Background/Purpose: Interleukin 1 receptor accessory protein (IL1RAP) serves as a co-receptor that forms receptor complexes with IL1R1, ST2, and IL36R and mediates signaling pathways triggered by IL1α/β, IL33, and IL36α/β/γ, which implicated in several autoimmune or inflammatory diseases, such as gout, psoriasis, and systemic sclerosis. IBI3011 is a fully humanized IgG1-LALA antibody targeting the extracellular segment of IL1RAP, blocks IL1α/β, IL33, and IL36α/β/γ signaling pathways and without ADCC. IBI3011 has shown potent anti-inflammatory properties in several preclinical models and is currently under development for treatment of gout and auto-inflammatory diseases.

Methods: We evaluated the binding affinity of IBI3011 with human, cynomolgus monkey and mouse IL1RAP in protein level by Biosensor Layer Interferometry (BLI), and in cellular level by flow cytometry. The blocking activity of IBI3011 was evaluated via ELISA to quantify target cell activation in vitro. Human peripheral blood mononuclear cells (PBMCs) were stimulated with IL1α/β, IL33, or IL36α, respectively, and the secreted inflammatory cytokines were detected. The in vivo efficacy of IBI3011 was evaluated in humanized IL1RAP knock-in mice with MSU induced gout and collagen antibody-induced arthritis (CAIA) models. In both studies, mice were treated with IBI3011 or control reagent in a therapeutic fashion, and the blockade efficacy were analyzed by footpad thickness and/or inflammatory cytokines level in footpad tissue.

Results: IBI3011 showed high binding affinity with human and cynomolgus monkey IL1RAP at protein and cellular levels, but not with mouse IL1RAP. For in vitro function assay, IBI3011 blocked the inflammatory cytokines TNFα, IFNγ secretion from PBMC when stimulated with IL1α/β, IL33, and IL36α/β/γ. In the acute gout model, IBI3011 demonstrated a dose-dependent inhibition of the gout development in hIL1RAP mice compared to controls, as 10 mg/kg and 20 mg/kg of IBI3011 significantly reduced the thickness and inflammation of the footpad tissues. In the rheumatoid arthritis model, IBI3011 dose-dependently reduced the ankle joint thickness and inhibited the inflammation in joint. The 3 mg/kg and 10 mg/kg dosage groups exhibited significant inhibitory effect on the arthritic joint redness and inflammatory response in mice, while the lower dose of 1 mg/kg showed no significant inhibition, suggesting that IBI3011 can dose-dependently inhibit the initiation of rheumatoid arthritis in the preclinical model.

Conclusion: The in vitro study has shown that IBI3011 inhibits the activation of IL1, IL33, and IL36 signaling pathway effectively through blocking the co-receptor IL1RAP. The preclinical mouse models have demonstrated that IBI3011 exerts a dose-dependent anti-inflammatory effect. These preclinical results underscore the potential of IBI3011 as a therapeutic candidate for autoimmune and inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ibi3011-a-humanized-anti-il1rap-monoclonal-antibody-inhibits-il1-il33-il36-driven-inflammation-pathway-and-attenuates-inflammation-in-preclinical-inflammatory-disease-model/