Session Information
Date: Sunday, November 17, 2024
Title: Innate Immunity Poster
Session Type: Poster Session B
Session Time: 10:30AM-12:30PM
Background/Purpose: Despite advances in treatment, chronic inflammatory diseases such as rheumatoid arthritis (RA) represent areas of high unmet medical need. IRAK4 is a proximal mediator of TLR and IL-1R family signaling and has emerged as a therapeutic target in multiple chronic inflammatory diseases. Due to the dual functions of IRAK4 as (A) a serine/threonine kinase and (B) as the key scaffolding component of the Myddosome, kinase inhibition alone is insufficient for full blockade of TLR/IL-1R signaling in certain cellular contexts1. In contrast, targeted protein degradation of IRAK4 nullifies both kinase and scaffolding functions, thus fully inhibiting the pro-inflammatory outputs of TLR and IL-1R engagement in immune and non-immune cell types. Here, we report that IRAK4 degradation by GS-6791 inhibits TLR- and IL-1R-driven responses in vitro and in vivo across a range of cell types and achieves robust efficacy in a preclinical arthritis model.
Methods: IRAK4 protein levels and TLR- or IL-1R-induced cytokine production were measured in cells treated with GS-6791 or control inhibitors, by flow cytometry or ELISA. In vivo IRAK4 degradation was assessed in rodents (using Western blot or mass spectrometry) and non-human primates (NHP, using flow cytometry) after oral dosing with GS-6791. Pharmacodynamic effects of IRAK4 degradation on pro-inflammatory cytokine production in plasma were assessed in mice challenged with TLR ligand or IL-1b. The effect of IRAK4 degradation on joint swelling and pathology was assessed in an 18-day rat collagen-induced arthritis (CIA) model.
Results: GS-6791 demonstrated potent IRAK4 degradation and inhibited R848, CpG, and LPS-induced cytokine secretion in human PBMCs, as well as human and NHP whole blood, and mouse splenocytes. Importantly, IRAK4 degradation resulted in deeper inhibition of TLR9 and IL-1b-driven responses in human B cells and rheumatoid-arthritis synovial fibroblasts, respectively, compared to IRAK4 kinase inhibition. Oral administration of the degrader achieved >90% IRAK4 degradation in rodents, resulting in dose-dependent reduction of induced plasma cytokines following acute challenge with CpG or IL-1β. Robust IRAK4 degradation was similarly achieved in NHP (PBMC, >85%) at a daily oral dose of 6 mg/kg. Importantly, IRAK4 degradation ameliorated disease in a rat CIA efficacy model, effectuating dose-dependent reduction of ankle swelling and comparable reduction of joint pathology to a dexamethasone-treated control group.
Conclusion: IRAK4 protein degradation by GS-6791 inhibited in vitro TLR and IL-1R-mediated cellular responses, with a differentiated profile from IRAK4 kinase inhibition in human B cells and RA synovial fibroblasts. Similarly, GS-6791 robustly inhibited pro-inflammatory signaling in vivo, triggered by both TLR ligands and IL-1-family cytokines. The striking efficacy of GS-6791 in a preclinical arthritis model supports the use of this treatment modality in RA and supports further evaluation in other TLR- or IL-1R-driven inflammatory indications.
1. DeNardo et al. JBC 2018 (DOI 10.1074/jbc.RA118.003314)
To cite this abstract in AMA style:
Teng G, Fung T, Mocciaro A, Llapashtica C, Hammond A, Gurgel J, Huang z, Mouchess M, Gorney V, Minto W, Mohanan S, Schrier A, Palmer W, Borodovsky A, Min-oo G. IRAK4 Degrader GS-6791 Inhibits TLR and IL-1R-Driven Inflammatory Signaling, and Ameliorates Disease in a Preclinical Arthritis Model [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/irak4-degrader-gs-6791-inhibits-tlr-and-il-1r-driven-inflammatory-signaling-and-ameliorates-disease-in-a-preclinical-arthritis-model/. Accessed .« Back to ACR Convergence 2024
ACR Meeting Abstracts - https://acrabstracts.org/abstract/irak4-degrader-gs-6791-inhibits-tlr-and-il-1r-driven-inflammatory-signaling-and-ameliorates-disease-in-a-preclinical-arthritis-model/