title: Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog.
abstract: Effector memory T lymphocytes (TEMcells) 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-TEMcell activation. Blocking Kv1.3 inhibits TEMcell activation and attenuates inflammation in autoimmunity, and as such, Kv1.3 has emerged as a promising target for the treatment of TEMcell-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-TEMcell 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 TEMcell-mediated autoimmune diseases. PEG-HsTX1[R14A] has the additional advantages of reduced non-specific adsorption to inert surfaces and enhanced circulating half-life.
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Tanner
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Rajeev B
authors.initials: RB
authors.lastname: Tajhya
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Redwan
authors.initials: R
authors.lastname: Huq
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Gehrmann
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Kathia E
authors.initials: KE
authors.lastname: Rodarte
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Atik
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.affiliation: Peptides International, 11621 Electron Drive, Louisville, KY 40299, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pennington
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Biology of Inflammation Center and Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: beeton@bcm.edu.
authors.forename: Christine
authors.initials: C
authors.lastname: Beeton
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D056747:Immunomodulation / Q000187:drug effects; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear; D051379:Mice; D008875:Middle Aged; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012604:Scorpion Venoms / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013729:Terpenes; D055815:Young Adult
chemical_list: D000485:Allergens; D051664:Kv1.3 Potassium Channel; D010455:Peptides; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; C109471:TX1 toxin, Heterometrus spinnifer; D013729:Terpenes; C009042:pristane; D011092:Polyethylene Glycols; D010047:Ovalbumin
keywords: Disulfide rich peptide; Effector memory T lymphocyte; Immunomodulation; KCNA3; PEGylated Kv1.3 blocker; Voltage-gated channel