Effect of a Humanized Anti‐Cocaine Monoclonal Antibody on the Pharmacokinetics of Cocaine in Rats and Mice

• Published in: The FASEB journal 2013-04, Vol.27 (S1)
• Main Authors: Gooden, Felicia CT, Tabet, Michael R, Bartley, Erin L, Ball, William J, Norman, Andrew B
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.27.1_supplement.lb518

Abstract only Monoclonal antibody (mAb) h2E2 is a further humanized version of the high‐affinity anti‐cocaine mAb 2E2. h2E2 is a potential immunotherapeutic for cocaine abuse that retains the same high‐affinity (4 nM Kd) and specificity as 2E2 for cocaine over its inactive metabolites. Infused h2E2 (1.6 μmol/kg i.v.) in both mice and rats produced dramatic increases in the area under the plasma cocaine concentration‐time curve (AUC) and a concomitant decrease of >;90% in the brain AUC following an i.v. injection of an equimolar cocaine dose. Consequently, h2E2 substantially reduced cocaine's volume of distribution in both species by sequestering cocaine in plasma, indicating potential clinical efficacy. Furthermore, h2E2 did not inhibit the clearance of cocaine in either rats or mice. Interestingly, h2E2 restricted cocaine distribution and metabolism from plasma to a single‐compartment model in mice but cocaine disappearance remained multi‐compartmental in rats. This differential effect of h2E2 on cocaine distribution between species may be related to the metabolism of cocaine predominantly to ecgonine methylester (EME) in mice but to benzoylecgonine (BE) in rats. The metabolism of cocaine to BE and EME in humans is between that in mice and rats. Thus, these studies will help determine whether differences in cocaine metabolism are relevant to h2E2's clinical efficacy. Supported by NIH grant DP1DA031386.