Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases

Abstract

Electrophysiological and pharmacological studies coupled with molecular identification have revealed a unique network of ion channels—Kv1.3, KCa3.1, CRAC (Orai1 + Stim1), TRPM7, Clswell—in lymphocytes that initiates and maintains the calcium signaling cascade required for activation. The expression pattern of these channels changes during lymphocyte activation and differentiation, allowing the functional network to adapt during an immune response. The Kv1.3 channel is of interest because it plays a critical role in subsets of T and B lymphocytes implicated in autoimmune disorders. The ShK toxin from the sea anemone Stichodactyla helianthus is a potent blocker of Kv1.3. ShK-186, a synthetic analog of ShK, is being developed as a therapeutic for autoimmune diseases, and is scheduled to begin first-in-man phase-1 trials in 2011. This review describes the journey that has led to the development of ShK-186.

Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

“…ShK-186 treatment significantly reduced TNFα expression in visceral WAT (Fig. 2F), possibly via its known immunomodulatory effects on T cells and macrophages (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The low uncoupling protein 1 (UCP1) Fig.…”

“…Adult mice were fed an obesity-inducing diet (Table S2) that mimics the Western diet linked to risk of cardiovascular diseases in humans (13)(14)(15), and immediately started on a therapeutic regimen of ShK-186 or vehicle. ShK-186's durable pharmacological activity in rodents and nonhuman primates (16) allowed us to administer the peptide every other day by s.c. injection. ShK-186-treated male mice (20 or 500 μg/kg every Significance Obesity is a global epidemic in need of novel and safe therapeutics.…”

“…Classically activated M1 macrophages within fat depots are also causally linked to the development of obesity-induced adipose tissue inflammation and insulin resistance (65)(66)(67)(68)(69)(70)(71). Importantly, Kv1.3 regulates membrane potential and calcium signaling in T EM cells, and ShK-186 suppresses cytokine production, proliferation, and in vivo migration and activation of these cells (16)(17)(18)(19)(20)(21). Kv1.3 channels also play a critical role in macrophages, and Kv1.3 blockers suppress cytokine production and cholesterol accumulation in macrophages (22-25, 72, 73).…”

“…In this model, mice fed an obesity-inducing diet rich in both fat and fructose (Tables S2 and S3) gain significant weight and adiposity, and develop insulin resistance within 6-8 wk (12)(13)(14)(15). As a Kv1.3 blocker we chose ShK-186 because of its picomolar potency (IC 50 69 pM), >100-fold selectivity over closely related channels, weak immunogenicity, and excellent safety profile in rodents and nonhuman primates (16)(17)(18)(19)(20)(21). Furthermore, ShK-186 is the first Kv1.3-specific blocker to advance to human safety trials as a potential therapeutic for autoimmune diseases.…”

Ion channels and anti-cancer immunity

“…(b) Subset-specific expression of K þ channels in T lymphocytes [52][53][54]. The subset specific to ion channels allows a differential inhibition of the function of T-cell subsets, which has therapeutic advantage in autoimmune diseases as well as in anti-tumour immunity, as discussed below.…”