An antibody blocking IL-1 receptor accessory protein reduces cardiac inflammation and preserves heart function in viral and autoimmune myocarditis

Abstract IL-1, IL-33 and IL-36 have complementary pro-inflammatory roles during the immune response promoting autoimmune and inflammatory diseases, such as myocarditis. Therapeutic blockers targeting the IL-1 pathway have previously been developed. However, we hypothesized that blockade of the shared co-receptor of these three pathways, IL-1 receptor accessory protein (IL1RAP), would exhibit a more potent and broader anti-inflammatory profile. To investigate this hypothesis, we induced coxsackievirus B3 (CVB3)-mediated or experimental autoimmune myocarditis (EAM) in BALB/c mice, followed by treatment with mCAN10, an Fc-modified IL1RAP-blocking monoclonal antibody. IL1RAP blockade strongly reduced the severity of acute viral myocarditis when compared to isotype, saline or IL-1 receptor antagonist (IL1Ra) treatment (the gold standard of IL-1 receptor blockade), without affecting viral clearance from the heart. Spectral flow cytometry of heart immune populations showed that mCAN10 significantly reduced the infiltrating numbers of several populations, especially effector CD4 + and CD8 + T cells, inflammatory Ly6C + CCR2 + monocytes, neutrophils and eosinophils. Spatial gene expression revealed reduction in canonical inflammatory gene and pathway expression in the cardiac immune foci. This translated into protection from cardiac function deterioration and ejection fraction loss during viral and experimental autoimmune myocarditis. Altogether, our data show that a monoclonal antibody targeting 3 pro-inflammatory cytokine systems simultaneously, IL-1, IL-33 and IL-36, potently reduces viral and autoimmune myocarditis severity in a broad fashion not recapitulated by IL-1 blockade, and shows translational promise for development into therapeutics against cardiac inflammatory disease.