Abstract

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by systemic inflammation and tissue damage in multiple organs. Auto-antibodies directed against nucleic acids are a hallmark of the disease. Toll-like receptor (TLR) 7 and TLR8 are endosomal receptor of nucleic acids, which have been implicated in SLE pathogenesis; however, the relative contribution of the two is uncertain. This point deserves clarification in consideration of several dual TLR7/TLR8 small molecule inhibitors that are being developed for the treatment of SLE in contrast with DS-7011a,1) an anti-TLR7-specific monoclonal antibody that inhibits only TLR7. Objectives: In this study, we performed gene signature (GS) analysis using public transcriptome datasets to investigate the involvement of TLR7 and TLR8 in the pathogenesis of SLE and to further characterize TLR7 involvement with reference to treatment and ethnicity. Methods: Three whole blood transcriptome datasets from SLE patients and one skin transcriptome dataset from discoid and subacute cutaneous lupus erythematosus (CLE) patients were obtained from the Gene Expression Omnibus (GEO) database. The TLR7 and TLR8 GS were defined based on our own experimental data and the interferon (IFN)-Type I GS as published.2,3) GS scores were calculated as published,4) compared between healthy subjects and SLE patients and among subgroups of SLE patients, and analyzed for correlation between GS. Results: TLR7 GS scores were higher in SLE patients compared with healthy subjects, but TLR8 GS scores were similar between the two groups (Figure 1a). TLR7 GS scores remained higher in SLE patients than healthy subjects, even when treated with standard therapies such as steroids, hydroxychloroquine, and mycophenolate mofetil (Figure 1b). TLR7 GS scores were higher in SLE patients than healthy subjects across all the evaluated ethnicities, including African Americans, whose SLE may be particularly difficult to treat (Figure 1c). In addition, TLR7 GS scores were also high in SLE patients with different degrees of disease activity, including those with low SLEDAI scores, and regardless of skin lesions. TLR7 GS scores correlated with IFN-Type I GS scores and, in discoid and subacute CLE patients, not only in blood but also in skin. On the other hand, TLR8 GS scores did not show correlation with IFN-Type I GS scores. Conclusion: These results indicate that TLR7 rather than TLR8 is involved in the pathogenesis of SLE. TLR7 involvement is evident under various conditions of treatment and ethnicity. These results support TLR7 as a critical pharmacological target against SLE rather than TLR8, justifying and valorizing the development of DS-7011a, a TLR7-specific inhibitor, for the treatment of SLE. REFERENCES: [1] Manno A, Honda T, Kuwata C, et al., Targeting Toll-Like Receptor 7 with DS-7011a, a Promising Novel Antagonistic Antibody for the Treatment of Systemic Lupus Erythematosus. ACR 2023; 0896 [2] Furie R, Khamashta M, Merrill JT, et al., Anifrolumab, an anti–Interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017;69:376-386 [3] Chia YN, Tummala R, Mai TH, et al., Relationship between anifrolumab pharmacokinetics, pharmacodynamics, and efficacy in patients with moderate to severe systemic lupus erythematosus. J Clin Pharmacol. 2022;62:1094-1105 [4] Martin F, Thomson TM, Sewer A, et al. Assessment of network perturbation amplitudes by applying high-throughput data to causal biological networks. BMC Syst Biol. 2012;6:54. Acknowledgements: NIL. Disclosure of Interests: Tomohiro Honda Daiichi Sankyo Co., Ltd., Atsushi Manno Daiichi Sankyo Co., Ltd., Shinnosuke Yamada Daiichi Sankyo Co., Ltd., Jun Ishiguro Daiichi Sankyo Co., Ltd., Yoshiaki Tomimori Daiichi Sankyo Co., Ltd., Giorgio Senaldi Daiichi Sankyo, Inc., Jun Tanaka Daiichi Sankyo, Inc.