A Monoclonal Antibody Specific for 6-Monoacetylmorphine Reduces Acute Heroin Effects in Mice

Abstract

Immunotherapy against drugs of abuse is being studied as an alternative treatment option in addiction medicine and is based on antibodies sequestering the drug in the bloodstream and blocking its entry into the brain. Producing an efficient vaccine against heroin has been considered particularly challenging because of the rapid metabolism of heroin to multiple psychoactive molecules. We have previously reported that heroin's first metabolite, 6-monoacetylmorphine (6-MAM), is the predominant mediator for heroin's acute behavioral effects and that heroin is metabolized to 6-MAM primarily prior to brain entry. On this basis, we hypothesized that antibody sequestration of 6-MAM is sufficient to impair heroin-induced effects and therefore examined the effects of a monoclonal antibody (mAb) specific for 6-MAM. In vitro experiments in human and rat blood revealed that the antibody was able to bind 6-MAM and block the metabolism to morphine almost completely, whereas the conversion of heroin to 6-MAM remained unaffected. Mice pretreated with the mAb toward 6-MAM displayed a reduction in heroin-induced locomotor activity that corresponded closely to the reduction in brain 6-MAM levels. Intraperitoneal and intravenous administration of the anti-6-MAM mAb gave equivalent protection against heroin effects, and the mAb was estimated to have a functional half-life of 8 to 9 days in mice. Our study implies that an antibody against 6-MAM is effective in counteracting heroin effects.

Pharmacological Effects of a Monoclonal Antibody against 6-Monoacetylmorphine upon Heroin-Induced Locomotor Activity and Pharmacokinetics in Mice

“…Here, we report a considerable reduction in locomotor activity and 6-MAM levels in brain tissue after both heroin and 6-MAM administration in mAb-pretreated mice. These findings agree with previous reports that 6-MAM is the main contributor to the acute behavioral effects of heroin (Way et al, 1960Inturrisi et al, 1983Andersen et al, 2009;Gottås et al, 2013), and that 6-MAM sequestration is crucial for the efficacy of immunotherapy against heroin effects (Stowe et al, 2011;Bogen et al, 2014).…”

“…The anti-6-MAM mAb used in this study displayed high specificity for 6-MAM, lower specificity for heroin, and no specificity for morphine (Bogen et al, 2014). One may question whether the immediate heroin effect could have been inhibited more successfully by using a mAb with high specificity for heroin.…”

“…Antibody: Anti-6-MAM mAb [human immunoglobulin G1 (IgG1)] was provided by Affitech Research AS (Oslo, Norway) and has been described in more detail by Bogen et al (2014) and Moghaddam et al (2003). The mAb was dialyzed against phosphate buffer, diluted in 0.9% NaCl, and stored at -80°C.…”

“…Immunotherapy comprises active vaccination, in which the immune system is triggered to endogenously produce drugspecific antibodies, or passive immunization, in which preformed antibodies are administered directly by injection (Peterson and Owens, 2009;Shen and Kosten, 2011). Whereas recent studies have used an active vaccine strategy against opioids (Stowe et al, 2011;Pravetoni et al, 2012;Raleigh et al, 2013Raleigh et al, , 2014Schlosburg et al, 2013), the potential for monoclonal antibodies (mAbs) against heroin-induced effects has received minor attention (Killian et al, 1978;Bogen et al, 2014).…”

“…On the assumption that 6-MAM is the principal contributor to acute heroin effects and is delivered from the blood, we showed previously that a human mAb against 6-MAM (anti-6-MAM mAb) markedly reduced acute locomotor activity and the brain 6-MAM concentration after heroin injection in mice (Bogen et al, 2014). To develop efficient mAbs for immunotherapy against heroin, we need a better understanding of the individual contributions of heroin and its metabolites to the acute effects upon administration.…”