Toxicokinetics of a humanized anti-cocaine monoclonal antibody in male and female rats and lack of cross-reactivity

Abstract

A humanized monoclonal antibody h2E2 designed to bind cocaine with high affinity, specificity, and a long half-life (~7 d in rats) is being developed as a treatment for cocaine use disorder. We report here a pharmacokinetic (PK) study of h2E2 using male and female rats conducted under a Good Laboratory Practice (GLP) protocol over a dose range of 40 to 1200 mg/kg. The maximum concentration measured in rat plasma (C_max) varied proportionately to the dose administered in both male and female rats. The terminal elimination half-lives (t_1/2β) were not significantly different in male and female rats at all doses tested. Importantly, this study reports pharmacokinetics for a humanized monoclonal antibody at a dose never tested before. h2E2 has a high affinity for cocaine, whereas low or no affinity was demonstrated for cocaine metabolites (all except cocaethylene), endogenous monoamines, and methamphetamine. This demonstrates its specificity and a potential lack of interactions with physiological and endocrine systems. A review of the clinical signs in single-dose toxicity studies in rats revealed no effects on the central nervous, respiratory, or cardiovascular systems following single intravenous doses of 40 to 1200 mg/kg. This study predicts that this monoclonal antibody may be safe and effective in humans.

Keywords: Cocaine addiction; h2E2; humanized; monoclonal antibody; pharmacokinetics; toxicokinetics.

Figure 1.

The pharmacokinetics of h2E2 mAb in male (Panel A) and female rats (Panel B).

Figure 2.

Area under the curve (AUC)and peak plasma concentration (C_max) for h2E2.

Figure 3.

ELISA binding curves for cocaine, its metabolites and other amines.