Anti-IL-1 agents
There are at least 8 clinical trials on pharmacological strategies specifically aimed to target the main product of NLRP3 inflammasome activation, the cytokine IL-1β. They include studies on the human anti-IL-1β monoclonal antibody Canakinumab (ClinicalTrials.gov identifier: NCT04362813, NCT04365153, NCT04348448) and the recombinant non-glycosylated human IL-1 receptor antagonist Anakinra (NCT04324021, NCT04330638, NCT0432402, NCT04357366 and NCT04339712). Besides, several other clinical trials are evaluating the effects of drugs targeting IL-6, whose serum concentration are drastically increased in patients with NLRP3 inflammasome-mediated condition (Abbate, Toldo, Marchetti, Kron, Van Tassell & Dinarello, 2020). A cross-talk mechanism linking IL-1β to IL-6 has been documented. IL-1β induces IL-6 gene transcriptionvia a PI-3-kinase/AKT-dependent pathways (Cahill & Rogers, 2008) and, at the same time, blockade of IL-6 signalling blunts the activation of NLRP3 inflammasome (Powell et al., 2015; Wu et al., 2018). Thus, drugs able to interfere with IL-6 receptor activation may inhibit NLRP3-dependent IL-1β release and, in a similar way, anti-IL-1β strategies significantly reduce IL-6 release, with an effective control of the cytokine-storm. Several clinical trials have been approved to test the efficacy of Sarilumab (NCT04315298 and NCT04327388, EudraCT identifier: 2020-001162-12 and 2020-001390-76) and Tocilicizumab (ChinaXiv identifier: 202003.00026 and 20000.30894), two humanized monoclonal antibodies against the IL-6 receptor, thus confirming that targeting cellular machineries leading to cytokine overproduction, such as the NLRP3 inflammasome, holds promise for COVID-19 therapy.