In mice, the mAb 2E2 was shown to decrease the brain area under the time-concentration curve (AUC) by 78 %. This was accompanied by an increase in plasma concentrations (Norman et al. 2007). Similarly, in mice, when cocaine was injected i.v. one hour after i.v. administration of h2E2, there was a dramatic decrease in the brain cocaine AUC and an increase in plasma cocaine concentrations (unpublished data). These results support the proposed mechanism of action and indicate that these antibodies will be clinically efficacious.

The effectiveness of h2E2 against cocaethylene was tested in mice. Cocaethylene is an active metabolite of cocaine that is formed in the presence of ethanol. The mAb dramatically decreased the area under the cocaethylene time-concentration curve in the brain, consistent with h2E2’s high affinity for cocaethylene. This indicates that h2E2 will be effective in addicts that co-abuse cocaine and alcohol (Wetzel et al. 2014).

It may be expected that binding of cocaethylene to a large protein would slow its elimination by preventing enzymatic degradation. Indeed, the terminal elimination half-life of cocaethylene may have been decreased in the presence of h2E2. However, plasma cocaethylene concentrations did decline quite rapidly in the presence of h2E2 over the first hour after i.v. injection (Wetzel et al. 2014). More work is needed to see if this represents distribution to other compartments, metabolism, or clearance.

The murine antibody GNC92H2 has been shown to decrease premorbid behavior (convulsions, loss of righting posture, Straub tail response, agitation, and tonic seizures) (Carrera et al. 2005; Treweek and Janda 2012). The human antibody GNCgzk and its F(ab’)2 fragment prevented premorbid ataxia (Eubanks et al. 2014). Both these antibodies also decreased the lethality of cocaine.

Self-administration of cocaine in rats is the most commonly used model of addiction. The effects of four different anti-cocaine mAbs on self-administration have been characterized (Fox et al. 1996; Carrera et al. 2000; Kantak et al. 2000; Norman et al. 2009). Depending on the schedule of cocaine delivery, dose of antibody, and unit dose of cocaine, opposite effects on the rate of self-administration were observed both between and within studies. Our proposed explanation for this phenomenon is achieved by applying the compulsion zone theory to the observed results.

This theory states that self-administration events (lever presses) will only occur when cocaine concentrations are between two set points (Norman and Tsibulsky 2006). The upper limit of this zone is called the satiety threshold (Tsibulsky and Norman 1999), and the lower limit is the priming threshold (Norman et al. 1999). Therefore, rats will only press the lever when cocaine concentrations are above the priming threshold but below the satiety threshold. Reinstatement occurs when cocaine concentration is above the priming threshold. At this point, the rat will rapidly press the lever until concentrations cross the satiety threshold at which point self-administration will be very regular as concentrations periodically rise above and then fall to satiety threshold as the dose of cocaine is eliminated. An important feature of this model is that there are two important parameters: priming threshold, which is a measure of reinstatement probability, and satiety threshold, which is the pharmacodynamic parameter regulating maintained self-administration. Any study that only reports the number of presses or rate of pressing during a session does not differentiate these two parameters, making meaningful interpretation difficult, especially when the limited schedule of delivery potentially interferes with priming. Therefore, all studies conducted in the Norman lab separate reinstatement from maintenance and use an FR-1 schedule (Norman et al. 1999, 2002, 2009; Tsibulsky and Norman 1999; Norman and Tsibulsky 2006).

The simplest way to explain the potentially contradictory effects of mAbs on self-administration is in the context of the effects of the mAb 2E2 on priming threshold and satiety threshold (Norman et al. 2009). In this study, priming threshold was measured by giving non-contingent programmed injections of cocaine until self-administration was reinstated. This is a model of relapse and essentially measures the amount of cocaine needed to adequately raise plasma concentrations of the antibody to allow enough cocaine to cross into the brain and raise concentrations above the priming threshold. By this method of measurement, 2E2 initially raised the cocaine priming threshold threefold. In a human, this would mean that the patient is less likely to relapse after a given dose of cocaine. This increase in priming threshold accounts for the decrease in self-administration observed after treatment with the catalytic antibody 15A10 and the murine mAb GNC92H2. These results are consistent with each other, in that 15A10 decreased cocaine intake only at lower cocaine unit doses (Baird et al. 2000), while GNC92H2 only decreased intake at high antibody unit doses (Carrera et al. 2000). In both these cases, it is likely that the stoichiometric relationship between cocaine and antibody more favored the antibody, preventing enough cocaine to induce priming from ever reaching the brain. The mAb MO240 was shown to decrease self-administration, regardless of cocaine unit dose or mAb dose (Fox et al. 1996; Kantak et al. 2000).