Background: Systemic lupus erythematosus (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, 2, 3]. TLR7/8 are important endosomal receptors involved in innate immunity, and their activation via nuclear factor-кB 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].

Objectives: To provide 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 dimethyl sulfoxide (DMSO) 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 interleukin-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, interferon-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.

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

[2] Dudhgaonkar S, et al. Poster presentation at LUPUS & CORA 2021; Venice, Italy; Oct 6–9, 2021. Abstract 238.

[3] Sreekantha RK, et al. ACS Med Chem Lett 2022;13:812–818.

[4] Dudhgaonkar S, et al. Poster presentation at ACR Convergence 2023; San Diego, CA, USA; Nov 10–15, 2023. Abstract 0897.

Reprinted from the ACR Convergence held in November 2024. The American College of Rheumatology does not guarantee, warrant, or endorse any commercial products or services. Reprinted by Bristol Myers Squibb.

Acknowledgements: This study was supported by Bristol Myers Squibb. Professional medical writing and editorial assistance were provided by Alexus Shirk, PhD, of Caudex, a division of IPG Health Medical Communications, and were funded by Bristol Myers Squibb.

Disclosure of Interests: Shailesh Dudhgaonkar Bristol Myers Squibb, Bristol Myers Squibb, Siva Subramani Syngene International Limited, Puneet Chopra Syngene International Limited, Syngene International Limited, Anjuman Rudra Syngene International Limited, Sourabha Palachandra Syngene International Limited, Nikita Bhatt Syngene International Limited, Veeresh Pabbala Syngene International Limited, Sabariya Selvam Syngene International Limited, Mobeen Shaik Syngene International Limited, Amit Anand Syngene International Limited, Benjamin King Bristol Myers Squibb, Kristina Chadwick Bristol Myers Squibb, Alaric Dyckman Bristol Myers Squibb, Bristol Myers Squibb, Qihong Zhao Bristol Myers Squibb, Frédéric Baribaud Bristol Myers Squibb, Bristol Myers Squibb, Ramya Janardana: None declared , Vineeta Shobha: None declared .

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.