IL-18 Binding Protein (IL-18BP) In Inflammatory Diseases

Abstract

The present invention provides means and methods for treating Interleukin 18 (IL-18)-associated diseases and disorders. In particular, the present invention discloses antibodies specific for free IL-18 and IL-18 Binding Protein (IL-18BP) for use in such treatments and for the diagnosis of the indications.

1 . A method of reducing the level of free IL-18 in a subject, the method comprising administering to the subject a therapeutically effective amount of an IL-18 inhibitor, wherein the IL-18 inhibitor is an IL-18 binding protein (IL-18BP). 
     
     
         2 . The method of  claim 1 , wherein the subject has detectable levels of free IL-18. 
     
     
         3 . The method of  claim 2 , wherein the detectable level of free IL-18 is between 5 to 10,000 pg/mL. 
     
     
         4 . The method of  claim 1 , wherein the subject has abnormal levels of free IL-18 and/or an abnormal ratio of free IL-18/IL-18 binding protein (IL-18BP) in the body fluids compared to the levels in the body fluids of a healthy control subject. 
     
     
         5 . The method of  claim 4 , wherein the abnormal level of free IL-18 in the body fluids exceeds the level in body fluids of a healthy control subject by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%. 
     
     
         6 . The method of  claim 5 , wherein the abnormal levels of free-IL-18 are ≥5 pg/mL. 
     
     
         7 . The method of  claim 5 , wherein the body fluid is serum. 
     
     
         8 . The method of  claim 1 , wherein the administration of the IL-18 inhibitor leads to inhibition of increased expression of IFNg, IL-13, or IL-17A in the subject as compared to an untreated subject. 
     
     
         9 . The method of  claim 1 , wherein the IL-18BP is a human IL-18BP (hIL-18BP). 
     
     
         10 . The method of  claim 9 , wherein the hIL-18BP is a recombinant IL-18BP. 
     
     
         11 . The method of  claim 1 , wherein the IL-18BP is an isoform of IL-18BP. 
     
     
         12 . The method of  claim 1 , wherein the IL-18BP comprises the amino acid sequence of SEQ ID NO:7 or a functional variant thereof. 
     
     
         13 . The method of  claim 1 , wherein the subject is diagnosed with having abnormal levels of free IL-18 and/or an abnormal ratio of free IL-18/IL-18 binding protein (IL-18BP) in the body fluids compared to the levels in the body fluids of a healthy control subject, wherein the level of free IL-18 in the body fluids of the subject has been determined by an immunoassay. 
     
     
         14 . The method of  claim 13 , wherein the immunoassay comprises an IL-18BP as a capturing molecule. 
     
     
         15 . The method of  claim 14 , wherein the IL-18BP is a human IL-18BP (hIL-18BP). 
     
     
         16 . The method of  claim 15 , wherein the hIL-18BP is a recombinant hIL-18BP. 
     
     
         17 . The method of  claim 14 , wherein the IL-18BP is an isoform of IL-18BP. 
     
     
         18 . The method of  claim 13 , wherein the IL-18BP comprises the amino acid sequence of SEQ ID NO: 7 or a functional variant thereof. 
     
     
         19 . The method of  claim 13 , wherein the abnormal levels of free IL-18 and/or abnormal ratio of free IL-18/IL-18BP in the body fluids compared to the levels in the body fluids of a healthy control subject have been determined by a method comprising the steps of:
 a) bringing a sample or a specific body part or body area suspected to contain free IL-18 into contact with an IL-18 binding molecule, which specifically binds to free IL-18, but not to IL-18 bound in a complex;   b) allowing the IL-18 binding molecule to bind to free IL-18;   c) detecting the binding of IL-18 to the IL-18 binding molecule and determining the amount of free IL-18 and/or the ratio of free IL-18/IL-18BP in the sample.   
     
     
         20 . The method of  claim 13 , wherein the abnormal level of free IL-18 in the body fluids exceeds the level in body fluids of a healthy control subject by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%. 
     
     
         21 . The method of  claim 1 , wherein the subject has an IL-18 associated disease or disorder. 
     
     
         22 . The method of  claim 21 , wherein the IL-18 associated disease or disorder is selected from the group consisting of chronic obstructive pulmonary disease (COPD), transfusion-related lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), Adult Still's disease, juvenile Still's disease, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension, asthma, bronchiectasis, heart failure, amyotrophic lateral sclerosis (ALS), dry eye disease (DED), keratitis, corneal ulcer and abrasion, corneal neovascularization, pathological intraocular neovascularization, iritis, glaucoma, macular degeneration, Sjögren's syndrome, autoimmune uveitis, Behçet's disease, conjunctivitis, allergic conjunctivitis, dermatitis of eyelid, diabetes type 2, non-alcoholic fatty liver disease (NAFLD), steato hepatitis, solid organ and hematologic transplantation, ischemia reperfusion injury, familial Mediterranean fever, tumor necrosis factor receptor 1-associated periodic syndromes, cryopyrin-associated periodic fever syndromes, hyper-IgD syndromes, gout, Schnitzler syndrome, Wegener's granulomatosis also called granulomatosis with polyangitis (GPA), Hashimoto's thyroiditis, Crohn's disease, ulcerative colitis, immunoglobulin-4 (IgG4)-related diseases and stem cell therapies; or wherein the IL-18 associated disease or disorder is induced by smoking or second-hand smoke exposure, viral infection, or is an IL-18 induced systemic manifestation of inflammation and associated comorbidities.