Novel Targets for Medication Development

Immunopharmacotherapy

A novel approach to the pharmacotherapy of addiction is largely pharmacokinetic. Immunopharmacotherapy uses highly specific antibodies to sequester the drug of interest while it is still in the bloodstream, thus preventing the drug from reaching the brain. An antibody-drug complex will prevent the drug from crossing the blood-brain barrier into the brain and thus, by definition, will block the pharmacodynamic actions of the drug. The reinforcing effects of the drug are blocked, and the detrimental side effects on the central nervous system or other organs of the body are blocked. How does immunopharmacotherapy work? In an active immunization approach, an appropriate antigenic drug protein conjugate is directly administered, which causes immune cell activation, leading to the generation of specific antibodies to the drug protein conjugate. The immune system has not evolved to generate a response for molecules that are less than about 10 kDa, a limit that is well above the molecular weight of any drug of abuse. Thus, small-molecule drugs, such as drugs of abuse, must be linked to a carrier protein to trigger an immune response, and this small molecule part of the vaccine is termed a hapten (Box 9.5). The active immunization approach is able to confer longer-lasting protection through immunological memory with minimal treatment compliance and thus is very cost effective. Nevertheless, active immunization requires some exposure time to generate antibodies before protection is conferred; it is also subject to a significant amount of individual variability.

In passive immunization, administration provides immediate protection through the injection of pre-generated high affinity antibodies, typically of the monoclonal type (Box 9.5). Such an approach to the addiction field has been argued to be particularly relevant in a drug overdose scenario as well as during the critical time points during relapse to addiction. However, in passive immunization, the effects are shorter-lasting, depend on the antibody half-life, and are limited to the amount of antibodies supplied.

Successful active immunization with vaccines in animal models has been reported for cocaine, nicotine, phencyclidine, methamphetamine, and heroin. Two nicotine vaccines have been tested in clinical trials. One of these vaccines, NicVAX, was shown to be safe and well tolerated in Phase I and II clinical trials in both smokers and non-smokers. However, it failed to meet its primary endpoints in two separate Phase III trials, even though approximately one-third of the highest-dose vaccine subjects quit smoking. Another nicotine vaccine, NIC002, met a similar fate. A cocaine vaccine (TA-CD) has produced marginal results in promoting continuous abstinence in humans because of substantial variability in the generation of high antibody titers. Another cocaine vaccine and a heroin vaccine are in different stages of preparation for clinical trials. Despite the failure to date of these clinical candidates to meet their primary endpoints, the results demonstrate the feasibility of a vaccine approach for the treatment of addiction: active immunization using nicotine or cocaine immunoconjugates can produce high titers of anti-drug antibodies. However, the magnitude of the immune response to vaccination in humans has been highly variable to date and will need to be addressed in future studies (for further reading, see Brimijoin et al., 2013; Moreno and Janda, 2009).

BOX 9.5

IMMUNOLOGICAL TERMS

Vaccine

A biological preparation that is administered to produce or increase immunity, usually to a particular disease. In the case of vaccines for drugs of abuse, the hapten combined with a carrier protein stimulates antibodies to form in the blood that recognize the drug as a foreign object and destroy it.

Hapten

A small separable part of an antigen that reacts specifically with an antibody but is incapable of stimulating antibody production except in combination with a carrier protein molecule.

Antigen

Any substance that is capable of inducing a specific immune response and reacting with a specific antibody.

B cells

A group of white blood cells, known as lymphocytes, which can bind to a specific antigen and produce antibodies to it.

Monoclonal antibody

Any of a large number of high-molecular-weight proteins that are normally produced by specialized B cells but derived from a single B cell after stimulation by an antigen and act specifically against the antigen in an immune response.

Adjuvant

A substance that is added to a vaccine that enhances the immune response to an antigen.

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