Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog

Abstract

Effector memory T lymphocytes (TEM cells) that lack expression of CCR7 are major drivers of inflammation in a number of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis. The Kv1.3 potassium channel is a key regulator of CCR7− TEM cell activation. Blocking Kv1.3 inhibits TEM cell activation and attenuates inflammation in autoimmunity, and as such, Kv1.3 has emerged as a promising target for the treatment of TEM cell-mediated autoimmune diseases. The scorpion venom-derived peptide HsTX1 and its analog HsTX1[R14A] are potent Kv1.3 blockers and HsTX1[R14A] is selective for Kv1.3 over closely-related Kv1 channels. PEGylation of HsTX1[R14A] to create a Kv1.3 blocker with a long circulating half-life reduced its affinity but not its selectivity for Kv1.3, dramatically reduced its adsorption to inert surfaces, and enhanced its circulating half-life in rats. PEG-HsTX1[R14A] is equipotent to HsTX1[R14A] in preferential inhibition of human and rat CCR7− TEM cell proliferation, leaving CCR7+ naïve and central memory T cells able to proliferate. It reduced inflammation in an active delayed-type hypersensitivity model and in the pristane-induced arthritis (PIA) model of rheumatoid arthritis (RA). Importantly, a single subcutaneous dose of PEG-HsTX1[R14A] reduced inflammation in PIA for a longer period of time than the non-PEGylated HsTX1[R14A]. Together, these data indicate that HsTX1[R14A] and PEG-HsTX1[R14A] are effective in a model of RA and are therefore potential therapeutics for TEM cell-mediated autoimmune diseases. PEG-HsTX1[R14A] has the additional advantages of reduced non-specific adsorption to inert surfaces and enhanced circulating half-life.

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

“…Kv1.3 in T lymphocytes is responsible for controlling the membrane potential which is critical for the activation of these immune cells (Veytia-Bucheli et al, 2018). Several studies have confirmed that Kv1.3 is highly expressed in macrophages, microglia, and TEM cells, suggesting that Kv1.3 plays a crucial role in immune and inflammatory responses to human diseases such as multiple sclerosis (MS), rheumatoid arthritis, Type 1 diabetes, and asthma (Toldi et al, 2010;Huang et al, 2017;Tanner et al, 2017;Zhou et al, 2018). In these conditions, the expression of Kv1.3 channels is significantly elevated (Rangaraju et al, 2009), which is beneficial to define the role of Kv1.3 in autoimmune diseases as well as to clarify the significance of developing Kv1.3 blocker drugs.…”

Regulation of Arthritis Severity by the Acid Sphingomyelinase

“…Effector memory T (T EM ) cells are the subset generally associated with autoimmune- and other chronic inflammatory diseases [24-31]. Specifically in RA, T EM cells have been reported to be increased in the synovial fluid [32] and recently an inhibitor of the Kv1.3 channel (HsTX1[R14A]) was reported to reduce inflammation in the pristine-induced arthritis model by inhibiting T EM cell activation [33]. Central memory T cells (T CM ) cells do not migrate to inflamed tissues and have little to no effector function, but proliferate and differentiate to effector cells in response to antigenic stimulation.…”

ShK toxin: history, structure and therapeutic applications for autoimmune diseases

“…[5][6][55] [28] A scorpion toxin inhibitor of KV1.3 was also effective in this model. [70] In both these studies, blockade of Kv1.3 alone was sufficient to ameliorate disease and simultaneous blockade of KCa3.1 was not necessary as has been suggested. [49] [71]…”