NLRP3 Inflammasome Inhibition by the Novel Bispecific Antibody InflamAb Attenuates Atherosclerosis in Apolipoprotein E–Deficient Mice
Lucie Delfos, Marie A.C. Depuydt, Melody Chemaly, Sophie Coyle, Frank H. Schaftenaar, Peter J. van Santbrink, Pier Pieterszoon Lindenbergh, Mireia N. A. Bernabé Kleijn, C. Costello, Christopher Power, Rebecca C. Coll, Aaron Peace, Meredith Gregory‐Ksander, Amanda C. Foks, Johan Kuiper, Victoria McGilligan, Ilze Bot
Abstract
• We developed a novel bispecific antibody, InflamAb, designed to target the IL-1R1 for cell entrance and inhibit the intracellular NLRP3 inflammasome. • InflamAb potently inhibits NLRP3 inflammasome–induced IL-1β production in vitro in BMDMs. • InflamAb potently inhibits NLRP3 inflammasome–induced IL-1β production upon hyperlipidemia in vivo in Apoe -/- mice. • InflamAb inhibits atherosclerotic plaque development in Apoe -/- mice. • InflamAb enhances stabilization parameters of advanced plaques in Apoe -/- mice. The NLRP3 inflammasome contributes to the inflammatory process in atherosclerosis by producing IL-1β. Components of the intracellular NLRP3 inflammasome have been shown to be expressed by macrophages in the atherosclerotic plaque and are a potential therapeutic target. We aimed to determine the efficacy of the novel bispecific antibody InflamAb, designed to target the interleukin-1 receptor type 1 and the NLRP3 inflammasome, in inhibiting atherosclerosis. InflamAb effectively inhibited IL-1β secretion from bone marrow–derived macrophages and reduced circulating IL-1β levels in vivo. Furthermore, InflamAb treatment significantly inhibited atherosclerotic plaque development, accompanied by a reduction in relative macrophage and necrotic core content. InflamAb treatment did not affect the size of established atherosclerotic lesions; however, InflamAb significantly reduced relative macrophage and necrotic core content in these plaques. To conclude, inhibition of the NLRP3 inflammasome by the bispecific antibody InflamAb shows promising efficacy in inhibiting atherosclerotic plaque development and destabilization in Apoe -/- mice.