Interleukin-18 binding proteins, their preparation and use for the treatment of sepsis

Abstract

The present invention provides a method of treatment or prevention of sepsis and other diseases characteristic to the Systemic Inflammatory Response Syndrome (SIRS), including severe sepsis, septic shock, and sepsis related to cardiac dysfunction.

1 . A method for treatment and/or prevention of a sepsis and other diseases characteristic to the Systemic Inflammatory Response Syndrome (SIRS) comprising administering to a subject in need thereof a pharmaceutically effective amount of an inhibitor of IL-18 selected from a group consisting of caspase-1 (ICE) inhibitors, antibodies against IL-18, antibodies against any of the IL-18 receptor subunits, inhibitors of the IL-18 signaling pathway, antagonists of IL-18 which compete with IL-18 and block the IL-18 receptor, and inhibitors of IL-18 production, and a pharmaceutically acceptable carrier. 
     
     
         2 . The method according to  claim 1 , further comprising administering a therapeutically effective amount of an IL-12 inhibitor. 
     
     
         3 . The method according to  claim 1 , further comprising administering a cytokine inhibitor selected from a group consisting of a Tumor Necrosis Factor (TNF) inhibitor, an IL-1 inhibitor and an IL-8 inhibitor. 
     
     
         4 . The method according to  claim 2 , further comprising administering a cytokine inhibitor selected from a group consisting of a Tumor Necrosis Factor (TNF) inhibitor, an IL-1 inhibitor and an IL-8 inhibitor. 
     
     
         5 . The method according to  claim 3 , wherein the TNF inhibitor is a soluble portion of TNFRI or TNFRII. 
     
     
         6 . The method according to  claim 1 , wherein the method further comprises administering an interferon. 
     
     
         7 . The method according to  claim 2 , wherein the method further comprises administering an interferon. 
     
     
         8 . The method according to  claim 3 , wherein the method further comprises administering an interferon. 
     
     
         9 . A method according to  claim 6 , wherein the interferon is interferon-α or interferon-β. 
     
     
         10 . A method for the treatment and/or prevention of sepsis and other diseases characteristic to the Systemic Inflammatory Response Syndrome (SIRS) comprising administering to a subject in need thereof a pharmaceutically effective amount of a vector coding the sequence of an inhibitor of IL-18 selected from a group consisting of caspase-1 (ICE) inhibitors, antibodies against IL-18, antibodies against any of the IL-18 receptor subunits, inhibitors of the IL-18 signaling pathway, antagonists of IL-18 which compete with IL-18 and block the IL-18 receptor, inhibitors of IL-18 production, and IL-18 binding proteins, isoforms, muteins, fused proteins or circularly permutated derivatives thereof and a pharmaceutically acceptable carrier. 
     
     
         11 . A method for the treatment and/or prevention of sepsis and other diseases characteristic to the Systemic Inflammatory Response Syndrome (SIRS) comprising administering to a subject in need thereof a pharmaceutically effective amount of
 i) a vector for inducing and/or enhancing the endogenous production of an inhibitor of IL-18 in a cell or   ii) a cell that has been genetically modified to produce an inhibitor of IL-18.   
     
     
         12 . The method according to  claim 1 , wherein the sepsis is related to cardiac dysfunction. 
     
     
         13 . The method according to  claim 10 , wherein the fused protein comprises an Ig fusion. 
     
     
         14 . The method according to  claim 1 , wherein the inhibitor of IL-18 is an anti IL-18 specific antibody selected from chimeric, humanized and human antibodies. 
     
     
         15 . The method according to  claim 2 , wherein the IL-12 inhibitor is a neutralizing antibody.