PEGylation of a High-Affinity Anti-(+)Methamphetamine Single Chain Antibody Fragment Extends Functional Half-Life by Reducing Clearance.
Methamphetamine (METH) abuse is a worldwide drug problem, yet no FDA-approved pharmacological treatments are available for METH abuse. Therefore, we produced an anti-METH single chain antibody fragment (scFv7F9Cys) as a pharmacological treatment for METH abuse. ScFv's have a short half-life due to their small size, limiting their clinical use. Thus, we examined the pharmacokinetic effects of conjugating poly(ethylene) glycol (-PEG) to scFv7F9Cys to extend its functional half-life.



The affinity of scFv7F9Cys and PEG conjugates to METH was determined in vitro via equilibrium dialysis saturation binding. Pharmacokinetic and parameters of scFv7F9Cys and scFv7F9Cys-PEG20K (30 mg/kg i.v. each) and their ability to bind METH in vivo were determined in male Sprague-Dawley rats receiving a subcutaneous infusion of METH (3.2 mg/kg/day).



Of three PEGylated conjugates, scFv7F9Cys-PEG20K was determined the most viable therapeutic candidate. PEGylation of scFv7F9Cys did not alter METH binding functionality in vitro, and produced a 27-fold increase in the in vivo half-life of the antibody fragment. Furthermore, total METH serum concentrations increased following scFv7F9Cys or scFv7F9Cys-PEG20K administration, with scFv7F9Cys-PEG20K producing significantly longer changes in METH distribution than scFv7F9Cys.



PEGylation of scFv7F9Cys significantly increase the functional half-life of scFv7F9Cys, suggesting it may be a long-lasting pharmacological treatment option for METH abuse.
Department of Pharmacology & Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.
Emily E
EE
Reichard
Department of Pharmacology & Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.
Nisha
N
Nanaware-Kharade
Department of Pharmacology & Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.
Guillermo A
GA
Gonzalez
Department of Physiology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.
Shraddha
S
Thakkar
Department of Pharmacology & Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.
S Michael
SM
Owens
Department of Pharmacology & Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA. EPeterson@uams.edu.
Eric C
EC
Peterson
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000276:immunology*; D006207:Half-Life; D008297:Male; D008694:Methamphetamine / Q000276:immunology*; D011092:Polyethylene Glycols / Q000737:chemistry*; D017207:Rats, Sprague-Dawley; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D000697:Central Nervous System Stimulants; D057127:Single-Chain Antibodies; D011092:Polyethylene Glycols; D008694:Methamphetamine
drug abuse; methamphetamine; pharmacokinetics; poly(ethylene) glycol; single chain variable fragments