Pharmacological effects of two anti-methamphetamine monoclonal antibodies: Supporting data for lead candidate selection for clinical development

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...

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Bibliographic Details
Published in:Human vaccines & immunotherapeutics 2014-09, Vol.10 (9), p.2638-2647
Main Authors: Laurenzana, Elizabeth M, Stevens, Misty W, Frank, John C, Hambuchen, Michael D, Hendrickson, Howard P, White, Sarah J, Williams, D Keith, Owens, S Michael, Gentry, W Brooks
Format: Article
Language:English
Subjects:
1/2λz
addiction
AMP, (+)-amphetamine
Animals
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal - pharmacology
AUC, area under the concentration vs. time curve
concentration of inhibitor which prevents 50% of the target ligand from binding
Disease Models, Animal
dissociation constant
Drug Overdose - therapy
id, inner diameter
IV, intravenous
JVC, jugular venous catheter
lead candidate selection
LMA, locomotor activity
Locomotion - drug effects
locomotor activity
mAb, monoclonal antibody
Male
max
maximum concentration
MDMA, (+)-3, 4-methylenedioxy-N-methylamphetamine
METH, (+)-methamphetamine
methamphetamine
Methamphetamine - antagonists & inhibitors
mol-eq, molar equivalent
monoclonal antibody
overdose
pharmacokinetics
Placebos - administration & dosage
rat
Rats, Sprague-Dawley
Research Paper
SD, standard deviation
terminal elimination half-life
Time Factors
time of maximum concentration
total body clearance
Treatment Outcome
Vd, volume of distribution
Citations: Items that this one cites
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Summary: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.
ISSN:2164-5515
2164-554X
DOI:10.4161/hv.29707