Background/Purpose: IRF5 is a transcription factor and regulator of immune responses activated downstream of pattern recognition receptors, in particular endosomal toll-like receptors (TLR), TLR7, TLR8 and TLR9. IRF5 regulates pro-inflammatory cytokines (TNFα, IL-6, IL-12, IL-23), autoantibody production and Type I IFN, and is selectively expressed and activated in specific cell types such as dendritic cells, monocytes, macrophages, and B cells. Human genetic and functional studies have linked IRF5 in the pathogenesis of multiple autoimmune diseases, including SLE, RA, and Sjögren’s, and Irf5-deficient mice are protected from lupus onset and severity. In SLE, endosomal TLRs recognize nuclear self-antigens, triggering IRF5 activation and driving the breakdown of immune tolerance via a cascade involving B cell activation, autoantibody and pro-inflammatory cytokine production. 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. KT-579, an oral IRF5 degrader, has demonstrated potent and selective activity in preclinical studies, offering a novel approach to modulating this key driver of immunity.

Methods: Peripheral blood mononuclear cells (PBMCs) derived from healthy or SLE donors were cultured with KT-579 in the presence or absence of TLR7, TLR8 or TLR9, to evaluate KT-579 selectivity, potency and functional activity. Oral IRF5 degrader was tested in mouse models of acute TLR7 or TLR9 activation, and MRL.lpr and NZBW1 lupus models.

Results: KT-579 was selective for IRF5 in the detectable proteome, including other IRF family proteins. KT-579 demonstrated sub nanomolar potencies across relevant cell types tested, and inhibited pro-inflammatory cytokines, Type I IFN production and response, and IgG levels downstream of TLR7, TLR8 or TLR9 induction in healthy or SLE PBMC assays. In vivo, KT-579 led to dose-dependent inhibition of both TLR7 or TLR9 induced TNFα, IL-6 and IL-12, unlike a TLR7/8 inhibitor. In the MRL.lpr lupus model, KT-579 doses achieving >85% degradation led to significant reduction of proteinuria and 100% survival. In the long term NZBW1 spontaneous lupus model, daily oral doses achieving >80% IRF5 degradation resulted in sustained reduction of proteinuria, circulating ANA and total kidney lesions. In both lupus models, IRF5 degradation was well tolerated, and IRF5 degrader activity was superior to approved or clinically active drugs. KT-579 achieved deep 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 potent, selective, oral IRF5 degrader development candidate, KT-579, which depletes IRF5 in human primary cells, SLE patient derived cells, and lupus disease models, demonstrating superior activity to existing standards of care agents. These findings position KT-579 as a novel, first-in-class, oral therapeutic agent with the potential to transform the treatment landscape of lupus and multiple autoimmune diseases driven by IRF5 dysregulation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/potent-and-selective-oral-irf5-degrader-kt-579-demonstrates-in-vitro-and-in-vivo-activity-comparable-or-superior-to-approved-or-clinically-active-agents-in-human-cellular-assays-and-lupus-efficacy-m/