Background/Purpose:

The voltage-gated potassium channel Kv1.3 is highly expressed on activated T effector memory cells (TEM), is essential for T cell activation, and thus is a novel target for the treatment of autoimmune disorders. ShK-186 (dalazatide) is a specific, highly potent peptide inhibitor of Kv1.3 that has recently entered clinical development.  Previous reports associated TEM activation with the pathogenesis of SLE, suggesting a potential for dalazatide efficacy in SLE.

Methods:

Peripheral blood from pediatric patients with SLE and healthy controls  were studied.  Ex vivo Kv1.3 expression was assayed on T lymphocyte subsets by flow cytometry.  The effect of dalazatide on cytokine expression after no stimulation or following short term stimulation by PMA and thapsigargin or ionomycin was evaluated by flow cytometry. 

Results:

Kv1.3 was up-regulated on CD4⁺TEM from SLE patients with active disease (mean MFI 370) compared to and to patients with inactive disease (mean MFI 265, p=0.08), or to controls (mean MFI 208, p=0.005).  A larger effect on Kv1.3 expression was detected in CD8+TEM (active SLE 311, inactive SLE 185, p=0.02; controls 140, p=0.005). Dalazatide at concentrations of 10 pM-1nM decreased proinflammatory cytokine production ex vivo in a dose-dependent fashion in TEM, but not naïve cells from SLE patients and healthy controls.  In the CCR7low CD45RO+ CD4+ TEM subset, inhibition of TNF-a (mean 33-43%), interferon-g (33-55%), and IL-17 (28-53%) was detected.

Conclusion:

In vitro studies suggest that Kv1.3 on TEM may be a treatment target for SLE.  In addition, Kv1.3 expression may be useful as a biomarker of disease activity in SLE.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/dalazatide-shk-186-a-kv1-3-channel-inhibitor-that-targets-effector-memory-t-cells-ex-vivo-studies-in-pediatric-systemic-lupus-erythematosus/