NLRP3 Inflammasome inhibition by the novel bispecific antibody InflamAb attenuates atherosclerosis in apolipoprotein E-deficient mice

Background: Cardiovascular disease remains the most common cause of mortality worldwide, which is attributable to the underlying chronic inflammatory condition atherosclerosis. The NLRP3 inflammasome contributes to this 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 target for intervention.

Objectives: Here, 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.

Methods: We established the efficacy of InflamAb to inhibit IL-1β production upon NLRP3 inflammasome activation in bone marrow derived macrophages and in Western-type diet fed Apoe-/- mice. Subsequently, we treated Apoe-/- mice with developing collar-induced atherosclerosis and Apoe-/- mice with established atherosclerotic plaques with InflamAb.

Results: InflamAb inhibited IL-1β secretion from bone marrow derived macrophages and circulating IL-1β levels in vivo, upon NLRP3 inflammasome activation. Furthermore, InflamAb treatment significantly inhibited atherosclerotic plaque development, which was accompanied by a reduction in relative macrophage and necrotic core content. Established atherosclerotic lesion size in the aortic root was not affected by InflamAb treatment, however, InflamAb significantly reduced relative macrophage and necrotic core content in these plaques.

Conclusions: In conclusion, inhibition of the NLRP3 inflammasome by the bispecific antibody InflamAb shows promising efficacy in inhibiting atherosclerotic plaque development and destabilization in mice.