Kv1.3 expression on effector memory T cells in sporadic inclusion body myositis: potential for targeted immunotherapy with dalazatide

Dalazatide is a potent peptide inhibitor of the Kv1.3 potassium channel on activated effector memory T (T_EM) cells. T_EM cells rely on this channel to maintain their proliferation and granzyme-and perforin mediated cytotoxic effects, while other T cell subsets, such as naïve and central memory T cells, rely upon KCa3.1 channels. Thus, dalazatide is targeted and immune sparing. Dalazatide has been shown to have potent inhibition of T_EM cells in many in vitro, ex vivo, and in vivo models of autoimmune diseases, and has demonstrated safety and tolerability, target engagement, and proof of concept efficacy in human clinical trials. Sporadic inclusion body myositis (sIBM) is a rare progressive myopathy caused by both autoimmune and degenerative processes for which there is no effective treatment and no approved therapeutics. Pro-inflammatory T cells have been shown to be present in the blood and inflamed muscles of patients with sIBM and contribute to the destruction of the muscle fibers. Dalazatide inhibition of these T cells may be a safe and attractive strategy for treating sIBM. Here we show that muscle biopsy samples from patients with sIBM have large numbers of CD3+ T cells in the perivascular space and in the muscle fibers which express the Kv1.3 channel, providing a clear target for dalazatide treatment. Using this data along with the extensive safety profile of dalazatide, we are currently designing a proof of concept clinical study for dalazatide in patients with sIBM.