THU0285 Dalazatide, An Inhibitor of The Kv1.3 Channel on Activated Effector Memory T Cells, Has Immunotherapy Potential in Systemic Lupus Erythematosus

Background T cell activation depends upon a calcium signaling cascade that is regulated by voltage-gated potassium channels. Effector memory T cells (T EM ), which are implicated in the immunopathogenesis of a panel of autoimmune diseases, express the potassium channel Kv1.3. Dalazatide is a potent peptide inhibitor of the Kv1.3 channel that has recently shown efficacy in a Phase 1b plaque psoriasis trial. Evidence suggests that inflammatory cytokine producing T EM cells might be involved in the immunopathology of lupus nephritis. Objectives Provide proof-of-principle ex vivo data for therapeutically targeting chronic T cell activation in systemic lupus erythematosus (SLE) by using dalazatide to block the Kv1.3 channel and to evaluate the effect of dalazatide on the in vitro inflammatory cytokine production of T EM cells from SLE patients. Methods Peripheral blood mononuclear cells from pediatric and adult SLE patients as well as healthy controls were studied. T lymphocyte subsets were assayed ex vivo for Kv1.3 expression by flow cytometry. The effect of dalazatide on phorbol myristate acetate (PMA)/ionomycin-induced inflammatory cytokine expression by T EM cells was evaluated by intracellular cytokine staining. Results Kv1.3 expression by CD8 + T EM cells was significantly higher in patients with active lupus nephritis when compared to patients with inactive SLE or healthy controls. Dalazatide inhibited IFN-γ, IL-17 and TNF-α production by both CD4 + and CD8 + T EM cells from SLE patients in a dose-dependent manner. Higher levels of dalazatide-mediated inhibition were observed in IFN-γ and TNF-α-expressing CD4 + T EM cells from patients with active SLE when compared to samples from SLE patients with inactive disease. Conclusions Ex vivo studies suggest that dalazatide inhibition of Kv1.3 may be a therapeutic target for SLE. In addition, Kv1.3 expression may be a useful biomarker of disease activity in SLE. Disclosure of Interest A. Stevens Grant/research support from: Kineta, Inc., M. Yuasa Grant/research support from: Kineta, Inc., D. Peckham Grant/research support from: Kineta, Inc., Employee of: Kineta, Inc., C. Olsen Grant/research support from: Kineta, Inc., Employee of: KPI Therapeutics, Inc, S. Iadonato Grant/research support from: Kineta, Inc., Employee of: Kineta, Inc., P. Probst Grant/research support from: Kineta, Inc., Employee of: Kineta, Inc.