Probing Active Cocaine Vaccination Performance through Catalytic and Noncatalytic Hapten Design

Abstract

Presently, there are no FDA-approved medications to treat cocaine addiction. Active vaccination has emerged as one approach to intervene through the rapid sequestering of the circulating drug, thus terminating both psychoactive effects and drug toxicity. Herein, we report our efforts examining two complimentary, but mechanistically distinct active vaccines, i.e., noncatalytic and catalytic, for cocaine treatment. A cocaine-like hapten GNE and a cocaine transition-state analogue GNT were used to generate the active vaccines, respectively. GNE-KLH was found to elicit persistent high-titer, cocaine-specific antibodies, and blunt cocaine induced locomotor behaviors. Catalytic antibodies induced by GNT-KLH were also shown to produce potent titers and suppress locomotor response in mice; however, upon repeated cocaine challenges the vaccine’s protecting effects waned. In depth kinetic analysis suggested that loss of catalytic activity was due to antibody modification by cocaine. The work provides new insights for the development of active vaccines for the treatment of cocaine abuse.

Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anticocaine Vaccine

“…To attenuate the positive subjective effects and the direct reinforcing effects of cocaine, we have developed dAd5GNE, an anticocaine vaccine designed to prevent administered cocaine from reaching the brain (Hicks et al, 2011;Wee et al, 2012;Maoz et al, 2013). dAd5GNE is comprised of a disrupted serotype 5 adenovirus E1 -E3 -gene transfer vector to which GNE (Cai et al, 2013), a cocaine analog, is covalently attached. The vaccine is designed to leverage the strong antiadenovirus immune response in humans to produce high-avidity antibodies against cocaine (Harvey et al, 1999;Chirmule et al, 1999;Hackett et al, 2000;Hicks et al, 2011;Wee et al, 2012;Maoz et al, 2013;Cai et al, 2013).…”

“…dAd5GNE is comprised of a disrupted serotype 5 adenovirus E1 -E3 -gene transfer vector to which GNE (Cai et al, 2013), a cocaine analog, is covalently attached. The vaccine is designed to leverage the strong antiadenovirus immune response in humans to produce high-avidity antibodies against cocaine (Harvey et al, 1999;Chirmule et al, 1999;Hackett et al, 2000;Hicks et al, 2011;Wee et al, 2012;Maoz et al, 2013;Cai et al, 2013). High levels of high-avidity anticocaine antibodies prevent systemically administered cocaine from crossing the blood-brain barrier and entering the CNS and reaching the cognate receptors in the brain (Maoz et al, 2013;Cai et al, 2013).…”

“…The vaccine is designed to leverage the strong antiadenovirus immune response in humans to produce high-avidity antibodies against cocaine (Harvey et al, 1999;Chirmule et al, 1999;Hackett et al, 2000;Hicks et al, 2011;Wee et al, 2012;Maoz et al, 2013;Cai et al, 2013). High levels of high-avidity anticocaine antibodies prevent systemically administered cocaine from crossing the blood-brain barrier and entering the CNS and reaching the cognate receptors in the brain (Maoz et al, 2013;Cai et al, 2013). With the goal of assessing the fate of systemically administered cocaine in the context of vaccination with dAd5GNE, we have evaluated the levels of cocaine and its metabolites in the brain, blood, and peripheral organs after intravenous administration of cocaine to nonhuman primates vaccinated with dAd5GNE after chronic exposure to cocaine.…”

“…To quantify anticocaine titers after vaccination, wells of flat-bottomed 96-well EIA/RIA plates (Corning, New York, NY) were coated with 100 ll of 1 mg/ml of the cocaine hapten GNE (Hicks et al, 2011;Wee et al, 2012;Cai et al, 2013) conjugated to bovine serum albumin at a molar ratio of 66:1 in bicarbonate buffer, pH 9.4, overnight at 4°C. The plates were washed with 0.05% Tween 20 in PBS (PBSTween) and blocked with 5% dry milk in PBS for 30 min at 23°C.…”

“…On the basis of the concept that the effects of cocaine on the central nervous system (CNS) could be obviated if cocaine could be prevented from reaching its cognate receptors in the CNS, we have developed a vaccine (dAd5GNE) consisting of a disrupted serotype 5 E1 -E3 -human adenovirus to which the cocaine analog GNE has been covalently linked (Hicks et al, 2011;Wee et al, 2012;Maoz et al, 2013;Cai et al, 2013). Studies in mice, rats, and nonhuman primates have demonstrated that dAd5GNE induces high levels of high-affinity anticocaine antibodies that sequester systemically administered cocaine in the blood, preventing cocaine-induced hyperlocomotor activity and sensitization (Hicks et al, 2011;Wee et al, 2012;Maoz et al, 2013).…”