Jordan A. Marckel

Education

• 2020 (est). Ph.D in Pharmacology at University of Cincinnati, Ohio
• 2015. BS in Chemistry and Biology at University of Indianapolis, Indiana

Publications

Jordan A. Marckel, Hanna N. Wetzel, Sihame Amlal, Hassane Amlal, Andrew B. Norman (2019). A recombinant humanized anti-cocaine monoclonal antibody alters the urinary clearance of cocaine and metabolites in rats. Drug Metab Dispos 47; 184-188.

Research Summary

Currently, there are no FDA approved pharmacological treatments for cocaine addiction or overdose. The National Institute of Drug Abuse (NIDA) has deemed the development of new therapies and treatments be a top priority. There have been many approaches to this growing problem, such as targeting the dopaminergic system. However, these approaches have been largely unsuccessful. My lab has developed a humanized anti-cocaine monoclonal antibody, known as h2E2, which targets cocaine directly by binding to and sequestering cocaine into the body’s plasma compartment. We’ve observed in the presence of h2E2, cocaine’s distribution to the brain in mice decreased by 5-fold compared to the brains of vehicle control mice[1]. As previously published, h2E2 has a high binding affinity for cocaine and a long elimination half-life. Based on these characteristics, h2E2 is being studied for the use of relapse prevention in cocaine abusers and is at a late stage of preclinical development.

Cocaine self-administration in rats is a widely accepted animal behavior model for cocaine addiction. Using cocaine self-administration as a tool, potential therapies to alleviate cocaine abuse can be screened. The ability of a potential therapy to reduce reinstatement of self-administration behavior can determine how efficacious a therapy may be in humans. The priming threshold is the minimum concentration of cocaine that induces self-administration behavior. If a potential therapy can increase the priming threshold of cocaine and prevent the relapse of cocaine self-administration, it has the potential to be a useful treatment for cocaine abuse. In cocaine self-administration sessions in rats involving h2E2 (120 mg/kg dose), the priming threshold increases 3-fold compared to vehicle control rats[2]. A 3-fold increase in priming threshold is significant, but sparked another important question: does the priming threshold increase proportionally with increased h2E2 dose? Due to the long elimination half-life of h2E2 (7.1 days in mice [3], 7.8 days in rats[4]) a cumulative dosing schedule was designed to test h2E2 doses of 60 mg/kg, 120 mg/kg, 240 mg/kg, and 360 mg/kg on cocaine’s priming threshold in self-administering rats. Preliminary data analysis shows that there is a parallel rightward-shift in the dose-response curve, as the dose of h2E2 increases, so does too the priming threshold (unpublished data).

As h2E2 approaches clinical trials, we are thinking about the endpoint measures for clinical efficacy for h2E2. Classically, the endpoint measurement for potential cocaine abuse treatments is the presence of benzoylecgonine (BE), a major metabolite of cocaine, in the urine of clinical trial participants. However, h2E2 has a moderate binding affinity for BE and has the potential of altering BE’s urinary clearance. Therefore, we investigated the effects of h2E2 on the urinary clearance of cocaine and its metabolites in rats to determine if BE would remain an appropriate endpoint measure of clinical efficacy. In the presence of h2E2, cocaine and BE urinary excretion decreased by 92% and 91% compared to vehicle control rats (unpublished data). Therefore, the classical endpoint measurement of urine BE detection is not likely to provide an appropriate measure of h2E2’s clinical efficacy and should be avoided to prevent false positives in the clinical trials.

Cocaine is known as a sympathomimetic drug that has variety of effects on the human body besides the desirable euphoria-like effect. Several key cardiovascular effects include: increased vascular constriction, increased blood pressure, and hardening of blood vessels. Cocaine also increases norepinephrine activation on the beta1-adrenergic receptors in the myocardium, leading to increase contractility and heart rate. Plasma concentrations of cocaine in mice increase by 29-fold in h2E2 treated animals, due to h2E2’s ability to sequester cocaine into the plasma compartment[1]. A major issue that has been raised by the FDA and NIDA is the effects of cocaine on the cardiovascular system in the presence of h2E2. h2E2’s ability to bind to cocaine and sequester it into the plasma compartment could worsen that cardiovascular effects of cocaine. However, if cocaine is bound to the antibody with high affinity, h2E2 could possibly exert cardioprotective effects against cocaine. Using the guidance of an experienced cardiovascular physiologist Dr. Lorenz and his published technique, the above questions are currently being investigated [5].

Another potential application for h2E2 is its Fab fragment for the treatment of cocaine overdose. The Fab fragment is the smaller portion of the whole antibody that contains the cocaine binding pocket. Due to its smaller size, the Fab fragment is predicted to have a shorter distribution half-life and a larger volume of distribution compared to the whole antibody. Both of these characteristics are promising for the treatment of cocaine overdose. A pharmacokinetic study in mice revealed that the distribution half-life of the Fab fragment is 16.7 minutes (unpublished data) compared to h2E2 which has a distribution half-life of 13.5 hours[4]. The volume of distribution of the Fab fragment was indeed larger than h2E2 at 0.55 L/kg (unpublished data) compared to 0.2 L/kg[4]. The effects of the Fab fragment on cocaine’s distribution in mice samples currently being quantified to determine if the Fab fragment decreases cocaine from entering the brain as efficiently as h2E2. Once these studies have been completed, the Fab fragment therapeutic application can be further investigated.