Monoclonal IgG affinity and treatment time alters antagonism of (+)-methamphetamine effects in rats.
The roles of monoclonal antibody affinity and treatment time of (+)-methamphetamine-induced pharmacological effects in rats were studied using two anti-(+)-methamphetamine monoclonal antibodies. These studies tested the preclinical protective effects of monoclonal antibody antagonists in (+)-methamphetamine overdose and pretreatment scenarios. The higher affinity antibody (mAb6H4; KD=11 nM for (+)-methamphetamine) more effectively antagonized (+)-methamphetamine-induced behavioral effects (distance and rearing) than the low affinity antibody (designated mAb6H8; KD=250 nM) and had a longer duration of action. Both antibodies more effectively reduced (+)-methamphetamine effects in the overdose model than in the pretreatment model. (+)-Methamphetamine pharmacokinetic studies showed the mAb6H4 significantly reduced brain concentrations over time in both models. However, while mAb6H4 immediately reduced brain concentrations in the overdose model, it did not prevent the initial distribution of (+)-methamphetamine into the brain in the pretreatment model. Thus, anti-(+)-methamphetamine monoclonal antibody affinity and administration time (relative to (+)-methamphetamine dosing) are critical determinants of therapeutic success.
Byrnes-Blake
Kelly A
KA
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Laurenzana
Elizabeth M
EM
Landes
Reid D
RD
Gentry
W Brooks
WB
Owens
S Michael
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000915:Antibody Affinity / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity; D004195:Disease Models, Animal; D062787:Drug Overdose / Q000188:drug therapy / Q000517:prevention & control; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000276:immunology / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000911:Antibodies, Monoclonal; D000697:Central Nervous System Stimulants; D007074:Immunoglobulin G; D008694:Methamphetamine