Advances in Targeting IL-1 Family Cytokines for Inflammatory Disease Treatment
Key Insights
The IL-1 family of cytokines represents a critical therapeutic target across a broad spectrum of inflammatory diseases, with agents targeting IL-1, IL-18 (search), IL-33 (search), and IL-36 (search) showing clinical promise.
Canakinumab and anakinra have demonstrated efficacy in autoinflammatory syndromes including CAPS, systemic juvenile idiopathic arthritis (search), and adult-onset Still's disease (search), while newer agents like spesolimab target IL-36 (search) in generalized pustular psoriasis (search).
Bispecific antibodies such as MAS825, which targets both IL-1β (search) and IL-18 (search), represent an emerging therapeutic strategy for refractory macrophage activation syndrome (search) and severe Still's disease.
The interleukin-1 (IL-1) family of cytokines has emerged as a cornerstone of inflammatory disease pathogenesis, driving a rapidly expanding therapeutic landscape that spans autoinflammatory syndromes, rheumatic diseases, dermatologic conditions, and beyond. A comprehensive review published in Nature Reviews Rheumatology details the current state of IL-1 family biology and the clinical advances in targeting these pathways, highlighting both established therapies and novel agents in development.
The IL-1 family encompasses a diverse group of cytokines including IL-1α, IL-1β (search), IL-18 (search), IL-33 (search), IL-36 (search), IL-37, and IL-38, along with their respective receptors and endogenous antagonists. These cytokines orchestrate complex inflammatory cascades through inflammasome-dependent and independent mechanisms, with the NLRP3 (search) inflammasome serving as a central node in IL-1β and IL-18 activation.
IL-1 Blockade in Autoinflammatory Diseases
The clinical success of IL-1 inhibition is most firmly established in monogenic autoinflammatory diseases. Canakinumab, a monoclonal antibody targeting IL-1β (search), has demonstrated real-life effectiveness in cryopyrin-associated periodic syndrome (search) (CAPS), with studies showing sustained efficacy in neonatal-onset multisystem inflammatory disease over 24-month open-label treatment periods. In a landmark trial, canakinumab proved effective for the treatment of autoinflammatory recurrent fever syndromes including familial Mediterranean fever, mevalonate kinase deficiency, and TNF receptor-associated periodic syndrome.
Anakinra, a recombinant IL-1 receptor antagonist, has shown utility across multiple autoinflammatory conditions, including pyogenic arthritis in PAPA syndrome and acute calcium pyrophosphate deposition disease flares. A systematic review and meta-analysis confirmed the efficacy and safety of anakinra for acute CPPD flares.
The oral NLRP3 (search) inflammasome inhibitor dapansutrile represents a novel approach to IL-1 pathway blockade. In a proof-of-concept phase 2a trial for gout flares, dapansutrile demonstrated clinical benefit, offering an oral alternative to injectable biologics.
IL-18 (search): A Key Mediator in Still's Disease and Macrophage Activation Syndrome (search)
IL-18 (search) has emerged as a critical cytokine in adult-onset Still's disease (search) (AOSD) and systemic juvenile idiopathic arthritis (search) (sJIA). Elevated serum levels of free IL-18 have been shown to discriminate Still's disease from other autoinflammatory conditions, as demonstrated in the European ImmunAID cohort. Furthermore, IL-18 levels are associated with disease course in patients treated with IL-1 inhibitors.
Tadekinig alfa, a recombinant IL-18 (search) binding protein, was evaluated in an open-label, multicentre, dose-escalating phase II clinical trial in AOSD, showing safety and efficacy signals. The agent has also been used successfully in life-threatening NLRC4-associated hyperinflammation and XIAP deficiency.
A significant advance is the development of MAS825, a bispecific monoclonal antibody targeting both IL-1β (search) and IL-18 (search). Long-term efficacy of MAS825 has been reported in two patients with systemic JIA and recurrent episodes of macrophage activation syndrome (search), with sustained remission described in severe childhood Still's disease. This dual-targeting strategy addresses the intertwined roles of both cytokines in hyperinflammatory states.
IL-33 (search) and the ST2 Axis
IL-33 (search), a nuclear cytokine released upon cellular damage, signals through the ST2 receptor and has been implicated in rheumatoid arthritis, systemic sclerosis, and airway diseases. Elevated IL-33 levels have been detected in sera and synovial fluid from patients with active rheumatoid arthritis, with associations to autoantibody production and bone erosion.
Clinical development of IL-33 (search) pathway inhibitors has advanced in respiratory diseases. Tozorakimab, an anti-IL-33 monoclonal antibody, was studied in a phase 2a trial (FRONTIER-4) in patients with COPD. Astegolimab, an anti-ST2 monoclonal antibody, was evaluated in COPD-ST2OP, a phase 2a placebo-controlled trial, and in severe asthma. In dermatology, etokimab demonstrated proof-of-concept for IL-33 targeting in atopic dermatitis.
IL-36 (search) and Generalized Pustular Psoriasis (search)
The IL-36 (search) pathway has been firmly linked to generalized pustular psoriasis (search) (GPP), with loss-of-function mutations in the IL-36 receptor antagonist (IL-36RN) identified as a causative factor. Spesolimab, an anti-IL-36 receptor monoclonal antibody, was evaluated in a pivotal trial for GPP, leading to its approval. The Effisayil 2 trial demonstrated the efficacy and safety of subcutaneous spesolimab for the prevention of GPP flares in an international, multicentre, randomized, placebo-controlled study.
Imsidolimab, another anti-IL-36 (search) receptor monoclonal antibody, showed positive results in the phase II GALLOP trial for GPP. Beyond biologics, small molecule IL-36 receptor antagonists discovered through encoded library technologies represent a novel therapeutic modality, with selective low molecular weight antagonists showing promise in preclinical development.
Emerging Horizons
The therapeutic targeting of IL-1 family cytokines continues to evolve with several innovative approaches. Bispecific antibodies like MAS825 exemplify the potential of dual cytokine blockade. Small molecule inhibitors targeting the NLRP3 (search) inflammasome and IL-36 (search) receptor offer oral administration advantages. The development of IL-38-based therapies and the exploration of IL-37's proinflammatory form, which signals through the IL-36 receptor, represent additional frontiers.
The field is moving toward a systems-based classification of innate immune-mediated diseases, as proposed by Savic and colleagues, which may enable more precise targeting of specific cytokine pathways based on disease endotypes rather than clinical phenotypes alone.