Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease

Abstract

The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an 111 In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channelblocking IC 50 value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

“…Toxicity studies with PAP‐1 and the peptidic K V 1.3 blocker ShK‐186 have so far not revealed any toxicity despite 6 months or 28 days of continuous administration in rats or rhesus macaques 4, 8. PAP‐1 has further completed IND‐enabling toxicity studies, while ShK‐186 has passed both IND toxicity studies and Phase‐1 safety studies without any adverse findings 6, 9…”

“…Interest in Kv1.3 afterward waned but revived following reports from our group that Kv1.3 is overexpressed in activated CCR7 − effector memory T‐cells (T EM ) and that Kv1.3 blockers therefore constitute immunomodulators rather than general immunosuppressants 3, 4, 5. Subsequent proof‐of‐concept animal studies demonstrated that the Kv1.3 blocking sea anemone Stichodactyla helianthus peptide ShK and its derivatives treat rat models of multiple sclerosis and rheumatoid arthritis,4, 5, 6 while our small molecule Kv1.3 blocker PAP‐1 prevents autoimmune diabetes4 in rats and treats psoriasis in a mouse xenograft model 7. As Kv1.3 blockers preferentially target T EM cells, Kv1.3 blockers do not impair the ability to clear acute infections or develop vaccine responses.…”

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.…”

“…The antiobesity effects of ShK-186 therapy are remarkably similar to the effects of Kv1.3 gene deletion in dietinduced obesity (Table S1), strongly suggesting that the antiobesity activities of ShK-186 are predominantly due to pharmacological actions on Kv1.3. These actions are due to blockade of Kv1.3 channels in peripheral tissues because <0.1% of the peptide crosses the blood-brain barrier (17). At least three mechanisms contribute to the antiobesity effects of ShK-186: BAT activation leading to increased energy expenditure, altered metabolism in the liver, and reduction of obesity-induced inflammation of abdominal WAT.…”

“…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.…”