Background/Purpose: SLE is a highly heterogeneous chronic autoimmune disease, with glucocorticoid therapy as the standard of care. SLE control requires high steroid doses; long-term use can have serious side effects. Thus, a novel steroid-sparing therapeutic agent may markedly improve lupus management. Activation of toll-like receptors (TLRs) 7 and 8 plays a critical role in lupus disease biology, and their blockade leads to a significant reduction in lupus manifestations.^1-3 TLR7/8 are important endosomal receptors involved in innate immunity, and their activation via nuclear factor (NF)-кβ contributes to steroid resistance.⁴ Previously, we showed that afimetoran, an equipotent dual antagonist of TLR7/8 currently in clinical development for SLE treatment, demonstrates steroid-sparing effects with in vitro assays for apoptosis of human plasmacytoid dendritic cells (pDCs) and B cells, and in vivo in an NZB/W mouse model of spontaneous lupus.⁴ This study provides additional insights into the cellular and molecular mechanisms underlying the steroid-sparing effects of afimetoran in vitro and in vivo.

Methods: Whole blood (WB) samples from patients with SLE were treated in vitro with afimetoran and/or prednisolone with DMSO (dimethyl sulfoxide) as a control. Following incubation, supernatants were analyzed for cytokines using the Luminex platform, and the proportion of apoptotic B cells and pDCs was assessed using annexin V staining with flow cytometry. Steroid response was assessed in gardiquimod-stimulated peripheral blood mononuclear cells. Vehicle or selected doses of afimetoran and/or prednisolone (once daily) were further tested in vivo using BXSB mice, a model of spontaneous lupus and proliferative glomerulonephritis. Survival, kidney injury, serum titers of autoantibodies such as anti-Smith, anti-ribonucleoprotein, anti–Sjögren’s-syndrome-related antigen A autoantibodies, and plasma cytokines such as IL-12p40 were assessed in all treatment groups.

Results: WB samples treated with afimetoran alone or combined with prednisolone showed suppression of various cytokines. An improved steroid response was seen with afimetoran in gardiquimod-stimulated peripheral blood mononuclear cells. A notable increase in prednisolone-induced apoptosis of pDCs and B cells was also observed with afimetoran, compared with prednisolone alone or DMSO control. Afimetoran-treated mice showed significant suppression of kidney injury markers, plasma cytokines, IFN-secreting pDCs, and autoantibody titers compared with the control (P < 0.05 to P < 0.001). Afimetoran combined with prednisolone showed higher suppression of the above markers than either treatment alone.

Conclusion: These translational and preclinical data further demonstrate that afimetoran can block TLR7/8 and has steroid-sparing potential in patients with SLE, lupus nephritis, and other autoimmune conditions requiring immunosuppressant therapy.

Refs:

1. Dudhgaonkar S, et al. Arthritis Rheumatol 2021;73(suppl 9):0470.

2. Dudhgaonkar S, et al. Presented at LUPUS CORA 2021; Oct 6–9, 2021. Abst 238.

3. Sreekantha RK, et al. ACS Med Chem Lett 2022;13(5):812–818.

4. Dudhgaonkar S, et al. Presented at ACR Convergence 2023; Nov 10–15, 2023. Poster 0897

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/in-vitro-and-in-vivo-evidence-of-the-steroid-sparing-potential-of-afimetoran-an-equipotent-toll-like-receptor-7-8-dual-antagonist/