Abstract P3061: A Monoclonal Antibody Blocking Interleukin-1 Receptor Accessory Protein Reduces Acute Viral Myocarditis Severity

IL-1, IL-33 and IL-36 have complementary, pro-inflammatory roles during the immune response that promote autoimmune diseases, particularly myocarditis. While antibodies that neutralize circulating cytokines exist, we hypothesized that blockade of their shared co-receptor, IL-1 receptor accessory protein (IL1RAP), would exhibit a more potent and broader anti-inflammatory profile. The CAN10 antibody blocks IL1RAP and is currently under development for treating severe autoimmune and inflammatory diseases. To investigate if IL1RAP blockade is an effective treatment of cardiac inflammation, we induced autoimmune viral myocarditis in 8-week-old Balb/c male mice with Coxsackievirus B3 and treated them with mCAN10, an anti-mouse IL1RAP monoclonal antibody. Mice were euthanized at day 10, the peak of acute inflammation in the heart. IL1RAP blockade reduced the severity of myocarditis at this timepoint when compared to isotype, saline or IL-1 receptor antagonist (IL1RA) treatment (the gold standard in IL-1 receptor blockade), without affecting viral clearance from the heart. Spectral flow cytometry of heart immune populations revealed that mCAN10 significantly reduced the number of infiltrating leukocytes of broad populations, especially effector CD4 + and CD8 + T cells, inflammatory Ly6C + CCR2 + monocytes, neutrophils and eosinophils. We also observed early echocardiographical parameters suggesting improved heart function, including ejection fraction, fractional shortening and interventricular septum diameter. Interestingly, mCAN10-treated mice demonstrated reduced proliferation of bone marrow precursors of inflammatory myeloid and lymphoid lineage leukocytes. Splenic immune cell populations were not affected, indicating that mCAN10 does not cause global immune suppression in these animals. Altogether, our data show that a single monoclonal antibody targeting three inflammatory cytokine systems, IL-1, IL-33 and IL-36, potently reduces acute viral myocarditis severity in a broader fashion that is not recapitulated by IL-1α/β blockade, and shows translational promise for therapeutics of inflammatory disease. Phase I clinical studies of the CAN10 antibody are in preparation.