title: Immunopharmacotherapeutic manifolds and modulation of cocaine overdose.
abstract: Cocaine achieves its psychostimulant, reinforcing properties through selectively blocking dopamine transporters, and this neurobiological mechanism impedes the use of classical receptor-antagonist pharmacotherapies to outcompete cocaine at CNS sites. Passive immunization with monoclonal antibodies (mAb) specific for cocaine circumvents this problem as drug is sequestered in the periphery prior to entry into the brain. To optimize an immunopharmacotherapeutic strategy for reversing severe cocaine toxicity, the therapeutic properties of mAb GNC92H2 IgG were compared to those of its engineered formats in a mouse overdose model. Whereas the extended half-life of an IgG justifies its application to the prophylactic treatment of addiction, the rapid, thorough biodistribution of mAb-based fragments, including F(ab')₂, Fab and scFv, may correlate to accelerated scavenging of cocaine and reversal of toxicity. To test this hypothesis, mice were administered the anti-cocaine IgG (180 mg/kg, i.v.) or GNC92H2-based agent after receiving an LD₅₀ cocaine dose (93 mg/kg, i.p.), and the timeline of overdose symptoms was recorded. All formats lowered the rate of lethality despite the >100-fold molar excess of drug to antibody binding capacity. However, only F(ab')₂-92H2 and Fab-92 H2 significantly attenuated the progression of premorbid behaviors, and Fab-92H2 prevented seizure generation in a percentage of mice. The calculation of serum half-life of each format demonstrated that the pharmacokinetic profile of Fab-92H2 (elimination half-life, t½~100 min) best approximated that of cocaine. These results not only confirm the importance of highly specific and tight drug binding by the mAb, but also highlight the benefit of aligning the pharmacokinetic and pharmacodynamic properties of the immunopharmacotherapeutic with the targeted drug.
authors.affiliation: Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Treweek
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Roberts
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003042:Cocaine / Q000009:adverse effects*; D062787:Drug Overdose; D004797:Enzyme-Linked Immunosorbent Assay; D006207:Half-Life; D008297:Male; D051379:Mice
chemical_list: D000911:Antibodies, Monoclonal; D003042:Cocaine