Treatment with a Monoclonal Antibody against Methamphetamine and Amphetamine Reduces Maternal and Fetal Rat Brain Concentrations in Late Pregnancy

Abstract

We hypothesized that treatment of pregnant rat dams with a dual reactive monoclonal antibody (mAb4G9) against (+)-methamphetamine [METH; equilibrium dissociation rate constant (K D ) = 16 nM] and (+)-amphetamine (AMP; K D = 102 nM) could confer maternal and fetal protection from brain accumulation of both drugs of abuse. To test this hypothesis, pregnant Sprague-Dawley rats (on gestational day 21) received a 1 mg/kg i.v. METH dose, followed 30 minutes later by vehicle or mAb4G9 treatment. The mAb4G9 dose was 0.56 mole-equivalent in binding sites to the METH body burden. Pharmacokinetic analysis showed baseline METH and AMP elimination half-lives were congruent in dams and fetuses, but the METH volume of distribution in dams was nearly double the fetal values. The METH and AMP area under the serum concentration-versus-time curves from 40 minutes to 5 hours after mAb4G9 treatment increased >7000% and 2000%, respectively, in dams. Fetal METH serum did not change, but AMP decreased 23%. The increased METH and AMP concentrations in maternal serum resulted from significant increases in mAb4G9 binding. Protein binding changed from ∼15% to > 90% for METH and AMP. Fetal serum protein binding appeared to gradually increase, but the absolute fraction bound was trivial compared with the dams. mAb4G9 treatment significantly reduced METH and AMP brain values by 66% and 45% in dams and 44% and 46% in fetuses (P < 0.05), respectively. These results show anti-METH/AMP mAb4G9 therapy in dams can offer maternal and fetal brain protection from the potentially harmful effects of METH and AMP.

The Main Molecular Mechanisms Underlying Methamphetamine- Induced Neurotoxicity and Implications for Pharmacological Treatment

“… Miller et al (2013) found that, in rats receiving a KLH-conjugated METH-like hapten vaccine (MH6-KLH) and the vaccine succinyl MA (SMA–KLH), higher antibody titer-dependent METH serum concentrations, yet lower METH concentrations, in the CNS were observed, which suggested reduced METH concentrations in the brain. In addition, it was shown that anti-METH/AMP mAb4G9 therapy protected maternal and fetal rat brains from METH-induced damage ( Gentry et al, 2006 ; White et al, 2014 ). Another study reported that a human–mouse monoclonal antibody binding to methylphenidate, named anti-METH antibody (mAB7F9), elicited a significant reduction in the METH concentration ( Ballester et al, 2017 ).…”

Substance Use in the Perinatal Period

“…While RBT appears to be promising intervention for methamphetamine use, further work is needed, particularly to ascertain whether pejorative attitudes towards methamphetamine might influence reporting rates. Interestingly a recent study showed that treatment with a monoclonal antibody therapy in pregnant rat dams offered maternal and fetal brain protection from adverse drug effects by reducing brain concentrations of methamphetamine [145]. Further work is needed to understand mechanisms underlying risks for methamphetamine use, and individuals for whom interventions might be more effective.…”

Detrimental effects of self-administered methamphetamine during pregnancy on offspring development in the rat

“…Exposure to repeated, high doses of METH (e.g., 10 – 40mg/kg) during pregnancy has been shown to increase dam/pup mortality, significantly reduce birth weight and produce teratogenic effects (Acuff-Smith et al, 1996; White et al, 2014). Notably, repeated administration of more moderate METH doses (e.g., 2.5 – 5mg/kg), before and throughout pregnancy, also has been shown to have profound effects on dams and offspring.…”