An Antidote for Acute Cocaine Toxicity
- 20 March 2012
- journal article
- research article
- Published by American Chemical Society (ACS) in Molecular Pharmaceutics
- Vol. 9 (4), 969-978
- https://doi.org/10.1021/mp200588v
Abstract
Not only has immunopharmacotherapy grown into a field that addresses the abuse of numerous illicit substances, but also the treatment methodologies within immunopharmacotherapy have expanded from traditional active vaccination to passive immunization with anti-drug monoclonal antibodies, optimized mAb formats, and catalytic drug-degrading antibodies. Many laboratories have focused on transitioning distinct immunopharmacotherapeutics to clinical evaluation, but with respect to the indication of cocaine abuse, only the active vaccine TA-CD, which is modeled after our original cocaine hapten GNC, has been carried through to human clinical trials. The successful application of murine mAb GNC92H2 to the reversal of cocaine overdose in a mouse model prompted investigations of human immunoglobulins with the clinical potential to serve as cocaine antidotes. We now report the therapeutic utility of a superior clone, human mAb GNCgzk (K(d) = 0.18 nM), which offers a 10-fold improvement in cocaine binding affinity. The GNCgzk manifold was engineered for rapid cocaine clearance, and administration of the F(ab')₂ and Fab formats even after the appearance of acute behavioral signs of cocaine toxicity granted nearly complete prevention of lethality. Thus, contrary to the immunopharmacotherapeutic treatment of drug self-administration, minimal antibody doses were shown to counteract the lethality of a molar excess of circulating cocaine. Passive vaccination with drug-specific antibodies represents a viable treatment strategy for the human condition of cocaine overdose.Keywords
This publication has 37 references indexed in Scilit:
- Immunopharmacotherapeutic manifolds and modulation of cocaine overdosePharmacology Biochemistry and Behavior, 2011
- Superadditive Effects of Ethanol and Flunitrazepam: Implications of Using Immunopharmacotherapy as a TherapeuticMolecular Pharmaceutics, 2010
- Cocaine-Specific Antibodies Blunt the Subjective Effects of Smoked Cocaine in HumansBiological Psychiatry, 2010
- Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone-Maintained PatientsArchives of General Psychiatry, 2009
- Anti‐drug vaccines to treat substance abuseImmunology & Cell Biology, 2009
- Development and Preclinical Testing of a High-Affinity Single-Chain Antibody against (+)-MethamphetamineThe Journal of pharmacology and experimental therapeutics, 2008
- A Chimeric Human/Murine Anticocaine Monoclonal Antibody Inhibits the Distribution of Cocaine to the Brain in MiceThe Journal of pharmacology and experimental therapeutics, 2006
- Three-Dimensional Quantitative Structure−Activity Relationship Modeling of Cocaine Binding by a Novel Human Monoclonal AntibodyJournal of Medicinal Chemistry, 2003
- Treatment of Adverse Effects of Excessive Phencyclidine Exposure in Rats with a Minimal Dose of Monoclonal AntibodyThe Journal of pharmacology and experimental therapeutics, 2003
- Crystal structure of a cocaine-binding antibodyJournal of Molecular Biology, 2001