Advancing the therapeutic potential of the IL‐1 family in inflammatory diseases – Meeting report

On October 9th 2018 the Trinity College Dublin hosted a workshop forum at the Royal Irish Academy to discuss recent discoveries and current areas of focus in the field of IL-1 family biology. The aim of this meeting was to further efforts to target the activity of these cytokines in human diseases. Researchers from both academic and pharmaceutical industry backgrounds shared their expertise and insights into the latest developments in what is a field of continued intense basic scientific discovery and emerging drug development. The early seminal discoveries of Dinarello and colleagues in identifying IL-1 as a soluble endogenous pyrogen can justifiably be cited as one of the defining moments in the genesis of the field of cytokine biology [1]. This work paved the way for subsequent discoveries of evolutionarily related cytokines which are now grouped into the broader IL-1 family consisting of seven agonist ligands (IL-1α/β, IL-18, IL-33 and IL-36α,β,γ) as well as three specific antagonists (IL-1Ra, IL-36Ra and IL-38) and a single antiinflammatory member (IL-37) [2]. IL-1 family cytokines have been shown to play centrally important, and sometimes instructive roles, in regulating the interface between innate and adaptive immunity [3]. Somewhat paradoxically, they have also been described as often playing dichotomous roles in driving both inflammation and resolution depending on the disease setting [4]. As a result, these cytokines, and in particular, the specific inflammatory responses which they mediate are an area of intense investigation across academic as well as pharmaceutical drug development perspectives. The rationale for targeting the IL-1 family in human disease is underpinned by the development of inflammatory states in humans suffering from rare monogenic autoinflammatory conditions with genetic defects leading to altered expression/ activity of IL-1 cytokines. Indeed, this is validated by the success of biologics to target IL-1, such as Anakinra, a recombinant IL-1 receptor antagonist that binds the IL-1 receptor to impede binding of IL-1β and IL-1α, in conditions known to be IL-1β mediated inflammatory processes [5]. Furthermore, given their apparent prominent roles in driving more common chronic inflammatory diseases, it seems likely that strategies aimed at inhibiting specific IL-1 family member activity may achieve more significant results. This is perhaps best exemplified by the recent CANTOS study, one of the largest phase III clinical trials ever established, investigating the efficacy of the monoclonal anti IL-1β antibody canakinumab,to prevent secondary cardiac events among cardiovascular disease patients [6]. The results of this trial have confirmed the contributory role for inflammation, through an IL-1β mediated process, as an important driving factor in the pathogenesis of atherosclerosis, a concept which has long been suggested through pre clinical studies, opening the door to new even more specific modes of therapeutic intervention among patients. Against this background, experts with a diverse perspective of IL-1 family biology in various disease settings gathered in Dublin to discuss the potential of targeting this family of cytokines across a range of inflammatory diseases. Specific topics addressed included the apparent dichotomous roles of the IL-1 family in intestinal inflammation and the role of IL-1 family members as mediators of skin inflammation in the settings of psoriasis and atopic dermatitis. Novel insights on the beneficial effects of modulating IL-1 family activity in age related diseases such Alzheimer’s disease and Age related Macular Degeneration were also discussed as were recent discoveries surrounding mechanisms which regulate IL-1 family activity, including negative regulatory pathways, cellular metabolism and endogenous protease activity. These findings were placed into translational context with an overview of the current drug development landscape in terms of active clinical programmes aimed at targeting IL-1 family members as well as insight into the complexities of efficient trial design to ensure optimal successful outcomes for patients.