Background/Purpose: IRF5, an undrugged transcription factor, is an autoimmune susceptibility gene that has been linked to RA and other autoimmune diseases including SLE, Sjögren’s, and SSc. IRF5 is a regulator of immune responses activated downstream of pattern recognition receptors, like toll-like receptors (TLR). IRF5 regulates pro-inflammatory cytokines (TNFα, IL-6, IL-12, IL-23), autoantibody production and Type I IFN. IRF5 is selectively expressed and activated in specific cell types such as dendritic cells, monocytes, M1 macrophages, and B cells. RA is a chronic disease where the target tissue is synovial joints. The joints are characterized by heavy leukocyte infiltration. Inflamed synovium contains a larger number of activated macrophages and T cells in addition to B cells and dendritic cells. Studies in IRF5 deficient mice show attenuated arthritis severity in models of RA. Despite its strong mechanistic and genetic validation, IRF5 has historically remained undrugged likely due to its activation complexity and multiple functional isoforms. IRF5 is well suited for targeted protein degradation, where a single binding event drives activity. KT-579, an oral IRF5 degrader, has demonstrated potent and selective activity in preclinical in vitro myeloid assays and in vivo RA models, offering a new approach to modulating this key driver of immunity.

Methods: THP-1 monocytic cell line or peripheral blood mononuclear cells, monocytes, M1 macrophages, and dendritic cells were cultured with KT-579 in the presence or absence of TLR4, TLR7, or TLR8 stimulation and measured for pro-inflammatory cytokines including TNFα, IL-6, IL-12, IL-23, IFN𝛾 and IL-1β. KT-579 was tested in the antigen-induced arthritis (AIA) mouse model of RA and compared to the JAK inhibitor, tofacitinib.

Results: KT-579 was highly selective for IRF5 in the detectable proteome, including other IRF family proteins. In vitro, KT-579 demonstrated nanomolar inhibition of IL-1𝛽, TNFα, IL-12, IL-23 and IFN𝛾, in a cell-type and stimulant-dependent manner, downstream of TLR activation. In the AIA model of RA, daily oral dosing with KT-579, achieved ~90% degradation of IRF5 and led to significant reduction in joint swelling comparable to tofacitinib. IRF5 degradation led to reduction of circulating pro-inflammatory cytokines including IL-12, IL-6 and CXCL1 and infiltrating Th1 T cells, that was differentiated from tofacitinib. In addition, KT-579 achieved deep IRF5 depletion (≥90%) across multiple species with low oral doses, and did not show adverse effects at concentrations up to 200-fold the projected human efficacious levels in preclinical safety studies.

Conclusion: We report here the first selective, potent, oral IRF5 degrader that can sufficiently deplete IRF5 and impact myeloid cell effector function by potently inhibiting pro-inflammatory cytokines found to be critical in amplifying inflammatory responses, including cytokines that promote Th1 and Th17 T cell responses, and can reduce joint swelling in a mouse model of RA. These findings support KT-579 as a novel therapeutic agent with the potential to be a first-in-class oral therapy for the treatment of RA and other autoimmune diseases.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/potent-and-selective-oral-irf5-degrader-kt-579-blocks-pro-inflammatory-cytokines-and-reduces-joint-swelling-in-a-mouse-model-of-rheumatoid-arthritis/