Safety and efficiency of an anti-(+)-methamphetamine monoclonal antibody in the protection against cardiovascular and central nervous system effects of (+)-methamphetamine in rats

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Abstract

The purpose of these studies was to determine if a high-affinity, anti-(+)-methamphetamine (METH) monoclonal antibody (mAb6H4; KD = 11 nM) protects against METH-induced central nervous and cardiovascular system effects in rats. Rats (n = 5 per group) received one of three anti-METH mAb6H4 doses, equal to 0.32, 0.56 or 1 times the mole equivalent (mol-eq) amount of METH in the body following a 1 mg/kg iv METH dose. Each rat was challenged with METH (1 mg/kg, iv) 1 and 4 days after the anti-METH mAb dose. The 1 mol-eq anti-METH mAb dose significantly reduced the duration of METH-induced locomotor activity (horizontal locomotion and rearing events), heart rate and blood pressure effects from 2 to 3 h to about an hour. This resulted in a significant reduction in total locomotor activity and the area under the hemodynamic effect vs. time curve for heart rate and blood pressure. In addition, the time to peak locomotor activity was decreased after the 1 mol-eq mAb dose vs. the lower doses. These changes were limited to the first METH challenge. The responses to the second METH challenge were not different from baseline. The peak hemodynamic and locomotor activity values were unchanged after both challenges. These results indicate anti-METH mAb6H4 can safely reduce the hemodynamic and locomotor effects of METH given one day after anti-METH IgG, and that the mAb is safe when administered in the absence of METH. These results are important because they indicate these antibody medications have simultaneous beneficial effects in multiple organ systems.

Introduction

New medications are needed to treat the broad spectrum of effects caused by drug abuse. Specific, high-affinity anti-drug antibodies have begun to be evaluated in animal models for use in passive immunization regimens to prevent and to reverse the effects of the abused drug. For example, anti-drug antibodies have been shown to attenuate central nervous system- (CNS) mediated hyperactivity in animal models of (+)-methamphetamine (METH) [1], phencyclidine (PCP) [2] and nicotine toxicity [3]. The significant reductions in spontaneous locomotion caused by each of these antibodies suggest antibody antagonists can protect against drug effects.

Pharmacologic protection against the CNS effects of subsequent human drug use is important because of its potential for use in long-term treatment programs. By reducing the pleasurable effects of drug abuse in humans, antibodies could provide potentially long-lasting protection against the reinforcing effects of the drug, and thereby reduce the chance of reinstatement of drug use. Indeed, a major therapeutic goal for passive immunization with anti-drug antibodies is relapse prevention [4]. Preclinical studies have shown that a single dose of a high affinity anti-METH monoclonal antibody (mAb) is effective in reducing self-administration of intravenous METH in rats [5]. These data suggest anti-drug antibodies could be a useful medication in human treatment programs by reducing drug effects that promote self-administration.

The use of a passive approach to the treatment of METH abuse is also advantageous because of the potential for treatment in an immunocompromised population. Unlike active vaccines, which rely on a functional immune system to generate the antibody response, passive antibody administration results in immediate protection. This is particularly important in the treatment of METH abuse, since METH has now been shown to reduce the user's ability to fight infection, including HIV.

Previous studies for METH have shown that a single dose of a high-affinity anti-METH mAb given prior to a single intravenous METH dose significantly reduces brain METH concentrations by about 60% while increasing serum concentrations over 6000% [6]. Because of their ability to bind drugs in the blood stream, specific anti-drug antibodies also reduce drug concentrations in other tissues. For instance, Valentine and Owens report that a single dose of a high-affinity monoclonal anti-PCP Fab administered after an intravenous bolus dose of PCP significantly reduces heart PCP concentrations [7]. Therefore, a significant therapeutic advantage of anti-drug antibody medications is that they have the potential to attenuate or prevent adverse drug effects in multiple organ systems via reduction in tissue drug concentrations.

Because of the widespread sympathomimetic effects of METH, the cardiovascular system (CVS) is particularly vulnerable. METH can cause severe, dangerous CVS stimulation resulting in hypertension, tachycardia and dysrhythmias that can cause myocardial infarction and sudden cardiac death [8], [9], [10]. These serious medical consequences can occur at the same METH doses that produce effects desired by the user such as increased energy, euphoria, and heightened awareness. These doses may also result in undesired CNS effects like paranoia, seizures and stroke. Because of the potential for METH-induced CVS morbidity, any medication used during the treatment of METH addiction should at least cause no increase in CVS morbidity, and, at best, attenuate its effects.

While previous data show that passive immunization is effective in preventing some CNS effects of METH in rodent models [1], the effects of anti-METH antibodies on the hemodynamic effects of METH have not been tested. This is important to test because the mechanism of mAb action is redistribution of the target drug back into the bloodstream. The redistribution has the potential to increase the exposure of the heart and blood vessels to higher drug concentrations, potentiating its effect on this organ system.

The purpose of the current studies was to determine the anti-METH mAb dose–response and time-dependent relationships involved in the reduction of METH-induced CVS and CNS stimulant effects. Rats received one of three anti-METH mAb doses prior to challenges with single METH doses administered one and four days after the mAb dose. Measures of CNS (locomotor activity) and CVS (hemodynamics) effects of METH were used to determine the effectiveness of the antibody. Finally, METH and the metabolite (+)-amphetamine (AMP) serum concentrations were determined following the 2nd METH challenge in all rats.

Section snippets

Antibodies, drugs and reagents

(+)-Methamphetamine HCl was obtained from the National Institute of Drug Abuse (Rockville, MD). The monoclonal antibody used in this study (designated mAb6H4) was developed, produced and purified as previously described [11]. Anti-METH mAb6H4 is a murine IgG1, κ light chain with a KD = 11 nM for METH and no significant cross reactivity for (+)-amphetamine. All other reagents were purchased from Sigma Chemical Company (St. Louis, MO) unless otherwise specified.

Animals

All animal experiments were carried

General experimental observations

All animals tolerated all four METH doses (2 control and 2 challenge doses) well and completed the study. Over the course of the repeated METH dosing, none lost weight or demonstrated other signs of stress such as chromodacryorrhea. Similarly, the average pre-METH baseline values (i.e., − 40 to − 10 min data) for the locomotor activity did not change within each antibody dose group from the administration of the second control METH dose through the second METH challenge dose (Table 1).

Discussion

This is the first study to demonstrate the therapeutic effectiveness of an anti-METH mAb in the simultaneous prevention and reduction of METH effects in two critical organ systems, the CNS and CVS. METH causes its harmful (and user-desired) effects via action on multiple catecholamine transporter and vesicular storage systems throughout the body; therefore, an effective mechanism for blocking or reducing its effects would be to prevent METH from reaching its sites of action, or to facilitate

Acknowledgements

The authors wish to thank Yingni Che, Melinda Gunnell, Howard Hendrickson, Alessandra Milesi-Hallè, and Sherri Wood for their invaluable technical assistance. This work was supported by National Institute on Drug Abuse grants DA11560 and DA14361.

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