Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease.
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 ¹¹¹In-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 channel-blocking IC₅₀ 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.
Kineta Inc., 219 Terry Ave N., Suite 300, Seattle, WA 98109-5208, USA. eric@kineta.us
Eric J
EJ
Tarcha
Victor
V
Chi
Ernesto J
EJ
Muñoz-Elías
David
D
Bailey
Luz M
LM
Londono
Sanjeev K
SK
Upadhyay
Kayla
K
Norton
Amy
A
Banks
Indra
I
Tjong
Hai
H
Nguyen
Xueyou
X
Hu
Greg W
GW
Ruppert
Scott E
SE
Boley
Richard
R
Slauter
James
J
Sams
Brian
B
Knapp
Dustin
D
Kentala
Zachary
Z
Hansen
Michael W
MW
Pennington
Christine
C
Beeton
K George
KG
Chandy
Shawn P
SP
Iadonato
D000042:Absorption / Q000187:drug effects / Q000276:immunology; D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D026902:Potassium Channel Blockers / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D011506:Proteins / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D011506:Proteins; C533637:Shk-186 peptide