Detailed Mechanistic Analysis Of Gevokizumab, An Allosteric Anti-Il-1 Beta Antibody With Differential Receptor-Modulating Properties

Interleukin-1 beta (IL-1 beta) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1 beta activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1 beta antibody being developed as a treatment for diseases in which IL-1 beta has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1 beta signaling through an allosteric mechanism. Because IL-1 beta signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1 beta signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1 beta system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1 beta for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL1 receptor type II). Gevokizumab inhibits both the binding of IL-1 beta to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1 beta to its receptor by altering the electrostatic surface potential of IL-1 beta, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1 beta signaling that may offer an alternative to current therapies for IL-1 beta-associated autoinflammatory diseases.