Molecular construction and optimization of anti-human IL-1α/β dual variable domain immunoglobulin (DVD-IgTM) molecules

Signal transduction through the interleukin-1 receptor (IL-1R) pathway mediates a strong pro-inflammatory response, which contributes to a number of human diseases such as rheumatoid arthritis.  Within the IL-1 family, IL-1α and IL-1β are both agonistic ligands for IL-1R, whereas IL-1 receptor antagonist (IL-1ra) is an endogenous antagonist that binds to IL-R, but does not signal.  Therefore, the ideal therapeutic strategy would be blocking both IL-1α and IL-1β, but not IL-1ra.  However, due to low sequence homology between the three members of the family, it has been exceedingly difficult to identify potent therapeutic agents, e.g., monoclonal antibodies (mAbs), that selectively recognize both IL-1α and IL-1β, but not IL-1ra.  Currently, several anti-IL-1 therapeutic agents in clinical development either inhibit only IL-1β (i.e. anti-IL-1β mAb), or recognize all three ligands (i.e. anti-IL-1R mAb or IL-1R Trap).  We have recently developed a novel dual variable domain immunoglobulin (or DVD-IgTM) technol...