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

Clin Immunol. 2017 Jul;180:45-57. doi: 10.1016/j.clim.2017.03.014. Epub 2017 Apr 4.

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.

Keywords: Disulfide rich peptide; Effector memory T lymphocyte; Immunomodulation; KCNA3; PEGylated Kv1.3 blocker; Voltage-gated channel.

MeSH terms

  • Adult
  • Allergens / immunology
  • Animals
  • Arthritis, Experimental / chemically induced
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid / chemically induced
  • Arthritis, Rheumatoid / pathology
  • Cell Line
  • Cells, Cultured
  • Female
  • Humans
  • Hypersensitivity, Delayed / immunology
  • Immunomodulation / drug effects
  • Kv1.3 Potassium Channel / antagonists & inhibitors*
  • Leukocytes, Mononuclear
  • Mice
  • Middle Aged
  • Ovalbumin / immunology
  • Peptides / chemistry
  • Peptides / pharmacokinetics
  • Peptides / pharmacology*
  • Polyethylene Glycols / chemistry
  • Polyethylene Glycols / pharmacokinetics
  • Polyethylene Glycols / pharmacology*
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / pharmacokinetics
  • Potassium Channel Blockers / pharmacology*
  • Rats
  • Rats, Inbred Lew
  • Scorpion Venoms / chemistry
  • Scorpion Venoms / pharmacokinetics
  • Scorpion Venoms / pharmacology*
  • Spleen / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Terpenes
  • Young Adult

Substances

  • Allergens
  • Kv1.3 Potassium Channel
  • Peptides
  • Potassium Channel Blockers
  • Scorpion Venoms
  • TX1 toxin, Heterometrus spinnifer
  • Terpenes
  • pristane
  • Polyethylene Glycols
  • Ovalbumin