Abstract

The IL1 receptor accessory protein (IL1RAP) is a coreceptor for the IL1, IL33, and IL36 receptors. We have developed a fully humanized antibody (CAN10) that binds IL1RAP with high affinity and disrupts IL1α, IL1β, IL33, IL36α, IL36β and IL36γ signaling without inducing ADCC. CAN10 is currently undergoing preclinical development in preparation for clinical studies.

The efficacy of IL1RAP-blockade as an anti-inflammatory treatment was investigated in a mouse model of acute peritonitis (i.p injection of MSU crystals). A CAN10 surrogate (mCAN10) decreased the recruitment of neutrophils and monocytes to the peritoneum as well as the production of e.g IL6 and KC. Blocking only IL1α/β had similar effects but notably, mCAN10 also induced additional anti-inflammatory responses including reductions in e.g IL5 and eotaxin. In addition, mCAN10, but not anti-IL1β, reduced skin inflammation in a mouse model of psoriasis. Taken together, these results indicate that blocking IL1RAP is a potent anti-inflammatory strategy that is qualitatively different from blocking IL1α/β alone.

IL1, IL33 and IL36 may have disease promoting roles in myocarditis, an inflammatory heart disease with no available treatment. Therefore, we investigated if IL1RAP blockade can counteract inflammation and decline in heart function in a model of autoimmune myocarditis (EAM). EAM was induced by immunizing Balb/C mice with αMHC peptide on day 0 and 7. Treatment with mCAN10 or isotype control started day 7 and heart function was analyzed by echocardiography at days 0, 28 and 42. Interestingly, anti-inflammatory treatment with mCAN10 potently counteracted the decline in heart function. These studies highlight the potential of blocking IL1RAP to treat inflammatory diseases.

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