Elsevier

Drug and Alcohol Dependence

Volume 48, Issue 3, 15 December 1997, Pages 153-158
Drug and Alcohol Dependence

Development of a therapeutic vaccine for the treatment of cocaine addiction

https://doi.org/10.1016/S0376-8716(97)00121-XGet rights and content

Abstract

No pharmacotherapies have yet been approved for the treatment of cocaine addiction. One new approach is to block the effects of cocaine with anti-cocaine antibodies induced by a therapeutic cocaine vaccine. A cocaine vaccine has been developed which induces a cocaine-specific antibody response in rodents. The antibody binds to cocaine in the circulation and can be shown to inhibit the ability of cocaine to enter the brain. Furthermore, anti-cocaine antibody can inhibit cocaine self-administration in rats. These data suggest that a cocaine vaccine may be a powerful therapeutic tool. The intent is to immunized motivated patients with the vaccine as part of a comprehensive treatment program. If the patient uses cocaine after being vaccinated, the antibody will inhibit the reinforcing activity of cocaine and decrease the likelihood of relapse.

Introduction

Cocaine abuse is a major medical and public health concern in the United States, with 2.1 million people estimated to be dependent on cocaine (Institute of Medicine, 1995). The cumulative effects of cocaine-associated violent crime, loss in individual productivity, illness and death, has led the National Institute on Drug Abuse (NIDA) to identify the development of an effective pharmacological treatment for cocaine addiction as its top priority. Despite the intense interest in this area, no effective long term pharmacotherapies are yet available (Carroll et al., 1994).

A new strategy being developed for the treatment of cocaine addiction is to block the effects of cocaine through the use of a therapeutic cocaine vaccine. The vaccine induces anti-cocaine antibodies within the subject that bind cocaine in the circulation. If the patient uses cocaine after being vaccinated, the antibodies will inhibit the ability of cocaine to enter the brain. As a result, the reinforcing activity of cocaine is expected to be reduced. Motivated patients would be immunized with the vaccine as part of a comprehensive treatment program aimed at relapse prevention.

Cocaine has been described as a `dirty drug' (Uhl et al., 1996), with multiple targets in the CNS. The reinforcing properties of cocaine are largely due to the drug's ability to block the dopamine transporter, thus resulting in prolonged stimulation of dopamine receptors (Ritz et al., 1988, Giros et al., 1996). However, cocaine binding to the transporters for serotonin and norepinephrine also contributes to the action of cocaine (Miller et al., 1989, Carroll et al., 1994). The inability to generate an effective pharmacotherapy for the treatment of cocaine addiction is, at least in part, due to the complexities of cocaine pharmacology. These complexities would be by-passed by the use of a cocaine vaccine. Anti-cocaine antibodies induced by a cocaine vaccine, by inhibiting the entry of cocaine into the brain, will inhibit the ability of cocaine to interact with all of its targets in the CNS.

The specificity of the cocaine vaccine for the drug, rather than for its target, should also minimize interference with other therapies. The cocaine vaccine would be expected to synergize with other experimental therapies that target cocaine's action in the brain or the symptoms associated with cocaine withdrawal. This is particularly important because it is unlikely that any one therapy will provide a `magic bullet' for the complex disease of addiction. The utility of the vaccine in a therapeutic setting should also be enhanced by the fact that the antibodies should not have any direct psychoactive effect and should not themselves be reinforcing. The lack of reinforcing activity should not limit compliance with the medication, because antibody responses are long-lasting. Following a series of 3 monthly immunizations, it should be possible to achieve a high-titer anti-cocaine antibody response that is maintained for months or years.

The idea of developing antibodies against abused drugs as a research tool has been around for more than 20 years. In 1974, Bonese et al. immunized a rhesus monkey against morphine and demonstrated that the antibodies specifically altered the animal's response to heroin (Bonese et al., 1974). This was followed by another report 2 years later that passive transfer of morphine-immune serum could alter the self-administration of heroin in rhesus monkeys (Killian et al., 1978). While these data were very promising, at the time the prospects with naltrexone appeared even better (Schuster, personal communication). Research in the area of immunotherapy for drug abuse moved away from addiction therapy and towards the more limited area of passive transfer of specific antibody for the treatment of drug overdose (Kelly and Smith, 1996).

In the last several years, two groups have reported on the possibility of treating cocaine addiction with a therapeutic vaccine. Investigators at Scripps described the synthesis of a cocaine–protein conjugate that could induce cocaine-specific antibodies in rats (Carrera et al., 1995). The induced antibodies were shown to inhibit the locomotor activity of cocaine following intraperitoneal injection of the drug. Furthermore, brain levels of cocaine were reduced in immunized rats 30 min after cocaine injection. These data have been extended by Fox et al. at ImmuLogic, using a different cocaine–protein conjugate vaccine (Fox et al., 1996). We demonstrated that anti-cocaine antibodies could block the reinforcing effects of cocaine following intravenous administration of the drug. Furthermore, the vaccine could induce long-lasting antibody responses in immunized mice. This paper summarizes these data.

Section snippets

Induction of antibody response

Cocaine itself cannot induce an immune response and must be covalently attached to a protein in order to be immunogenic. The carrier protein serves two functions. It both stimulates T-cells to provide help for antibody production and it provides a scaffolding, rendering cocaine multivalent and able to cross-link immunoglobulin on the surface of B-cells. Similar technology is used for several conjugate vaccines currently on the market, including the series of Haemophilus influenzae type b

Effect of vaccine on cocaine pharmacokinetics

These data suggested that the antibodies produced by immunization of mice with the cocaine vaccine had the appropriate specificity and were present in sufficient quantities to significantly alter the distribution and behavior of cocaine in vivo. To test this directly, the effect of the vaccine-induced antibody on cocaine pharmacokinetics was analyzed. Immunized mice were injected intravenously with [3H]cocaine at 1 mg/kg and tissue distribution was measured. Intravenous injection not only

Effect of vaccine on cocaine self-administration

These data demonstrate that the cocaine vaccine induced levels of antibody in mice that altered the pharmacokinetics of cocaine at clinically relevant doses and routes of administration. The presence of the antibody significantly inhibited the levels of cocaine present in the brain, but it did not completely prevent entry of the drug into the brain. Is this level of inhibition sufficient to affect behavior? Data from the literature strongly suggests that blunting the response to cocaine will be

Acknowledgements

Partial funding for these studies was received from an SBIR grant from NIDA. I would like to thank Drs K. Kantak and T. Briner for critical review of this manuscript and Heather Tighe for excellent secretarial assistance.

References (20)

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