medicine will preferably be in the range of 0.1 to 10 mg / kg.

[0104] Furthermore, IL-18 inhibitors, in particular functional derivatives of IL-18BP, can be conjugated to polymers to improve protein properties such as stability, half-life, bioavailability, tolerance by the human body, immunogenicity, etc. To achieve this goal, IL-18BP is linked, for example, to polyethylene glycol (PEG). PEGylation can be carried out by known methods, for example as described in WO 92 / 13095.

[0105] Thus, in another embodiment of the present invention, IL-18BP is PEGylated.

[0106] In yet another embodiment of the invention, IL-18BP is a fusion protein comprising all or a part of IL-18BP fused to all or a part of an immunoglobulin, preferably to the constant region (Fc) of an immunoglobulin, which fusion protein is still capable of binding to IL-18. More specifically, the immunoglobulin may be of the IgG1 or IgG2 isotype.

[0107] In a further embodiment of the invention, IL-18BP is PEGylated and fused to all or part of an immunoglobulin, preferably to the constant region (Fc) of an immunoglobulin; this fusion protein is still capable of binding to IL-18. More specifically, the immunoglobulin may be of the IgG1 or IgG2 isotype.

[0108] The skilled artisan will understand that the resulting fusion protein retains the biological activity of IL-18BP, in particular 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 in length or longer, for example 13 amino acid residues in length. The linker can be, for example, a tripeptide of the sequence EFM (Glu-Phe-Met) introduced between the IL-18BP sequence and the immunoglobulin sequence, or a linker sequence of 13 amino acids consisting of Glu-Phe-Gly-Ala-Gly-Leu-Val-Leu-Gly-Gly-Gln-Phe-Met. The resulting fusion protein has improved properties, such as an increased residence time (half-life) in body fluids, an increased specific activity, an increased expression level, or an easier purification of the fusion protein.

[0109] Preferably, it is fused to a heavy chain region, such as the CH2 and CH3 domains of human IgG1. The production of a particular fusion protein comprising IL-18BP and a portion of an immunoglobulin is described, for example, in Example 11 of WP99 / 09063. Other isoforms of Ig molecules, such as IgG2 or IgG4 isoforms, or other Ig classes, such as IgM or IgA, are also suitable for the production of fusion proteins according to the invention. The fusion protein may be monomeric or multimeric, and may be hetero- or homo-multimeric.

[0110] definition Technical terms and expressions used within the scope of this application are generally to be given the meanings commonly applied to them in the relevant technical field, unless otherwise noted below.

[0111] As used herein and in the embodiments described therein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes one or more compounds.

[0112] As used herein, the terms "treatment", "treating" and the like generally refer to obtaining a desired pharmacological and / or physiological effect. This effect may be preventive in that it completely or partially prevents a disease or its symptoms, and / or it may be therapeutic in that it partially or completely cures a disease and / or the adverse effects caused by the disease. As used herein, the term "treatment" covers any treatment of a disease in a subject, including: (a) preventing the occurrence of a disease, i.e., a disease associated with an undesirable immune response, in a subject that may be predisposed to the disease; (b) suppressing the disease, i.e., arresting its progression; (c) alleviating the disease, i.e., causing regression of the disease; or (d) reversing the symptoms of the disease, i.e., causing the recovery of damaged tissue.

[0113] As used herein, the term "IL-18 binding protein (IL-18BP)" includes full-length proteins, muteins, fragments, peptides, functional derivatives, functional fragments, subportions, circularly permuted derivatives, fusion proteins comprising IL-18BP, isoforms, or salts thereof.

[0114] As used herein, the term "free IL-18" refers to the monomeric, soluble, uncomplexed form of interleukin-18 protein.

[0115] The terms "functional" and "active" are used interchangeably herein and refer to a modified IL-18 inhibitor, in particular a modified IL-18BP, or a part or fragment of an IL-18 inhibitor, in particular a part or fragment of IL-18BP, or an equivalent of an IL-18 inhibitor, in particular an equivalent of IL-18BP, which still has / retains the same or essentially the same biological, pharmacological and therapeutic properties as an unmodified or full-length IL-18 inhibitor, in particular unmodified or full-length IL-18BP, and therefore may be used within the scope of the present invention for the treatment of diseases and disorders as disclosed herein, similar to an unmodified or full-length IL-18 inhibitor, in particular unmodified or full-length IL-18BP. In particular, "functional" means that the modified, partial or equivalent IL-18 inhibitor, in particular the modified, partial or equivalent IL-18BP, still retains the IL-18 blocking activity of the unmodified or full-length IL-18 inhibitor, in particular the unmodified or full-length IL-18BP, in the treatment of VEXAS or a VEXAS-associated condition, and is therefore capable of blocking the pro-inflammatory activity of IL-18 and therefore interrupting the immunopathological cascade that is responsible for VEXAS or a VEXAS-associated condition.

[0116] In various embodiments of the invention, the term "IL-18BP" refers to human IL-18BP, in particular recombinant human IL-18BP, in particular isoforms a, b, c, or d of IL-18BP, in particular isoform a, in particular isoform c, in particular isoforms a, b, c, or d as depicted in SEQ ID NO: 2, as well as in SEQ ID NOs: 3, 4, and 5, but especially isoform a of IL-18BP as depicted in SEQ ID NO: 2, or isoform c as depicted in SEQ ID NO: 4.

[0117] An "immunoglobulin" is a tetrameric molecule. In naturally occurring immunoglobulins, each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light chain" (about 25 kDa) and one "heavy chain" (about 50-70 kDa). The amino-terminal portion of each chain contains a variable region of about 100-110 or more amino acids that is primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region that is 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], which define the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively. In the light and heavy chains, the variable and constant regions are connected by a "J" region of about 122 or more amino acids, and the heavy chains also contain a "D" region of about 10 or more amino acids. See generally, 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.

[0118] Immunoglobulin chains exhibit the same overall structure, with relatively conserved framework regions (FR) 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, allowing binding to a specific epitope. From the N-terminus to the C-terminus, both light and heavy chains contain the domains FR1, CDR1, FR2, CDR.2, FR3, CDR3, and FR4. The assignment of amino acids to each domain follows the definitions of the Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991); or Chothia & Lesk J. Mol. Biol. 196:901-917 (1987). The Kabat complementarity determining regions are based on sequence variability and are the most commonly used.

[0119] Chothia instead refers to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987); Chothia et al. Nature 342:878-883 (1989)).

[0120] An alternative system for assigning amino acids to each domain is the IMGT system (http: / / www.imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html). The term "antibody" as used herein is an art-recognized term and is understood to refer to molecules or active fragments of molecules that bind to a known antigen, in particular 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 invention can be of any type (IgG, IgM, IgD, IgE, IgA and IgY) or class (IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule.

[0121] The term "antibody" for the purposes of this invention refers to an intact immunoglobulin or an antigen-binding portion thereof which competes with the intact antibody for specific binding. In particular, "antibody" is intended within the scope of the present invention to include monoclonal antibodies, polyclonal antibodies, chimeric antibodies, single-chain antibodies, bispecific or bipotent antibodies, simianized antibodies, human antibodies and humanized antibodies.

[0122] Examples of antigen-binding portions include, among others, Fab, Fab', F(ab')2, scFv, dAb and Fv fragments, including the products of a Fab immunoglobulin expression library, as well as epitope-binding fragments of any of the above antibodies and fragments. 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 antigen binding to the polypeptide.

[0123] Such active fragments can be derived from the antibody of the present invention by many techniques known in the art. For example, purified monoclonal antibody can be cleaved with an enzyme such as pepsin and subjected to HPLC gel filtration. Then, the appropriate fraction containing Fab fragments can be collected and concentrated by membrane filtration or the like. For further description of the 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.

[0124] "Patient" or "subject" in the present invention are used interchangeably and are meant to include humans and other animals, particularly mammals, as well as other organisms. Thus, the present method is applicable to both human and animal medical applications. In a preferred embodiment, the patient or subject is a mammal, and in a most preferred embodiment, the patient or subject is a human.

[0125] The expressions "pharmaceutical composition" and "therapeutic composition" are used interchangeably herein in the broadest sense and are intended for the purposes of the present invention to refer to a therapeutically effective amount of the active ingredient, i.e. IL-18BP, and optionally a pharma- ceutically acceptable carrier or diluent.

[0126] It includes compositions suitable for therapeutic treatment, control, alleviation, amelioration, or prevention of disease or disorder in humans or non-human animals.It therefore includes pharmaceutical compositions for use in human or animal medicine.Such "therapeutic compositions" are characterized in that they contain at least one IL-18BP compound or its physiologically acceptable salt, and optionally a carrier or excipient, said salt and said carrier and excipient being tolerated by the target organism to be treated.

[0127] A "therapeutically effective amount" refers to an amount that produces a therapeutic effect for a given condition and administration regimen. In particular, a "therapeutically effective amount" refers to an amount that is effective to prevent, reverse, alleviate or ameliorate a disease, or prolong the survival of a subject to be treated, which may be a human or a non-human animal. The determination of a therapeutically effective amount is within the skill of a person skilled in the art. In particular, in this case, a "therapeutically or prophylactically effective amount" refers to an amount of a protein or peptide, mutein, functional derivative, subpart, circularly permuted derivative, fusion protein, isoform, or salt thereof, as well as a formulation or pharmaceutical composition, that produces a therapeutic or prophylactic effect in a human or animal when administered to said human or animal. This effective amount can be easily determined by a person skilled in the art following routine procedures. The therapeutically effective amount or dosage of a compound according to the invention can vary within a wide range and can be determined by methods known in the relevant technical field. The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.

[0128] The term "transmucosal" administration refers to various routes of administration in which a compound is absorbed through the mucous membrane of any part of the body, including, but not limited to, intranasal, buccal, oral mucosal, intratracheal, urinary, rectal, vaginal, sublingual, intrabronchial, pulmonary, and transdermal administration.

[0129] The definition of "pharmaceutically acceptable" is meant to encompass any carrier, excipient, diluent, or vehicle that does not interfere with effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which it is administered.

[0130] The term "fusion protein" refers to a polypeptide in which an IL-18BP, or a viral IL-18BP, or a mutein or fragment thereof, is fused to another protein, e.g., which has an increased residence time in body fluids. Thus, an IL-18BP or a viral IL-18BP can be fused to another protein, polypeptide, etc., e.g., an immunoglobulin or a fragment thereof.

[0131] These isoforms, muteins, fusion proteins or functional derivatives retain the biological activity of IL-18BP, in particular the binding to IL-18, and preferably have essentially at least the same activity as IL-18BP. Ideally, such proteins have an increased biological activity compared to unmodified IL-18BP. Suitable active fractions have an activity superior to that of IL-18BP, or have additional advantages such as better stability, lower toxicity or immunogenicity, or they are easier to produce in large quantities or easier to purify.

[0132] The term "interleukin-18 binding protein" (IL-18BP) also includes functional equivalents of IL-18BP, including muteins, functional derivatives, subportions, biologically active peptides, circularly permuted derivatives, fusion proteins, isoforms, and salts thereof.

[0133] In particular, a functional equivalent of IL-18BP has 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the sequence shown in SEQ ID NO: 2 and retains the ability to block the pro-inflammatory activity of IL-18, preferably retains the IL-18 blocking activity of IL-18BP in a virus-induced infection process in the lung and is thus able to block the pro-inflammatory activity of IL-18 and therefore interrupt the immunopathological cascade responsible for irreversible lung damage.

[0134] The term "mutein" as used herein refers to an analog of IL-18BP or an analog of a viral IL-18BP in which one or more of the amino acid residues of the native IL-18BP or a viral IL-18BP are replaced with a different amino acid residue or deleted, or one or more amino acid residues are added to the native sequence of IL-18BP or a viral IL-18BP, without significantly changing the activity of the resulting product compared to the wild-type IL-18BP or a viral IL-18BP. Such muteins are generated by known synthesis and / or site-directed mutagenesis, high-throughput mutagenesis, DNA shuffling, protein evolution, or other known techniques suitable therefor.

[0135] Any such mutein preferably has an amino acid sequence that is sufficiently overlapping with the amino acid sequence of IL-18BP or sufficiently overlapping with 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 this mutein has substantial binding activity to IL-18, it can be used to purify IL-18, for example by affinity chromatography, and thus can be considered to have substantially similar activity to IL-18BP. Therefore, whether a given mutein has substantially the same activity as IL-18BP can be confirmed by routine experimentation, including subjecting such mutein to a simple sandwich competition assay, such as radioimmunoassay or ELISA assay, to determine whether it binds to appropriately labeled IL-18.

[0136] Muteins of IL-18BP polypeptides or viral IL-18BPs, or nucleic acids encoding same, that may be used in accordance with the present invention include a finite set of substantially corresponding sequences as substituted peptides or polynucleotides that can be routinely obtained by one of ordinary skill in the art without undue experimentation, based on the teaching and guidance provided herein.

[0137] Preferred changes for muteins according to the invention are what are known as "conservative" substitutions. Conservative amino acid substitutions in IL-18BP polypeptides or proteins, or viral IL-18BPs, may involve synonymous amino acids within a group having sufficiently similar physicochemical properties, such that substitutions between members of the group will retain the biological function of the molecule (Grantham, 1974). It is clear that insertions and deletions of amino acids can also be made in the above defined sequences without altering their function, especially when the insertions or deletions concern only a small number of amino acids, e.g. less than 30, preferably less than 10, and do not remove or replace amino acids important for the functional conformation, e.g. cysteine ​​residues. Proteins and muteins made by such deletions and / or insertions come within the scope of the present invention.

[0138] "Functional derivatives" as used herein covers derivatives of IL-18BP or viral IL-18BP, its muteins and fusion proteins that can be made from functional groups present as side chains on residues or as N- or C-terminal groups by means known in the art and are encompassed by the present invention so long as they remain pharma- ceutically acceptable, i.e., they do not destroy the activity of the protein substantially similar to that of IL-18BP or viral IL-18BP and do not impart toxicity to compositions containing it.

[0139] These derivatives can, for example, contain polyethylene glycol side chains, which may mask antigenic sites and extend the residence time 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 with primary or secondary amines, N-acyl derivatives of free amino groups of amino acid residues formed with an acyl moiety (e.g., an alkanol group or a carbocyclic aroyl group), or O-acyl derivatives of free hydroxyl groups formed with an acyl moiety (e.g., that of a seryl or threonyl residue).

[0140] By "functional fragments" of IL-18BP or viral IL-18BP, muteins and fusion proteins, the present invention covers fragments or precursors of the polypeptide chain of the IL-18BP protein molecule alone or together with related molecules or residues (e.g. sugar or phosphate residues) linked thereto or the protein molecule or collection of sugar residues itself, provided that said fragments have substantially similar activity to IL-18BP.

[0141] In this specification, the term "salt" refers to both the salt of carboxyl group and the acid addition salt of amino group of IL-18BP molecule or its analog. The salt of carboxyl group can be formed by means known in the art, and includes inorganic salts such as sodium salt, calcium salt, ammonium salt, ferric salt or zinc salt, and salts with organic bases such as salts formed with amines such as triethanolamine, arginine or lysine, piperidine, procaine, etc. Acid addition salts include salts with mineral acids such as hydrochloric acid and sulfuric acid, and salts with organic acids such as acetic acid and oxalic acid. Of course, all such salts must retain the biological activity of IL-18BP, such as the ability to bind to IL-18.

[0142] An "isoform" of IL-18BP is a protein capable of binding to IL-18 or a fragment thereof that may be generated by alternative splicing.

[0143] The term "circularly permuted derivatives" as used herein refers to linear molecules in which the ends of a linear molecule are joined together, either directly or through a linker, to produce a circular molecule that is then opened at another position to produce a new linear molecule with ends different from those of the original molecule. Circular permutations include molecules that are structurally equivalent to molecules that have been circularized and then opened. Thus, circularly permuted molecules can be synthesized de novo as linear molecules without the circularization and opening steps. The preparation of circularly permuted derivatives is described in WO 95 / 27732.

[0144] The expression "abnormal levels of free IL-18" refers to increased or decreased levels of free IL-18 compared to the values ​​detected in the body fluids and / or body tissues of healthy control subjects. In particular, these abnormal levels refer to an increase in the detectable value of free IL-18. In particular, abnormal levels of free IL-18 in body fluids and / or body tissues are levels of free IL-18 above the limit of quantification, in particular levels of free IL-18 >12 pg / mL and / or above the limit of detection, in particular levels of free IL-18 >4 pg / mL, in particular levels of free IL-18 that are 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100% higher than the levels in the body fluids and / or body tissues of healthy control subjects. In a particular 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. Those skilled in the art will recognize that the limit of detection and / or limit of quantification of free IL-18 may depend on the method of measuring free IL-18 employed, and therefore what can be detected may change with the development of improved and / or alternative methods.

[0145] The expression "abnormal ratio of free IL-18 / IL-18BP" refers to an increase in the ratio of IL-18 to IL-18BP compared to the value found in the body fluids and / or tissues of healthy control subjects. In particular, the abnormal ratio of free IL-18 to IL-18BP in the body fluids and / or tissues 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 fluids and / or tissues of healthy control subjects. In a particular 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.

[0146] The terms "gene silencing" and "post-transcriptional gene silencing" refer to the negative regulation of gene expression by mechanisms other than genetic modification. Silencing occurs by neutralization of mRNA at the post-transcriptional level, where translation of the mRNA to form an active gene product, most often a protein, is prevented.

[0147] The term "predisposition" refers to an increased susceptibility of a subject to developing a particular disease. In the present case, for example, a subject is classified as predisposed if elevated levels of IL-18 are found in the lungs, serum, sputum, bronchoalveolar lavage fluid (BALF) or in the circulation.

[0148] "Alveolar macrophages" are a subtype of macrophages found in the alveoli of the lungs. They often contain granules of exogenous material that they have picked up from respiratory surfaces. Such black granules are particularly common in people with long-term exposure to fine dust and particulates, for example smokers or long-term city dwellers.

[0149] 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, whereas a "Th1 cytokine response" is mediated by interferon gamma (IFN-γ), IL-2, and tumor necrosis factor alpha (TNF-α).

[0150] The expression "IL-18 / IL-18BP imbalance" relates to dysregulation of the interaction between IL-18 and IL-18BP, which ultimately leads to elevated levels of unbound IL-18.

[0151] A "disease" is a condition of the health of a subject, especially a human, in which the subject is unable to maintain homeostasis and in which the subject's health will continue to deteriorate if the disease is not remedied. In contrast, a "disorder" in a subject is a condition of the health of a subject in which the subject is able to maintain homeostasis, but in which the subject's health is not better than it would be in the absence of the disorder. If left untreated, a disorder does not necessarily cause a further deterioration in the subject's health.

[0152] A disease or disorder is "alleviated" if the severity of a symptom of the disease or disorder, the frequency with which a subject experiences such symptoms, or both, are reduced.

[0153] The term "dysregulated" or "dysregulation" as used herein refers to a disturbance in a biological process that in turn leads to adverse physiological sequelae 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 a level that is outside of what would be considered the normal range of expression of 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 confirmed by measuring the level of the gene, nucleic acid, protein, peptide, or other biomolecule in the mammal and comparing the level measured in the mammal with the level measured in a matched population known not to suffer from dysregulation of the gene, nucleic acid, protein, peptide, or other biomolecule. Alternatively, the level can be compared to levels measured in the same individual at different times.

[0154] As used herein, "endogenous" refers to any substance that originates from or is produced within an organism, cell, tissue, or system. The term "exogenous" refers to any substance that is introduced from or produced outside an organism, cell, tissue, or system.

[0155] The terms "inhibit", "neutralize" or "block" as used herein should be understood as synonyms meaning to reduce or completely prevent the expression, stability, function or activity of a molecule, reaction, interaction, gene expression, mRNA, and / or protein by a measurable amount. Inhibitors are compounds, such as antagonists, that, for example, bind to proteins, genes, and mRNAs, partially or completely block stimulation, reduce, impede, delay activation of, inactivate, desensitize, or downregulate the stability, expression, function, and activity of proteins, genes, and mRNAs.

[0156] A brief description of the sequence SEQ ID NO: 1 : 13 amino acid linker sequence of hIL-18BP: Glu-Phe-Gly-Ala-Gly-Leu-Val-Leu-Gly-Gly-Gln-Phe-Met SEQ ID NO: 2 : Amino acid sequence of IL-18 binding protein (hIL-18BP), isoform a TIFF2025507007000001.tif17160 SEQ ID NO: 3 : Amino acid sequence of IL-18 binding protein (hIL-18BP), isoform b TIFF2025507007000002.tif10160 SEQ ID NO: 4 : Amino acid sequence of IL-18 binding protein (hIL-18BP), isoform c TIFF2025507007000003.tif17160 SEQ ID NO: 5 : Amino acid sequence of IL-18 binding protein (hIL-18BP), isoform d TIFF2025507007000004.tif17160 [Brief description of the drawings]

[0157] [Figure 1] Distribution of total IL-18 levels within the VEXAS cohort. [Diagram 2] Distribution of free IL-18 levels within the "VEXAS cohort-64". [Diagram 3] Correlation between total and free IL-18 levels. This analysis was performed on the VEXAS cohort-64 and excluded three outliers. [Figure 4] Concentration of free IL-18 in patients with high total IL-18 levels. This analysis was performed in the VEXAS cohort-64. [Diagram 5] Correlation between total IL-18 and IL-18BP levels. This analysis was performed on the entire VEXAS cohort and excluded one outlier. EXAMPLES

[0158] Extensive genotype-driven studies have revealed that the genetic cause of the rare and often fatal inflammatory disease VEXAS (vacuolar, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is acquired somatic mutations in UBA1 on the X chromosome. This gene encodes the main E1 enzyme involved in the activation of ubiquitin, a small regulatory protein that binds to substrate proteins in a process termed ubiquitylation. Mutations at methionine 41 in UBA1 result in decreased ubiquitylation, especially in hematopoietic stem cells, with subsequent activation of the innate immune system. Patients affected by VEXAS syndrome develop inflammatory and hematological symptoms.

[0159] Initially thought to be rare, since first reported in October 2020, it has been increasingly diagnosed through retrospective genetic testing of patient cohorts identified by clinical characteristics, including case series from France, the Netherlands and the United States, as well as individual case reports. VEXAS syndrome affects almost exclusively males, with most cases diagnosed in mid-to-late adulthood. One female with VEXAS syndrome has been reported, who has a single X chromosome.

[0160] VEXAS syndrome is clinically heterogeneous, but has recently been described as an association of severe autoinflammatory manifestations, mainly affecting the skin and bone marrow, with myelodysplasia. Patients usually respond poorly to treatment, but some clinical improvement has been observed with high doses of immunosuppressants (methotrexate or corticosteroids), proinflammatory cytokine targeting drugs (tocilizumab or adalimumab), and signaling inhibitors (cyclosporine or JAK inhibitors). However, most of these treatments have been shown to be only temporarily effective against inflammation, without any real improvement in cytopenias, leaving VEXAS syndrome with a high unmet medical need.

[0161] Patients diagnosed with VEXAS syndrome exhibit severe autoinflammatory signs, with recurrent fevers and elevated inflammatory markers. Similar to other autoinflammatory diseases, these patients experience uncontrolled immune activation in the form of cytokine release syndrome (CRS). Currently, management of CRS is dominated by the use of corticosteroids, tocilizumab and / or anakinra, the latter drugs blocking IL-6 and IL-1 stimulatory pathways, respectively. However, these therapeutic approaches have been reported to show limited efficacy. One working hypothesis to interpret the molecular basis of CRS is that it results from the induction of two distinct cytokine stimulatory pathways, the IL-1β / IL-6 pathway and the IL-18 / IFN-γ pathway.

[0162] IL-18 is a proinflammatory cytokine belonging to the IL-1 family that was first identified for its IFN-γ-inducing properties. By binding to IL-18, IL-18 binding protein (IL-18BP) neutralizes it and acts as a key regulator of the immune response. In healthy conditions, all IL-18 is bound by IL-18BP, and active free IL-18 is absent or present in only small amounts. In patients suffering from systemic inflammatory diseases, the levels of both IL-18 and IL-18BP are dramatically elevated, but the elevation of IL-18 is higher, and IL-18BP is unable to efficiently neutralize the active free form of IL-18, which leads to the pathological presence of free IL-18. Free IL-18 that is not inactivated by IL-18 BP can continuously trigger the immune system and cause severe autoinflammatory conditions and CRS with potentially life-threatening consequences.

[0163] High levels of IL-18 have been measured in the serum of some patients diagnosed with VEXAS syndrome (unpublished results), and these findings suggest that the IL-18 pathway may be involved in this rare and fatal autoinflammatory disease.

[0164] The aim of this study is to provide evidence that the IL-18 pathway is involved in VEXAS syndrome and that active free IL-18 appears pathogenically in the serum of patients with this autoinflammatory disease, which may support the rationale for administering exogenous rhIL-18BPs, such as Tadekinig alfa, currently under development by AB2 Bio, to effectively neutralize uncontrolled IL-18 activity and help resolve hyperinflammation.

[0165] In this study, serum samples from a cohort of 73 VEXAS syndrome patients were monitored. Measurement of free IL-18 and IL-18BP was performed using a proprietary assay from AB2 Bio and a commercial assay (DY119 from R&D), respectively. Both assays are based on a sandwich ELISA method, and analyte detection is performed using colorimetric reagents.

[0166] Serum samples were tested in duplicate and analyte concentrations were extrapolated from an internal calibration curve. These concentrations were qualified if the coefficient of variation (CV) between duplicate tests was acceptable (CV<40%). As 64 out of 73 samples showed eligible values ​​for free IL-18 measurement, we decided to restrict the analysis of free IL-18 data to this sample set and refer to the corresponding patient subgroup as "VEXAS cohort-64".

[0167] Statistical analysis was performed using the built-in regression function of Excel software (Microsoft Office 2019). The generated regression curves and correlation coefficients (R 2 ) were recorded on a scatter plot graph. The correlation coefficient indicates the correlation between a pair of variables. It is a number between -1 and 1; a correlation coefficient near 0 indicates no linear relationship between the two variables (a collection of points with no clear structure connecting the two variables); the closer the value is to 1, the stronger the positive linear association. Similarly, the closer the value is to -1, the stronger the negative linear association (as the value of one increases, the value of the other tends to decrease).

[0168] result High total IL-18 levels in the VEXAS cohort Serum samples from the VEXAS cohort showed total IL-18 levels ranging from 145 pg / mL to 9,339 pg / mL, with a median of 1,719 pg / mL and a mean of 2,247 pg / mL. Total IL-18 concentrations in 73 serum samples from the VEXAS cohort are reported in Table 3.

[0169] Twenty-two of the 73 patients had very high total IL-18 levels (>3,000 pg / mL) and 49 had high levels (>1,000 pg / mL) (Figure 1).

[0170] Table 1. Distribution of total IL-18 levels within the VEXAS cohort TIFF2025507007000005.tif33128

[0171] Detectable levels of free IL-18 in the VEXAS cohort-64 The raw data of free IL-18 measurements in serum of the VEXAS cohort are reported in Table 4. Of the 73 samples measured, 64 samples showed eligible free IL-18 concentrations, i.e., acceptable variation between duplicate tests (CV<40%), and constitute the "VEXAS cohort-64" set of samples.

[0172] Serum samples from "VEXAS Cohort-64" showed free IL-18 levels ranging from 0.76 pg / mL to 21.03 pg / mL, with a median of 4.40 pg / mL and a mean of 5.80 pg / mL.

[0173] Fourteen of the 64 patients showed quantifiable levels of free IL-18 (>8.0 pg / mL) and 52 showed detectable levels (>2.7 pg / mL) (Figure 2).

[0174] Table 2 Distribution of free IL-18 levels in the VEXAS cohort-64 TIFF2025507007000006.tif33128

[0175] Correlation between free and total IL-18 levels Patients with the highest levels of total IL-18 are those who also have high levels of free IL-18. Evaluation of the correlation between these two parameters was performed on the "VEXAS Cohort-64" subgroup of patients. The calculated correlation coefficient (R 2 = 0.6392), indicating a positive linear correlation between the parameters of total and free IL-18 (Figure 3).

[0176] In patients with high levels of total IL-18, free IL-18 is abundant. Quantifiable levels of free IL-18 are found in 24% of patients with above-normal levels of total IL-18 (>300 g / mL), whereas this proportion reaches 57% in patients with very high levels of total IL-18 (>6,000 pg / mL). Similarly, the proportion of patients showing detectable levels of free IL-18 increases from 81% to 100% between patients with normal and very high levels of total IL-18 (Figure 4).

[0177] No concomitant increase in IL-18BP and total IL-18 levels Serum samples from the VEXAS cohort showed IL-18BP levels ranging from 20,077 pg / mL to 303,422 pg / mL, with a median of 50,018 pg / mL and a mean of 60,401 pg / mL. Raw data for IL-18BP measurements are reported in Table 5.

[0178] The calculated correlation coefficient (R 2 = 0.0607), indicating no correlation between the parameters of total IL-18 and IL-18BP (Figure 5).

[0179] Monitoring total IL-18 in serum of the VEXAS syndrome cohort reveals that all but seven measurements are above normal (>260 pg / mL). One-third of patients (22 of 73) have very high total IL-18 levels (>3,000 pg / mL) and two-thirds (49 of 73) have high levels (>1,000 pg / mL). This demonstrates that the autoinflammation adversely affecting these patients is related to induction of the IL-18 pathway.

[0180] Nearly a quarter of these patients (14 of 64) exhibit quantifiable levels of free IL-18 (>8.0 pg / mL) and 81% (52 of 64) exhibit detectable levels (>2.7 pg / mL). Moreover, increased levels of free IL-18 correlate with increased levels of total IL-18. Since free IL-18 is the active pathological form of IL-18, the detection of free IL-18 in the serum of the majority of these patients strongly suggests that the autoinflammation they suffer from is caused, at least in part, by an excessive elevation of IL-18 and the resulting appearance of free IL-18 species.

[0181] This inflammation is accompanied by elevated levels of IL-18BP, with all patients having above normal levels of IL-18BP (>2,000 pg / mL). However, IL-18BP levels do not correlate with total IL-18 levels, providing a molecular basis for the detection of free IL-18 species, i.e., the increased amount of IL-18BP relative to the amount of IL-18 is not sufficient to bind IL-18 and keep it in an inactive state, leading to the appearance of proinflammatory free IL-18 species.

[0182] These findings indicate a strong involvement of the IL-18 pathway in patients with VEXAS syndrome, and the lack of association between elevated total IL-18 and elevated IL-18BP supports a therapeutic approach consisting of exogenous provision of IL-18BP to help neutralize increased IL-18 activity and thus promote control of hyperinflammation.

[0183] Table 3: Total IL-18 concentration TIFF2025507007000007.tif22597

[0184] Table 4. Raw data for free IL-18 TIFF2025507007000008.tif232158TIFF2025507007000009.tif194158Free IL-18 levels were measured in duplicate from 73 patient samples and means were eligible if the coefficient of variation (CV) was <40%. Means obtained with a CV >40% (bold) are shown in italics and were excluded from the final set of 64 eligible values. Two samples showing significant free IL-18 levels (>6 pg / mL) but unacceptable CV were tested repeatedly. Free IL-18 levels are either not highlighted (<2.7 pg / mL), highlighted in light grey (2.7-8 pg / mL), or highlighted in dark grey (>8 pg / mL).

[0185] Table 5: Raw data of IL-18BP TIFF2025507007000010.tif230135TIFF2025507007000011.tif193135IL-18BP levels were measured in duplicate from 73 patient samples, and means were eligible if the coefficient of variation (CV) was less than 40%.

Claims

1. A composition comprising an IL-18 inhibitor for use in treating VEXAS syndrome or a symptom associated with VEXAS syndrome in a subject.

2. The composition of claim 1, wherein the symptoms associated with VEXAS syndrome are characterized by signs of autoinflammation, particularly signs of severe autoinflammation, and / or hyperinflammation, particularly hyperinflammation characterized by known inflammatory markers, particularly hyperinflammation characterized by elevated levels of known inflammatory markers such as CRP.

3. 2. The composition of claim 1, wherein the subject has one or more mutations in the UBA1 gene on the X chromosome, particularly at locus p11.

3.

4. 4. The composition of claim 3, wherein the mutation results in an alternative isoform of the UBA-1 gene product, in particular a shorter isoform.

5. 5. The composition of claim 4, wherein the mutation results in an M41T, M41V, or M41L substitution.

6. The composition of claim 1, wherein the treatment is achieved and / or supported by blocking the pro-inflammatory activity of IL-18.

7. The IL-18 inhibitor comprises: Any functional equivalent or functional portion of IL-18 binding protein (IL-18BP) that retains the ability to block the pro-inflammatory activity of IL-18.

2. The composition of claim 1, wherein the IL-18 binding protein (IL-18BP) comprises:

8. The IL-18 inhibitor is Any functional equivalent or functional portion of human IL-18BP (hIL-18 BP) that retains blocking of the pro-inflammatory activity of IL-18.

8. The composition of claim 7, wherein the human IL-18BP (hIL-18BP) comprises:

9. The IL-18 inhibitor is Any functional equivalent or functional portion of recombinant human IL-18BP (rhIL-18 BP) that retains the ability to block the pro-inflammatory activity of IL-18.

9. The composition of claim 8, wherein the recombinant human IL-18BP (rhIL-18BP) comprises:

10. 9. The composition of claim 8, wherein the human IL-18BP is selected from the following: Any functional equivalent or functional portion of isoforms a, b, c, and / or d that retain the ability to block the pro-inflammatory activity of IL-18. isoforms a, b, c, and d of human IL-18BP, in particular isoform a as shown in SEQ ID NO: 2, isoform b as shown in SEQ ID NO: 3, isoform c as shown in SEQ ID NO: 4, or isoform d as shown in SEQ ID NO:

5.

11. The IL-18 inhibitor comprises: Any functional equivalent or functional portion of IL-18BP as set forth in SEQ ID NO: 2 that retains the ability to block the pro-inflammatory activity of IL-18.

9. The composition of claim 8, wherein the IL-18BP is as set forth in SEQ ID NO: 2, comprising:

12. 12. The composition of claim 11, wherein the functional equivalent has 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to the sequence shown in SEQ ID NO: 2 and retains the ability to block the pro-inflammatory activity of IL-18.

13. said functional equivalent or functional portion being Muteins, fragments, peptides, functional derivatives, functional fragments, fractions, circularly permuted derivatives of IL-18BP, fusion proteins comprising IL-18BP, isoforms, or salts thereof, which retain the ability to block the pro-inflammatory activity of IL-18.

8. The composition of claim 7, comprising:

14. 8. The composition according to claim 7, comprising, in addition to the IL-18 binding protein (IL-18BP), an N-terminal and / or C-terminal deletion variant of IL-18BP in an amount of at most 40%, particularly at most 30%, particularly at most 20%, particularly at most 15%, particularly at most 10%, particularly at most 7.5%, particularly at most 5%, particularly at most 2.5%, particularly at most 1%, particularly at most 0.5%, particularly at most 0.25%, particularly at most 0.1%, particularly at most 0.05%, particularly at most 0.01%.

15. The composition of claim 14, wherein the deletion variant comprises a deletion of 1 to 5 amino acid residues at the C-terminus of the IL-18BP and / or a deletion of 1 to 30 amino acid residues at the N-terminus of the IL-18BP.

16. The composition according to claim 14, wherein the N-terminal and / or C-terminal deletion variant of IL-18BP is present in an amount of up to 40%, in particular in an amount of 2% to 35%.

17. 2. The composition of claim 1, wherein the bodily fluids and / or tissues of the subject to be treated have been quantified as having an abnormal level of free IL-18 using an assay capable of detecting free IL-18 in bodily fluids and / or tissues, wherein the abnormal level of free IL-18 is greater than the level of free IL-18 in the bodily fluids and / or tissues of a healthy control subject, in particular by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%.

18. 18. The composition of claim 17, wherein the subject to be treated has a level of free IL-18 greater than about 2.7 pg / ml, particularly greater than about 8 pg / ml, or the body fluids and / or body tissues of the subject to be treated have been quantified to have a level of free IL-18 greater than about 2.7 pg / ml, particularly greater than about 8 pg / ml.

19. The composition of claim 1, wherein the subject has an abnormally elevated level of total IL-18.

20. 20. The composition of claim 19, wherein IFN-γ-mediated IL-18BP induction is impaired.

21. 18. The composition of claim 17, wherein the level of total IL-18 is greater than about 250 pg / ml, particularly greater than about 1000 pg / ml, and more particularly greater than about 3000 pg / ml, or wherein the body fluids and / or body tissues of the subject to be treated are quantified as having a level of total IL-18 greater than about 250 pg / ml, particularly greater than about 1000 pg / ml, and more particularly greater than about 3000 pg / ml.

22. 18. The composition of claim 17, wherein the subject has a ferritin level of more than 400 ng / ml, preferably more than 1000 ng / ml, or the body fluids and / or body tissues of the subject to be treated have been quantified to have a ferritin level of more than 400 ng / ml, preferably more than 1000 ng / ml.

23. Quantifying the level of free IL-18 in said body fluids and / or body tissues comprises the steps of: (a) contacting a sample of body fluid and / or body tissue suspected of containing free IL-18 with an IL-18 inhibitor as defined in any one of claims 7 to 16 as a capture molecule for free IL-18; (b) binding the IL-18 inhibitor to free IL-18; (c) detecting binding of the IL-18 inhibitor and determining the amount of free IL-18 in the sample.

18. The composition of claim 17, comprising:

24. 18. The composition of claim 17, wherein the body fluid and / or body tissue 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, expired or exhaled breath, sputum, bronchoalveolar fluid, sebum, cells, glands, mucous membranes, bone marrow, or tissue secretions.

25. 10. A composition for use in treating VEXAS syndrome or a condition associated therewith, comprising an IL-18 inhibitor as defined in claim 7 and a pharmaceutically acceptable carrier and / or excipient.

26. 26. The composition of any one of claims 1-25, wherein the IL-18 inhibitor or composition is administered to a subject in need thereof in a single dose per day, multiple doses per day, multiple doses per week, or multiple doses per month.

27. 26. The composition of any one of claims 1 to 25, wherein the IL-18 inhibitor or composition is administered in 1 dose per week, 2 doses per week, 3 doses per week, 4 doses per week, 5 doses per week, 6 doses per week, in particular 7 doses per week, preferably 3 or 4 doses per week.

28. The composition of any one of claims 1 to 25, wherein the IL-18 inhibitor or composition is administered every 24 to 48 hours, preferably every 48 hours.

29. 26. The composition of any one of claims 1 to 25, wherein the IL-18 inhibitor or composition is administered in a single dose every other day, for example for 3 weeks.

30. 30. The composition of claim 29, 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 1.5 mg IL-18 inhibitor / kg body weight and 6 mg IL-18 inhibitor / kg body weight, particularly between 2 mg IL-18 inhibitor / kg body weight and 4 mg IL-18 inhibitor / kg body weight.

31. 26. The composition of any one of claims 1 to 25, 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 or 48 hours, in particular a single dose of 2 mg IL-18 inhibitor / kg body weight is administered every 48 hours.

32. The composition of any one of claims 1 to 25, wherein the subject to be treated is a mammal.

33. 33. The composition of claim 32, wherein the subject to be treated is a human.

34. 1. A composition comprising recombinant human IL-18BP (rhIL-18 BP), including any functional equivalent or functional portion thereof that retains the ability to block the pro-inflammatory activity of IL-18, for use in treating VEXAS syndrome or a condition associated therewith in a human, wherein the human has detectable levels of free IL-18, and in particular wherein the recombinant human IL-18BP (rhIL-18 BP) or a composition comprising the recombinant human IL-18BP (rhIL-18 BP) is administered to the human in a single dose of 2 mg / kg body weight every 48 hours.

35. 35. A composition comprising recombinant human IL-18BP (rhIL-18BP), including any functional equivalent or functional portion thereof, for use as described in claim 34, wherein human patients suffering from VEXAS syndrome or symptoms associated therewith exhibit uncontrolled systemic inflammatory responses and have abnormally elevated levels of total IL-18.

36. 36. A composition comprising recombinant human IL-18BP (rhIL-18BP), including any functional equivalent or functional portion thereof, for use as described in claim 35, wherein the level of free IL-18 in the body fluids or tissues of the human patient is greater than 2.7 pg / mL.

37. 37. A composition comprising recombinant human IL-18BP (rhIL-18BP), including any functional equivalent or functional part thereof, for use according to claim 36, wherein the level of total IL-18 is greater than about 250 pg / ml, particularly greater than about 1000 pg / ml, and more particularly greater than about 3000 pg / ml, or wherein the bodily fluids and / or bodily tissues of the subject to be treated have been quantified to have a level of total IL-18 greater than about 250 pg / ml, particularly greater than about 1000 pg / ml, and more particularly greater than about 3000 pg / ml.

38. 1. A composition comprising recombinant human IL-18BP (rhIL-18 BP) for use in treating VEXAS syndrome or a symptom associated therewith in a human, optionally a human with confirmed VEXAS syndrome and a human with a ferritin level of greater than 400 ng / mL, preferably greater than 1000 ng / mL, the composition comprising said recombinant human IL-18BP (rhIL-18 BP), including any functional equivalent or functional portion thereof that retains the ability to block the pro-inflammatory activity of IL-18.

39. 39. A composition comprising recombinant human IL-18BP (rhIL-18BP), including any functional equivalent or functional part thereof, for use according to claim 38, wherein the level of total IL-18 is greater than about 250 pg / ml, particularly greater than about 1000 pg / ml, and more particularly greater than about 3000 pg / ml, or wherein the bodily fluids and / or bodily tissues of the subject to be treated have been quantified to have a level of total IL-18 greater than about 250 pg / ml, particularly greater than about 1000 pg / ml, and more particularly greater than about 3000 pg / ml.

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