Inflammasomes are multi-protein structures of the innate immune system, responsible for the activation of inflammatory responses. Activation and assembly of inflammasomes promotes maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as  Gasdermin-D, which induces pyroptosis, a pro-inflammatory form of programmed cell death and is responsible for secretion of the mature cytokines, through the formation of pores in the plasma membrane.

Inflammasome activation is initiated by different pattern recognition receptors (PRRs) that respond to either microbe-derived pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) generated by the host cell.

To date, most anti-inflammatory therapeutics have either aimed to broadly dampen down the inflammatory response (e.g. cortico-steroids), or selectively inhibit specific mediators of inflammation such as the cytokines TNFα and IL-1β. Both approaches have brought significant benefit to patients, but are either accompanied by tolerability issues due to effects on metabolic processes, show limited efficacy, or only offer benefits in certain patient populations. With all current approaches, patients are at risk of infections.

Increasing understanding of inflammasome biology, particularly of the NLRP3 inflammasome, has opened opportunities for next generation therapeutics delivering improved efficacy, with a better safety and tolerability profile. As the molecular mechanisms which lead to the assembly and activation of NLRP3 inflammasomes have become known, possibilities for selectively targeting this pathway have emerged.

NLRP3 inflammasome inhibitors promise anti-inflammatory efficacy without the metabolic adverse effects of corticosteroids and with improved efficacy compared to single cytokine inhibitor antibodies, such as anti-TNF alpha and anti-IL1 beta. NLRP3 inflammasomes are one of several types of inflammasome that respond to infectious and sterile danger signals. Selective inhibition of NLRP3 inflammasomes leaves other inflammasomes and immune pathways free to deal with pathogen-induced infections.

Apaxen’s unique approach to inhibiting NLRP3 inflammasome activation with MFC-1040, by targeting the interaction of intracellular MIF and NLRP3 units to block NLRP3 inflammasome construction and activation (Harris et al. Nature Comms 2020) has been shown to be highly effective in in-vitro and in-vivo models of disease .

SPECIFIC BENEFITS OF TARGETING MIF/NLRP3

MIF appears to play a unique role in regulating steroid biology. In contrast to other  cytokines, steroids stimulate rather than inhibit the release of MIF. MIF then reduces the effect of steroids, further exacerbating the effect. Overall,  this suggests that MIF plays a role in the development of steroid resistance. Clinically, blocking this aspect of MIF biology could therefore result in reduced corticosteroid dosing and reversal of steroid resistance for the many patients that depend on corticosteroid therapy for treatment of their inflammatory or auto-immune disease.

Macrophage migration inhibitory factor (MIF) is inked to many inflammatory diseases (Drug Discovery Today 2019, 24, 428-439) where NLRP3 inflammasomes are also involved.