The NLRP3 inhibitor MCC950 inhibits IL-1β production in PBMC from 19 patients with Cryopyrin-Associated Periodic Syndrome and in 2 patients with Schnitzler’s Syndrome

<ns7:p><ns7:bold>Background: </ns7:bold>The cryopyrin-associated periodic syndromes (CAPS) are a group of inherited disorders associated with systemic auto-inflammation. CAPS result from gain-of-function mutations in NLRP3, which result in formation of an intracellular protein complex known as the NLRP3 inflammasome. This leads to overproduction of IL-1β and other pro-inflammatory signals, resulting in inflammatory symptoms. Treatments for NLRP3-related diseases are biologic agents that directly target IL-1β. We sought to determine if the orally available small molecule NLRP3 inhibitor MCC950 could inhibit IL-1β <ns7:italic>ex vivo</ns7:italic> in a cohort of patients with autoinflammatory disease.</ns7:p><ns7:p> <ns7:bold>Methods:</ns7:bold> Patients were recruited to donate blood, from which PBMCs were isolated and assayed in the presence of MCC950 to determine inhibitory efficacy.</ns7:p><ns7:p> <ns7:bold>Results:</ns7:bold> We found that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and mature IL-1β was higher in <ns7:italic>ex vivo</ns7:italic> PBMCs from CAPS patients than healthy donors. MCC950 inhibited production of mature IL-1β in PBMC from CAPS patients with a range of mutations and blocked NLRP3 activity in an <ns7:italic>in vitro </ns7:italic>mutation reconstitution assay. Similar results were observed with PBMC from two patients with Schnitzler’s Syndrome, another auto-inflammatory disease.</ns7:p><ns7:p> <ns7:bold>Conclusions: </ns7:bold>The NLRP3 inflammasome inhibitor MCC950 blocked constitutive activation of NLRP3 observed in the PBMCs of CAPS patients. This study highlights the potential utility of NLRP3 inhibition by a small molecule for rare autoinflammatory diseases that are driven by NLRP3.</ns7:p>