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.