Session Type: Abstract Session
Session Time: 11:00AM-11:15AM
Background/Purpose: TLR7, a member of the Toll-Like Receptor family, recognizes ssRNA and is primarily expressed in plasmacytoid dendritic cells and B cells. TLR7 has been implicated in systemic lupus erythematosus (SLE) in knockout mouse studies, but effects of inhibition at disease onset or in established disease are not well understood. Mouse TLR7 carries out human TLR7 functions, whereas mouse TLR8 does not carry out human TLR8 responses. BMS-986256 is a potent and selective inhibitor of TLR7 and TLR8 currently in clinical development for immune-mediated diseases. BMS-986256 has similar human and mouse TLR7 potency and was used in murine lupus models to investigate the role of TLR7 in disease onset and in established disease.
Methods: MRL/lpr mice and NZB/W mice were treated orally, once daily with vehicle or selected doses of BMS‑986256 and/or prednisolone after anti-dsDNA antibodies developed but before onset of proteinuria. Alternatively, NZB/W mice were treated therapeutically in established disease (proteinuria at levels of 60–100 mg/dL) or advanced disease (proteinuria >100 mg/dL). Human blood was treated with BMS-986256 and prednisolone, stimulated with the TLR7 agonist gardiquimod or the TLR8 agonist TL8-506, and IL-6 production was measured to determine synergy.
Results: BMS-986256 treatment for 8 weeks in the MRL/lpr model provided robust inhibition of proteinuria onset and inhibition of IgG deposition in the kidney, with inhibition of autoantibody production. BMS-986256 treatment for 24 weeks in the NZB/W model resulted in nearly complete inhibition of proteinuria onset and IgG deposition in the kidney. Treatment of NZB/W mice with proteinuria of 60–100 mg/dL for 14 weeks and mice with proteinuria of >100 mg/dL for 10 weeks resulted in reversal of proteinuria, IgG deposition in the kidney, and kidney tissue damage, while markedly increasing survival in both established and advanced disease models. Production of anti-dsDNA, anti-SmRNP and anti-Ro autoantibody titers and cytokine production were inhibited in preventative, therapeutic and established models. BMS-986256 displayed steroid-sparing activity in all the disease models, when single agent and combination treatments with prednisolone were compared. BMS-986256 acted synergistically with steroid treatment to inhibit TLR7 and 8 responses in human blood.
Conclusion: The potent and selective TLR7/8 inhibitor BMS-986256 displayed robust efficacy in the MRL/lpr and NZB/W models of lupus. Therapeutic treatment with BMS-986256 reversed proteinuria, immune complex deposition, and kidney tissue damage in established and advanced disease NZB/W models. Treatment reduced titers of autoantibodies implicated in lupus as well as cytokine responses. BMS-986256 displayed steroid-sparing activity in the disease models and acted synergistically with steroid treatment in human blood. These results indicate that TLR7 plays an important role in both the initiation and progression of disease and support the potential of BMS-986256 in the treatment of SLE. Given the robust pharmacological efficacy observed in this study, BMS-986256, currently under investigation in patients with cutaneous lupus (CLE), was advanced to a Phase 2 trial in SLE patients.
To cite this abstract in AMA style:Dudhgaonkar S, Rudra A, Ranade S, Subramani S, Nagar J, Karunanithi P, Bhutani P, Kurawattimath V, Zhang R, Qiu H, DYCKMAN A, Schieven G. Inhibition of Toll-Like Receptor 7 (TLR7) with the Potent and Selective Inhibitor of Human TLR7 and TLR8 BMS-986256 Provides Robust Efficacy in Murine Lupus Models, Reversing Established Disease [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 10). https://acrabstracts.org/abstract/inhibition-of-toll-like-receptor-7-tlr7-with-the-potent-and-selective-inhibitor-of-human-tlr7-and-tlr8-bms-986256-provides-robust-efficacy-in-murine-lupus-models-reversing-established-disease/. Accessed October 19, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-toll-like-receptor-7-tlr7-with-the-potent-and-selective-inhibitor-of-human-tlr7-and-tlr8-bms-986256-provides-robust-efficacy-in-murine-lupus-models-reversing-established-disease/