A Humanized Anti‐Cocaine Monoclonal Antibody Decreases the Urinary Excretion of Cocaine from Mice (LB588)

Abstract

The recombinant humanized monoclonal antibody (mAb) h2E2 is a lead candidate for immunotherapy of cocaine abuse. This anti‐cocaine mAb has been shown in vivo to inhibit cocaine’s distribution to mouse brain by 19‐fold compared to controls, with an equivalent increase in plasma cocaine concentrations. Despite binding to h2E2 in plasma, cocaine appears to be eliminated more rapidly than in controls. However, in vitro studies using pH‐buffered (1:1) mouse plasma demonstrated that h2E2 protects cocaine from metabolism to the major inactive metabolites of cocaine, ecgonine methyl ester (EME) and benzoylecgonine (BE). As cocaine and its metabolites are also excreted renally, tests for abuse measure urine concentrations of cocaine and BE. It is hypothesized ‐ based upon h2E2’s high affinity and effects on cocaine’s distribution and metabolism ‐ that the presence of h2E2 would decrease urinary excretion of cocaine, EME, and BE. This hypothesis was tested in male Swiss‐Webster mice pre‐treated with an i.v. infusion of vehicle or h2E2 (1.6 µmol/kg) 1 hour prior to i.v. bolus injection of an equimolar dose of cocaine HCl. Excreted urine was collected 17‐20 minutes after cocaine administration and cocaine, EME, and BE concentrations were determined using GC/MS. The mAb h2E2 caused dramatic 8‐fold (88%), 7.7‐fold (87%), and 3.6‐fold (72%) decreases in urinary cocaine, BE, and EME concentrations, respectively, as compared to levels in the absence of h2E2. If similar effects occur in humans, caution should be used when interpreting efficacy measures of anti‐cocaine vaccines and mAbs that are based on urine cocaine and metabolite concentrations.Grant Funding Source: Supported by NIH grant DP1DAP31386.