1848: DS-7011a, An Anti-TLR7 Antagonistic Monoclonal Antibody, Suppresses Human Immune Cells and Multiple Cytokines/Chemokines Related to the Pathogenesis of SLE

Background/Purpose: Toll-like receptor (TLR) 7 is a pattern recognition receptor that recognizes nucleic acids and is implicated in the pathogenesis of systemic lupus erythematosus (SLE). We have previously shown that DS-7011a, an anti-TLR7 monoclonal antibody, inhibits IFNα and IL-6 release from TLR7 agonist-stimulated human peripheral blood mononuclear cells (PBMCs). As TLR7 is expressed in human plasmacytoid dendritic cells (pDCs), B cells and monocytes, in this study, we aim to investigate the inhibitory effects of DS-7011a on TLR7-mediated activation of pDCs, B cells and monocytes related to the pathogenesis of SLE. Additionally, we also aim to evaluate the inhibitory effects of DS-7011a on the production of multiple cytokines/chemokines implicated in the pathogenesis of SLE in human PBMCs.

Methods: Human PBMCs were isolated from fresh whole blood of healthy donors and frozen purified human pDCs, B cells and monocytes were purchased. These cells were stimulated with TLR7 agonists in the presence of DS-7011a to evaluate its inhibitory effects on TLR7-mediated activation in vitro. The production of cytokines/chemokines after stimulation was measured by Multiplex assay or AlphaLISA. The production of IgG from B cells was measured by cell-based ELISA,

Results: The production of IFNα, IL-6 and IgG stimulated with TLR7 agonists in human pDCs, monocytes and B cells respectively, was suppressed by DS-7011a dose dependently. Additionally, stimulation with a TLR7 agonist led to the production of several cytokines/chemokines implicated in the pathogenesis of SLE, including IL-6, monocyte chemoattractant protein (MCP) -1, MCP-3, monocyte inflammatory protein (MIP) -1α, MIP-1β, IL-12 (p40), and TNF-α in human PBMCs. All of these cytokine productions were also inhibited by DS-7011a in a dose-dependent manner.

Conclusion: DS-7011a demonstrated inhibitory effects on TLR7-mediated activation of immune cells and suppressed the production of IgG and pro-inflammatory cytokines/chemokines implicated in the pathogenesis of SLE. Since autoantibodies and pro-inflammatory cytokines/chemokines are known as therapeutic targets individually, DS-7011a has shown potential as a novel therapeutic agent for SLE by inhibiting these multiple mechanisms.