Development of active and passive human vaccines to treat methamphetamine addiction

Abstract

Methamphetamine (METH) abuse is a major worldwide epidemic, with no specific medications for treatment of chronic or acute effects. Anti-METH antibodies have the potential to save lives and reduce the crippling effects of METH abuse. While they are not expected to be the magic bullet to immediately cure addiction, immunotherapy could provide a breakthrough medication to continuously block or attenuate METH effects during a comprehensive addiction recovery plan. A unique challenge for METH antibody antagonists is the need to protect the brain from the complex direct and indirect adverse effects of long-term METH use. To meet this challenge, a new generation of passive monoclonal antibodies and active immunization therapies are at an advanced stage of preclinical development. Both of these vaccines could play an essential role in a well planned recovery program from human METH addiction by providing long-lasting protection from the rewarding and reinforcing effect of METH.

Figure 1

Upper panel: METH effects in the brain, BEFORE anti-METH antibody treatment. After taking METH (circles), the drug is delivered to the brain through the blood stream (left barrel) where the drug rapidly penetrates the blood brain barrier (①, dashed line). In the brain, METH interacts with the dopamine transporter, monoamine oxidase, and vesicular transport mechanisms (②), causing CNS-related effects of METH (③). Because of the concentration gradient of METH across the blood brain barrier, more METH initially enters the brain (“in” arrow) than is removed (“out” arrow). Lower Panel: METH effects in the brain, AFTER anti-METH antibody treatment. In the presence of anti-METH antibodies (Y-shaped objects), METH is no longer able to freely move across the blood brain barrier, due to high affinity binding to the antibody. Thus, a much smaller amount of METH is able to penetrate the blood brain barrier (①, dashed line). Due to this altered drug concentration gradient, METH leaves the brain (“out” arrow) at a relatively higher rate than it enters. This results in a cascade of significantly reduced amounts, and rates of association, of METH at the sites of action within CNS nerve terminals (②, compare K_on and K_off arrows at nerve terminals before and after antibody treatment). Antibody binding of METH leads to significantly attenuated CNS (③) and peripheral effects, symbolized by the smaller arrows for CNS and peripheral effects in the lower panel.