Il-18 binding molecules

Abstract

IL-18 participates in both innate and acquired immunity. The bioactivity of IL-18 is negatively regulated by the IL-18 binding protein (IL18BP), a naturally occurring and highly specific inhibitor. This soluble protein forms a complex with free IL-18 preventing its interaction with the IL-18 receptor, thus neutralizing and inhibiting its biological activity. The present invention discloses binding molecules, in particular antibodies or fragments thereof, which bind IL-18 and do not bind IL-18 bound to IL-18BP (IL-18/IL-18BP complex). Apart from its physiological role, IL-18 has been shown to mediate a variety of autoimmune and inflammatory diseases. The binding molecules of the inventions may be used as therapeutic molecules for treating IL-18-related autoimmune and inflammatory diseases or as diagnostic tools for characterizing, detecting and/or measuring IL-18 not bound to IL-18BP as component of the total IL-18 pool.

1 - 48 . (canceled) 
     
     
         49 . A method of treating and/or preventing sarcoidosis, hemophagocytic lymphohistiocytosis (HLH), familial hemophagocytic lymphohistiocytosis (FHL) and other immunodeficiency syndromes, Giant Cell Arthritis (GCA), chronic obstructive pulmonary disease (COPD), adult onset Still's Disease (AOSD), systemic juvenile idiopathic arthritis (SJIA), severe asthma, Uveitis, Geographic Atrophy, diabetes type 1, diabetes type 2 or atherosclerosis and any combination thereof in a mammalian patient which method comprises administrating to the mammalian patient a therapeutically effective amount of an isolated antibody or fragment thereof that specifically binds IL-18 comprising:
 i. a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 and   ii. a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4 or SEQ ID NO: 9 or SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 12 or SEQ ID NO: 13 and   iii. a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 and   iv. a light chain variable region L-CDR1 comprising SEQ ID NO: 6 and   v. a light chain variable region L-CDR2 comprising SEQ ID NO: 7 and   vi. a light chain variable region L-CDR3 comprising SEQ ID NO: 8.   
     
     
         50 . A method of treating and/or preventing sarcoidosis, hemophagocytic lymphohistiocytosis (HLH), familial hemophagocytic lymphohistiocytosis (FHL) and other immunodeficiency syndromes, Giant Cell Arthritis (GCA), chronic obstructive pulmonary disease (COPD), adult onset Still's Disease (AOSD), systemic juvenile idiopathic arthritis (SJIA), severe asthma, Uveitis, Geographic Atrophy, diabetes type 1, diabetes type 2 or atherosclerosis and any combination thereof in a mammalian patient which method comprises administrating to the mammalian patient a therapeutically effective amount of a pharmaceutical composition comprising an isolated antibody or fragment thereof that specifically binds IL-18 comprising:
 i. a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 and   ii. a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4 or SEQ ID NO: 9 or SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 12 or SEQ ID NO: 13 and   iii. a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 and   iv. a light chain variable region L-CDR1 comprising SEQ ID NO: 6 and   v. a light chain variable region L-CDR2 comprising SEQ ID NO: 7 and   vi. a light chain variable region L-CDR3 comprising SEQ ID NO: 8.   
     
     
         51 . The method according to  claim 49 , wherein the mammalian patient is a human patient. 
     
     
         52 . The method according to  claim 50 , wherein the mammalian patient is a human patient. 
     
     
         53 . A method for detecting and/or measuring the presence and/or amount of free IL-18 (i.e. IL-18 not bound to IL-18BP) in a sample, wherein the sample is optionally a human sample, wherein the method comprises contacting the sample with an isolated antibody or a fragment thereof that specifically binds IL-18 comprising:
 i. a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 and   ii. a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4 or SEQ ID NO: 9 or SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 12 or SEQ ID NO: 13 and   iii. a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 and   iv. a light chain variable region L-CDR1 comprising SEQ ID NO: 6 and   v. a light chain variable region L-CDR2 comprising SEQ ID NO: 7 and   vi. a light chain variable region L-CDR3 comprising SEQ ID NO: 8.   
     
     
         54 . The method according to  claim 53 , wherein the sample is blood, optionally human blood. 
     
     
         55 . A diagnostic kit comprising an isolated antibody or fragment thereof that specifically binds IL-18 comprising:
 i. a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 and   ii. a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4 or SEQ ID NO: 9 or SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 12 or SEQ ID NO: 13 and   iii. a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 and   iv. a light chain variable region L-CDR1 comprising SEQ ID NO: 6 and   v. a light chain variable region L-CDR2 comprising SEQ ID NO: 7 and   vi. a light chain variable region L-CDR3 comprising SEQ ID NO: 8, wherein the kit optionally comprises a first control compound.   
     
     
         56 . The diagnostic kit according to  claim 55  wherein the first control compound is free IL-18 and wherein the kit optionally comprises a second control compound wherein the second control compound is murine antibody 125-2H. 
     
     
         57 . A medical or diagnostic device comprising an isolated antibody or a fragment thereof that specifically binds IL-18 comprising:
 i. a heavy chain variable region H-CDR1 comprising SEQ ID NO: 3 and   ii. a heavy chain variable region H-CDR2 comprising SEQ ID NO: 4 or SEQ ID NO: 9 or SEQ ID NO: 10 or SEQ ID NO: 11 or SEQ ID NO: 12 or SEQ ID NO: 13 and   iii. a heavy chain variable region H-CDR3 comprising SEQ ID NO: 5 and   iv. a light chain variable region L-CDR1 comprising SEQ ID NO: 6 and   v. a light chain variable region L-CDR2 comprising SEQ ID NO: 7 and   vi. a light chain variable region L-CDR3 comprising SEQ ID NO: 8.   
     
     
         58 . The method of  claim 49  wherein the method comprises treating and/or preventing pulmonary sarcoidosis. 
     
     
         59 . The method of  claim 50  wherein the method comprises treating and/or preventing pulmonary sarcoidosis. 
     
     
         60 . The method of  claim 49 , wherein the antibody or fragment thereof comprises a heavy chain variable region H-CDR2 comprising SEQ ID NO: 9. 
     
     
         61 . The method of  claim 49 , wherein the antibody or fragment thereof comprises a heavy chain variable region H-CDR2 comprising SEQ ID NO: 13. 
     
     
         62 . The method of  claim 49 , wherein the isolated antibody or fragment comprises a light chain variable domain comprising SEQ ID NO: 16 or SEQ ID NO: 20. 
     
     
         63 . The method of  claim 49 , wherein the isolated antibody or fragment thereof comprises:
 i. a heavy chain variable domain comprising SEQ ID NO: 14 or SEQ ID NO: 22 or SEQ ID NO: 25 or SEQ ID NO: 28 or SEQ ID NO: 31 or SEQ ID NO: 34 and a light chain variable domain comprising SEQ ID NO: 16 or conservative variants thereof or   ii. a heavy chain variable domain comprising SEQ ID NO: 18 or SEQ ID NO: 37 or SEQ ID NO: 40 and a light chain variable domain comprising SEQ ID NO: 20.   
     
     
         64 . The method of  claim 49 , wherein the isolated antibody or fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO: 14 and a light chain variable domain comprising SEQ ID NO: 16. 
     
     
         65 . The method of  claim 49 , wherein the isolated antibody or fragment thereof amino acid lysine (Lys; K) in position 30 with reference to SEQ ID NO:14 is replaced by an amino acid selected from asparagine (Asn; N) or serine (Ser; S) or threonine (Thr; T) or alanine (Ala; A) or glutamate (Glu; E) or histidine (His; H) or leucine (Leu; L) or glutamine (Gln; Q) or arginine (Arg; R) or valine (Val; V) or tyrosine (Tyr; Y) or isoleucine (Ile; I). 
     
     
         66 . The method of  claim 63 , wherein the isolated antibody or fragment thereof comprises a heavy chain variable domain comprising SEQ ID NO: 18 and a light chain variable domain comprising SEQ ID NO: 20. 
     
     
         67 . The method of  claim 49 , wherein the isolated antibody comprises:
 i. a heavy chain comprising SEQ ID NO: 43 or SEQ ID NO: 47 or SEQ ID NO: 50 or SEQ ID NO: 56 and a light chain comprising of SEQ ID NO: 45 or   ii. a heavy chain comprising SEQ ID NO: 53 or SEQ ID NO: 100 or SEQ ID NO: 158 thereof and a light chain comprising SEQ ID NO: 160.   
     
     
         68 . The method of  claim 67 , wherein the isolated antibody comprises:
 i. a heavy chain comprising SEQ ID NO: 43 thereof and a light chain comprising of SEQ ID NO: 45 or   ii. a heavy chain comprising SEQ ID NO: 158 and a light chain comprising SEQ ID NO: 160.