Associate editor: T.C.Napier
Immunotherapy for the treatment of drug abuse

https://doi.org/10.1016/j.pharmthera.2005.06.009Get rights and content

Abstract

Antibody therapy (as either active or passive immunization) is designed primarily to prevent drugs of abuse from entering the central nervous system (CNS). Antidrug antibodies reduce rush, euphoria, and drug distribution to the brain at doses that exceed the apparent binding capacity of the antibody. This is accomplished through a pharmacokinetic antagonism, which reduces the amount of drug in the brain, the rate of clearance across the blood–brain barrier, and the volume of drug distribution. Because the antibodies remain primarily in the circulatory system, they have no apparent central nervous system side effects. Active immunization with drug–protein conjugate vaccines has been tested for cocaine, heroin, methamphetamine, and nicotine in animal, with 1 cocaine and 3 nicotine vaccines in Phase 2 human trials. Passive immunization with high affinity monoclonal antibodies has been tested for cocaine, methamphetamine, nicotine, and phencyclidine (PCP) in preclinical animal models. Antibodies have 2 immediate clinical applications in drug abuse treatment: to treat drug overdose and to reduce relapse to drug use in addicted patients. The specificity of the therapies, the lack of addiction liability, minimal side effects, and long-lasting protection against drug use offer major therapeutic benefit over conventional small molecule agonists and antagonists. Immunotherapies can also be combined with other antiaddiction medications and enhance behavioral therapies. Current immunotherapies already show efficacy, but improved antigen design and antibody engineering promise highly specific and rapidly developed treatments for both existing and future addictions.

Section snippets

Introduction—immunization as a medication

During the 200 years since Jenner first used an active immunization vaccine for the prevention and treatment of human disease, only improvements in water quality have provided a greater impact on worldwide public health and life expectancy. Active immunizations generate protective antibodies in body fluids by stimulating an immune response to attack disease-related organisms or toxins. These antibodies work by blocking or reducing the viability or dose of foreign agent.

Recently, we have begun

Types of antiaddiction immunotherapies

Either active immunization or passive immunization can reduce drug levels in the brain by binding the drug before it enters the brain. For active immunization, drug–protein conjugate vaccines are repeatedly administered to stimulate the body to make its own antidrug antibodies. This then creates circulating antibodies and at the same time creates a long-term immunological memory for a more rapid response to the future booster injections with the vaccine. An important consideration in this

Specific immunotherapies for addictions—active vaccinations

Active immunization has been examined for cocaine, heroin, nicotine, and methamphetamine in animal and/or human studies.

Specific immunotherapies for addiction and drug overdose—passive monoclonal antibodies

Passive immunization with monoclonal antibodies has been examined for cocaine, methamphetamine, nicotine, and PCP in preclinical models. Like the studies using active immunization, many of the studies have focused on the ability of mAb to affect drug discrimination and relapse to drug use. Treatment of drug overdose and excessive long-term drug abuse has been assessed for 2 abused drugs—methamphetamine and PCP. This model of reducing drug toxicity extends to the sustained neurotoxicity that can

Applications of antiaddiction immunotherapies

Antibodies have 3 clinical applications in drug abuse treatment: to treat drug acute and chronic overdose, to reduce drug use relapse, or to protect certain at risk populations who have not yet become drug dependent (Harwood & Myers, 2004). Active immunization could potentially be used in most of these situations, except for drug overdose, where only passive immunotherapy with monoclonal antibodies will be suitable. This is because the dose of antibody stimulated by active immunization is

Technology advances for future immunotherapies

Technology advances in manufacturing and delivery systems will improve future antiaddiction vaccines. Perhaps, the most important will be a marked increase in the speed for discovering and bringing new antiaddiction treatments to market, as new abused drugs constantly evolve and are spread among the world population. Related medical advances will increase the stability and longevity of antibody blood levels and produce combination vaccines and new mAb to simultaneously treat a variety of abused

Conclusions

Preclinical development is rapidly progressing, and there are promising results form human studies for a cocaine vaccine and 3 nicotine vaccines in progress. The cocaine vaccine, TA-CD, has shown few side effects, reasonable antibody production, and positive clinical trends. The nicotine vaccines may prove more effective than cocaine vaccines because the antibody levels needed for blocking nicotine effects are a thousand times lower for nicotine than cocaine. However, immunotherapies are

Acknowledgments

This research was supported by the following NIDA grants to T. Kosten: SPIRCAP 1U19DA10946, P50-DA12762, P50-DA18197, K05-DA0454, R01-DA15477, and the Veterans Administration Mental Illness Research, Education, and Clinical Center (New England MIRECC). The following research grants support the research program of S.M. Owens: P01-DA014361, R01-DA7610, and R01-DA11560.

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      The first vaccine to be studied in psychiatry dates back to 1974 where active immunization with Morphine in a rhesus monkey was found to block the effects of Heroin ingested (Bonese et al., 1974). Thereafter, animal studies have established evidence of vaccines in the management of SUD such as nicotine, cocaine, opioids and stimulants and Alzheimer Disease (Kosten and Owens, 2005; Monsonego and Weiner, 2003). Considerable debate and controversy have been noted regarding the role of Measles Mumps Rubella (MMR) vaccine in causing Autism (Brogan, 2015; Plotkin et al., 2009).

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