title: A recombinant humanized anti-cocaine monoclonal antibody inhibits the distribution of cocaine to the brain in rats.
abstract: The monoclonal antibody (mAb), h2E2, is a humanized version of the chimeric human/murine anti-cocaine mAb 2E2. The recombinant h2E2 protein was produced in vitro from a transfected mammalian cell line and retained high affinity (4 nM Kd) and specificity for cocaine over its inactive metabolites benzoylecgonine (BE) and ecgonine methyl ester. In rats, pharmacokinetic studies of h2E2 (120 mg/kg i.v.) showed a long terminal elimination half-life of 9.0 days and a low volume of distribution at steady state (Vdss) of 0.3 l/kg. Pretreatment with h2E2 produced a dramatic 8.8-fold increase in the area under the plasma cocaine concentration-time curve (AUC) and in brain a concomitant decrease of 68% of cocaine's AUC following an i.v. injection of an equimolar cocaine dose. Sequestration of cocaine in plasma by h2E2, shown via reduction of cocaine's Vdss, indicates potential clinical efficacy. Although the binding of cocaine to h2E2 in plasma should inhibit distribution and metabolism, the elimination of cocaine remained multicompartmental and was still rapidly eliminated from plasma despite the presence of h2E2. BE was the major cocaine metabolite, and brain BE concentrations were sixfold higher than in plasma, indicating that cocaine is normally metabolized in the brain. In the presence of h2E2, brain BE concentrations were decreased and plasma BE was increased, consistent with the observed h2E2-induced changes in cocaine disposition. The inhibition of cocaine distribution to the brain confirms the humanized mAb, h2E2, as a lead candidate for development as an immunotherapy for cocaine abuse.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio andrew.norman@uc.edu.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Norman
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Felicia C T
authors.initials: FC
authors.lastname: Gooden
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Tabet
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: William J
authors.initials: WJ
authors.lastname: Ball
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D003042:Cocaine / Q000097:blood / Q000276:immunology* / Q000493:pharmacokinetics; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000911:Antibodies, Monoclonal; D003042:Cocaine
references.citation: Biol Psychiatry. 2005 Jul 15;58(2):158-64
references.pmid: 16038686
references.citation: J Pharm Pharmacol. 1975 Oct;27(10):784-6
references.pmid: 241797
references.citation: Immunotherapy. 2012 Mar;4(3):335-43
references.pmid: 22401638
references.citation: Ther Drug Monit. 2000 Jun;22(3):266-70
references.pmid: 10850392
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10176-81
references.pmid: 9707620
references.citation: J Med Chem. 2004 Jan 1;47(1):133-42
references.pmid: 14695827
references.citation: Drug Metab Dispos. 2003 Nov;31(11):1320-6
references.pmid: 14570763
references.citation: Neurotoxicol Teratol. 1997 Jan-Feb;19(1):7-15
references.pmid: 9088006
references.citation: J Pharmacol Exp Ther. 2009 Mar;328(3):873-81
references.pmid: 19088302
references.citation: Nat Med. 1996 Oct;2(10):1129-32
references.pmid: 8837612
references.citation: Drug Alcohol Depend. 1997 Dec 15;48(3):153-8
references.pmid: 9449013
references.citation: Drug Metab Dispos. 2005 Jul;33(7):1056-61
references.pmid: 15843487
references.citation: J Pharm Pharmacol. 1997 Mar;49(3):277-81
references.pmid: 9231345
references.citation: Comput Methods Programs Biomed. 2010 Sep;99(3):306-14
references.pmid: 20176408
references.citation: Vaccine. 2002 Jan 15;20(7-8):1196-204
references.pmid: 11803082
references.citation: J Pharmacol Exp Ther. 2007 Jan;320(1):145-53
references.pmid: 17023573
references.citation: J Pharmacol Exp Ther. 2000 Mar;292(3):831-7
references.pmid: 10688594
references.citation: Pharmacol Ther. 2005 Oct;108(1):76-85
references.pmid: 16023218
references.citation: Biotechnol Bioeng. 2003 Jun 5;82(5):612-8
references.pmid: 12652485
references.citation: Nat Biotechnol. 2005 Sep;23(9):1117-25
references.pmid: 16151405
references.citation: Nature. 1995 Dec 14;378(6558):727-30
references.pmid: 7501020
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):6202-6
references.pmid: 10823960
references.citation: J Pharmacol Exp Ther. 1996 Aug;278(2):717-24
references.pmid: 8768723
references.citation: Stroke. 1997 Nov;28(11):2296-302
references.pmid: 9368579