The novel bispecific anti-NLRP3 inflammasome antibody InflamAb inhibits atherosclerosis in apolipoprotein E-deficient mice

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation Background/Introduction Atherosclerosis is the underlying pathology of many cardiovascular diseases and is characterized by chronic inflammation in the larger arteries. Activation of the NLRP3 inflammasome is one of the drivers of inflammation during atherosclerosis. Purpose Therefore, we aimed to determine the ability of the novel bispecific anti-NLRP3 inflammasome antibody, called InflamAb, to inhibit atherosclerosis. Methods and Results In vitro treatment of bone marrow derived macrophages with 25 ng/mL InflamAb effectively inhibited the IL-1β release induced by NLRP3 inflammasome activation with LPS and Aluminium hydroxide (P<0.05). In addition, InflamAb administration in western-type diet fed Apoe-/- mice significantly reduced circulating IL-1β at 4 hours post inflammasome activation (P<0.05), thereby showing in vivo efficacy of InflamAb. Subsequently, we assessed the effect of InflamAb on both the development of atherosclerosis and on pre-existing plaques. Treatment of western-type diet fed female Apoe-/- mice with 100 µg InflamAb or isotype control antibody (3x per week i.p) significantly inhibited collar-induced atherosclerotic plaque development in the carotid artery from 59±8*10^3 µm^2 in control mice to 36±5*10^3 µm^2 (P<0.05), which coincided with a reduction in relative macrophage (control: 36±2% versus InflamAb: 28±3%, P<0.05) and necrotic core content (control: 16±2% versus InflamAb: 8±1%, P<0.05). InflamAb treatment of male Apoe-/- with pre-existing atherosclerosis did not affect lesion size, but improved plaque stability parameters as illustrated by a reduced relative macrophage (control: 48±2% versus InflamAb: 42±2%, P<0.05) and necrotic core (control: 21±1% versus InflamAb: 18±1%, P<0.05) content. In addition, we observed a trend towards increased collagen levels upon InflamAb treatment (control: 39±2% versus InflamAb: 44±2%, P=0.08). Conclusion To conclude, NLRP3 inflammasome inhibition by the bispecific antibody InflamAb shows promising efficacy in inhibiting atherosclerotic plaque development and destabilization.