This multidisciplinary translational research project has generated a predominantly human sequence monoclonal antibody (mAb) with high affinity (Kd = 4 nM) for cocaine and specificity over cocaine's inactive metabolites. This unique new molecular entity (preclinical designation, 2E2, a human gamma 1 (?1) heavy chain and mouse lamda (?) light chain) is at an advanced stage of preclinical development for use in the prevention of relapse in treatment-seeking cocaine abusers. The development of 2E2 has met several key safety and efficacy milestones. The mostly human structure of this mAb should be safe for repeated treatments in patients and should confer long-term efficacy. Anti-cocaine mAbs bind to and sequester cocaine in the peripheral circulation and we have shown that 2E2 dramatically lowers brain cocaine concentrations in mice. Furthermore, 2E2 decreases the effect of cocaine in a rat model of relapse. Our industry collaborator, Vybion Inc., has reengineered a novel version of our mAb with a human kappa (?) light chain constant region replacing the mouse constant region. The reengineered mAb protein (h2E2) has been transiently expressed and h2E2 retains the identical affinity and specificity for cocaine as 2E2. This represents a proof-of-concept milestone and h2E2 represents our new lead candidate for commercialization. Work will be continued towards the development of a stably transfected mammalian cell line capable of the high level production of h2E2, which will be required for its clinical development. Targeted modifications of h2E2's primary structure aim to increase protein expression levels and stability, thereby enhancing the cost-effectiveness of production. The overall goal of the proposed studies is to provide the comprehensive structural and efficacy data for the highly expressed variant of h2E2 and then produce sufficient quantities of purified h2E2 to support the in vivo toxicology studies that are required for an IND applicati

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZDA1-SXC-E (16))
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Chiang, Nora
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University of Cincinnati
Schools of Medicine
United States
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Wetzel, Hanna N; Zhang, Tongli; Norman, Andrew B (2017) A mathematical model of a recombinant humanized anti-cocaine monoclonal antibody's effects on cocaine pharmacokinetics in mice. Life Sci 184:81-86
Wetzel, Hanna N; Tsibulsky, Vladimir L; Norman, Andrew B (2016) The effects of a repeated dose of a recombinant humanized anti-cocaine monoclonal antibody on cocaine self-administration in rats. Drug Alcohol Depend 168:287-292
Kirley, Terence L; Greis, Kenneth D; Norman, Andrew B (2016) Selective disulfide reduction for labeling and enhancement of Fab antibody fragments. Biochem Biophys Res Commun 480:752-757
Kirley, Terence L; Greis, Kenneth D; Norman, Andrew B (2016) Structural characterization of expressed monoclonal antibodies by single sample mass spectral analysis after IdeS proteolysis. Biochem Biophys Res Commun 477:363-8
Kirley, Terence L; Norman, Andrew B (2015) Characterization of a recombinant humanized anti-cocaine monoclonal antibody and its Fab fragment. Hum Vaccin Immunother 11:458-67
Norman, Andrew B; Gooden, Felicia C T; Tabet, Michael R et al. (2014) A recombinant humanized anti-cocaine monoclonal antibody inhibits the distribution of cocaine to the brain in rats. Drug Metab Dispos 42:1125-31
Wetzel, Hanna N; Tabet, Michael R; Ball, William J et al. (2014) The effects of a humanized recombinant anti-cocaine monoclonal antibody on the disposition of cocaethylene in mice. Int Immunopharmacol 23:387-90
Norman, Andrew B; Tabet, Michael R; Norman, Mantana K et al. (2014) Maintained cocaine self-administration is determined by quantal responses: implications for the measurement of antagonist potency. J Pharmacol Exp Ther 348:311-5
Norman, Andrew B; Ball Jr, William J (2012) Predicting the clinical efficacy and potential adverse effects of a humanized anticocaine monoclonal antibody. Immunotherapy 4:335-43
Norman, Andrew B; Tabet, Michael R; Norman, Mantana K et al. (2011) Using the self-administration of apomorphine and cocaine to measure the pharmacodynamic potencies and pharmacokinetics of competitive dopamine receptor antagonists. J Neurosci Methods 194:252-8

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