Monoclonal IgG affinity and treatment time alters antagonism of (+)-methamphetamine effects in rats

doi:10.1016/j.ejphar.2005.08.016

European Journal of Pharmacology

Volume 521, Issues 1–3, 3 October 2005, Pages 86-94

https://doi.org/10.1016/j.ejphar.2005.08.016 Get rights and content

Abstract

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; K_D = 11 nM for (+)-methamphetamine) more effectively antagonized (+)-methamphetamine-induced behavioral effects (distance and rearing) than the low affinity antibody (designated mAb6H8; K_D = 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.

Introduction

(+)-Methamphetamine is a widely abused drug that can cause long-lasting effects. Because tolerance develops to the desired euphoric effects, (+)-methamphetamine is often taken repeatedly at high doses, which increases the incidence and severity of (+)-methamphetamine's adverse effects and addiction liability (Cho, 1990). Clinically significant central effects range from acute psychosis to chronic schizophrenia-like symptoms and depression (Cho, 1990, Seiden et al., 1993). There are also reports of long-term neurotoxicity caused by (+)-methamphetamine use (McCann et al., 1998, Ernst et al., 2000, Volkow et al., 2001). These effects can be severe, debilitating and even lethal at high doses. Thus, users often require treatment for overdose and for long-term addiction.

Unfortunately for (+)-methamphetamine users, there are no specific medications for use in an overdose situation or for reducing the potential for relapse to drug use (NIDA Research Report Series, 2002). Patients with a (+)-methamphetamine overdose can receive supportive care for their most serious symptoms, but full recovery requires the patient to wait for elimination of the drug from the body. These supportive and passive clinical treatments can be life saving, but since they do not remove (+)-methamphetamine agent from its sites of action in the brain, the potential for neurotoxicity still exists even if patients appear to be stabilized. For preventive therapy and rehabilitation, behavioral modification treatments are helpful for some addicts, and antidepressants can be used to combat the depression often found during (+)-methamphetamine abstinence; however, the relapse rate is still very high (Murray, 1998, National Institute on Drug Abuse, 2002).

Due in part to (+)-methamphetamine's multiple sites (e.g., central nervous system, cardiovascular system) and diverse mechanisms of action (Cho, 1990, Seiden et al., 1993, Sulzer et al., 1995), development of a traditional receptor antagonist has not been proven successful. An alternative approach is antibody-based therapy. A purposely designed monoclonal antibody with the suitable characteristics (e.g., affinity and specificity) could be used as a drug specific antagonist of drug effects. Used this way the monoclonal antibody would serve as a pharmacokinetic antagonist, which limits the drug to serum and intracellular fluid compartments through high affinity binding.

Previous studies in our laboratory have shown that a single dose of a high-affinity anti-phencyclidine monoclonal Fab (K_D = 1.8 nM; the antigen binding fragment of IgG) effectively reverses phencyclidine overdose in rats (Valentine et al., 1996), and that the intact monoclonal antibody (K_D = 1.3 nM; McClurkan et al., 1993) can produce immediate and long-term, reductions in brain phencyclidine concentrations (Proksch et al., 2000a, Laurenzana et al., 2003b). Furthermore, only a single dose of this anti-phencyclidine monoclonal antibody significantly protects against phencyclidine-induced locomotor effects in rats after repeated i.v. challenges for up to 2 weeks (Hardin et al., 2002). The pharmacokinetic and protective effects of anti-phencyclidine monoclonal antibody persist even when the binding capacity of the antibody was far exceeded and apparently saturated.

One of the reasons the anti-phencyclidine monoclonal antibody is so effective is that it has a very high affinity for phencyclidine. Indeed, the affinity of this antibody for phencyclidine is about 80 times higher than the affinity of the highest PCP binding sites in the central nervous system (Proksch et al., 2000b). Previous studies have evaluated the role of antibody affinity in treating overdose of other drugs. In studies of the effects of monoclonal and polyclonal anti-imipramine antibodies, Ragusi et al. (1998) demonstrate that higher affinity antibodies are more effective in redistributing the drug from the brain. While it is intuitive that a high affinity antibody for a drug would provide a significant clinical advantage in vivo, the optimal balance between in vivo drug association with the antibody (to block effects) and drug dissociation from the antibody (to allow regeneration of the binding capacity) is inadequately elucidated.

The purpose of the current experiments was to study the role of monoclonal antibody affinity in antibody-induced reductions of (+)-methamphetamine-induced pharmacological effects (behavioral and pharmacokinetic), in two preclinical models of (+)-methamphetamine abuse. This was accomplished by conducting new studies and integrating these data with a single data set from the previously published study of Byrnes-Blake et al. (2003). Two different anti-(+)-methamphetamine monoclonal antibodies, differing by about 25-fold in their affinities for (+)-methamphetamine (K_D = 11 nM and 250 nM), were tested in each of the preclinical models. Because the higher affinity antibodies were more effective in both models, and because both antibodies were more effective in the overdose model, these studies showed that monoclonal antibody affinity and time of administration (relative to (+)-methamphetamine dosing) are critical determinants of therapeutic success.

Section snippets

Drugs

³H-(+)-methamphetamine ((+)-[2′,6′-³H(n)]methamphetamine; 23.5 Ci/mmol), (+)-methamphetamine, and (+)-amphetamine were obtained from the National Institute on Drug Abuse (Bethesda, MD). Other reagents were obtained from Sigma Chemical Corporation (St. Louis, MO), unless otherwise noted. The synthesis of the (+)-P6-METH hapten (S-(+)-4-(5-carboxypentyl) methamphetamine HCl) is described by Byrnes-Blake et al. (2003). The (+)-P4-METH hapten (S-(+)-4-(3-carboxypropyl) methamphetamine HCl) was

Anti-(+)-methamphetamine monoclonal antibodies

The low affinity monoclonal antibody (mAb6H8; K_D = 250 nM) was generated from immunization with the (+)-P4-METH-BSA antigen, and the high affinity monoclonal antibody (mAb6H4; K_D = 11 nM) was generated from immunization with the (+)-P6-METH-BSA antigen. The monoclonal antibodies (IgG1, κ light chain) were highly specific for (+)-methamphetamine. All of the structurally unrelated drugs and neurotransmitters that were tested had no significant cross-reactivity (Byrnes-Blake et al., 2003).

Discussion

The overall goal of these studies was to determine the role of antibody affinity and time of monoclonal antibody dosing (relative to (+)-methamphetamine dosing) in antibody antagonism of (+)-methamphetamine-induced pharmacological effects. Both monoclonal antibodies were of the same isotype and light chain, and they were highly specific for (+)-methamphetamine, with no significant cross-reactivity with (+)-amphetamine. They differed in only one important aspect: an approximate 25-fold

Acknowledgments

The authors wish to thank Sherri Wood, Yingni Che, Melinda Gunnell, Marie Selders, and Alessandra Milesi-Hallè for their invaluable technical assistance. We also thank William J. Gabello with the UAMS Office of Grants and Scientific Publications for editorial assistance during the preparation of this manuscript.

This work was supported by NIDA grants to DA14361 and DA11560, and an Individual National Research Service Award F31 DA05939 to K.A. Byrnes-Blake.

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Rather, we view the female and male rats as representative models of human patients with different levels of METH vulnerability. Optimizing and maximizing in vivo affinity of the mAb for METH is a critical first step (Byrnes-Blake, Laurenzana, Landes, Gentry, & Owens, 2005; Peterson et al., 2007). For instance, high-affinity anti-METH mAb6H4 (Kd = 4 nM) is much more effective at antagonizing METH locomotor effects than the lower affinity anti-METH mAb6H8 (Kd = 250 nM).
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¹: Current address: ZymoGenetics, 1201 Eastlake Ave. East, Seattle, WA 98102, USA.

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Monoclonal IgG affinity and treatment time alters antagonism of (+)-methamphetamine effects in rats

Abstract

Introduction

Section snippets

Drugs

Anti-(+)-methamphetamine monoclonal antibodies

Discussion

Acknowledgments

Eur. J. Pharmacol.

Anal. Biochem.

Neuropharmacology

Eur. J. Pharmacol.

Brain Res.

Pharmacokinetics of heterologous and homologous immunoglobulin G, F(ab′)2 and Fab after intravenous administration in the rat

J. Pharm. Pharmacol.

Ice: a new dosage form of an old drug

Science

Evidence for long-term neurotoxicity associated with methamphetamine abuse: a 1H MRS study

Neurology

Behavioral sensitization to methamphetamine in the rat: an ontogenic study

Psychopharmacology

Pharmacodynamics of a monoclonal antiphencyclidine Fab with broad selectivity for phencyclidine-like drugs

J. Pharmacol. Exp. Ther.

A single dose of monoclonal anti-phencyclidine IgG offers long-term reductions in phencyclidine behavioral effects in rats

J. Pharmacol. Exp. Ther.

Use of anti-(+)methamphetamine monoclonal antibody to significantly alter (+)methamphetamine and (+)amphetamine disposition in rats

Drug Metab. Dispos.

Treatment of harmful effects of excessive phencyclidine exposure in rats with a minimal dose of monoclonal antibody

J. Pharmacol. Exp. Ther.

Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN-35,428

J. Neurosci.

Disposition of a monoclonal anti-phencyclidine fab fragment of immunoglobulin G in rats

J. Pharmacol. Exp. Ther.