Abstract 12105: XOMA 052, a Monoclonal Antibody Targeting IL-1 Beta, Reduces Biomarkers of Atherosclerosis in vitro and Inhibits Atherosclerotic Plaque Formation in Apolipoprotein E-Deficient Mice
Recent clinical studies have underscored the interplay between inflammation and cardiovascular disease, but also suggest a need for safer and more powerful therapeutics. Atherosclerosis is a condition that is a major contributor to mortality worldwide through complications such as stroke and myocardial infarction. IL-1β plays multiple direct and local roles in the formation and stability of the atheroma by eliciting the production of additional cytokines and proteolytic enzymes from macrophages, endothelial cells (EC) and smooth muscle cells (SMC). We therefore tested whether anti-IL-1β beta antibody XOMA 052 might inhibit the secretion of pro-atherogenic cytokines from macrophages in vitro and affect a positive outcome in the Apolipoprotein E-deficient (ApoE−/−) model of atherosclerosis in vivo. In an in vitro co-culture model, XOMA 052 inhibited macrophage-induced secretion of key atherogenic cytokines from EC and SMC, including IL-6, IL-8, MCP-1 and TNFα. The release of degradative enzymes, such as the matrix metalloproteinases MMP-3 and MMP-9, was also decreased by XOMA 052. In addition, XOMA 052 inhibited the secretion of IL-7 from EC and IL-4 from SMC, cytokines previously unreported to be driven by IL-1β in this context. In vivo, XMA052 MG1K, a murine chimeric equivalent to XOMA 052, inhibited the formation of atherosclerotic lesions in the ApoE−/− model at all three doses tested. This effect was associated with decreases in lipid content and macrophage infiltration within atherosclerotic plaques. These results demonstrate for the first time that an antibody targeting IL-1β can inhibit the progression of atherosclerosis in vivo, highlighting the importance of this key cytokine in cardiovascular disease.
- © 2010 by American Heart Association, Inc.