title: Pharmacological effects of two anti-methamphetamine monoclonal antibodies. Supporting data for lead candidate selection for clinical development.
abstract: This lead candidate selection study compared two anti-(+)-methamphetamine (METH) monoclonal antibodies (mAb) to determine their ability to reduce METH-induced locomotor effects and redistribute METH and (+)-amphetamine (AMP) in a preclinical overdose model. Both mAbs have high affinity for METH, but mAb4G9 has moderate and mAb7F9 has low affinity for AMP. In the placebo-controlled behavioral experiment, the effects of each mAb on the locomotor response to a single 1 mg/kg intravenous (IV) METH dose were determined in rats. The doses of mAb binding sites were administered such that they equaled 1, 0.56, 0.32, and 0.1 times the molar equivalent (mol-eq) of METH in the body 30 min after the METH dose. METH disposition was determined in separate animals that similarly received either a 1 or 0.32 mol-eq dose of mAb binding sites 30 min after a 1 mg/kg METH dose. Total METH-induced distance traveled was significantly reduced in rats that received the highest three doses of each mAb compared with saline. The duration of METH effects was also significantly reduced by mAb7F9 at the highest dose. The disposition of METH was altered dose-dependently by both mAbs as shown in reductions of volume of distribution and total clearance, and increases in elimination half-life. These data indicate that both mAbs are effective at reducing METH-induced behavior and favorably altering METH disposition. Both were therefore suitable for further preclinical testing as potential human medications for treating METH use; however, due to results reported here and in later studies, mAb7F9 was selected for clinical development.
authors.affiliation: a University of Arkansas for Medical Sciences ; Dept. of Pharmacology and Toxicology ; Little Rock , AR USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Laurenzana
authors.forename: Misty W
authors.initials: MW
authors.lastname: Stevens
authors.forename: John C
authors.initials: JC
authors.lastname: Frank
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hambuchen
authors.forename: Howard P
authors.initials: HP
authors.lastname: Hendrickson
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: White
authors.forename: D Keith
authors.initials: DK
authors.lastname: Williams
authors.forename: S Michael
authors.initials: SM
authors.lastname: Owens
authors.forename: W Brooks
authors.initials: WB
authors.lastname: Gentry
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D062787:Drug Overdose / Q000628:therapy*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors*; D010919:Placebos / Q000008:administration & dosage; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D010919:Placebos; D008694:Methamphetamine
keywords: AMP, (+)-amphetamine; AUC, area under the concentration vs. time curve; ClT, total body clearance; Cmax, maximum concentration; IV, intravenous; JVC, jugular venous catheter; KD, dissociation constant; KI, concentration of inhibitor which prevents 50% of the target ligand from binding; LMA, locomotor activity; MDMA, (+)-3, 4-methylenedioxy-N-methylamphetamine; METH, (+)-methamphetamine; SD, standard deviation; Tmax, time of maximum concentration; Vd, volume of distribution; addiction; id, inner diameter; lead candidate selection; locomotor activity; mAb, monoclonal antibody; methamphetamine; mol-eq, molar equivalent; monoclonal antibody; overdose; pharmacokinetics; rat; t1/2λz, terminal elimination half-life