A second-generation vaccine protects against the psychoactive effects of cocaine

Abstract

The effects of immunization with the second-generation cocaine immunoconjugate GND-keyhole limpet hemocyanin (KLH) or with the anti-cocaine mAb GNC92H2 were assessed in a model of acute cocaine-induced locomotor activity. After i.p. administration of cocaine⅐HCl (15 mg͞kg), rats were tested in photocell cages, and stereotypy was rated to determine preimmunization drug response (baseline). Experimental animals were subjected to an immunization protocol with GND-KLH or treated with the mAb GNC92H2. Rats were then challenged with systemic cocaine, and their locomotor responses were again measured. Active immunization with GND-KLH produced a 76% decrease in the ambulatory measure (crossovers) in the experimental group and a 12% increase in the control group compared with baseline values. Also, stereotypic behavior was significantly suppressed in the vaccinated animals. Decreases in both measures were seen in the experimental group on two subsequent challenges. The maximum effect was observed at the time of the second challenge with a dramatic 80% decrease in crossovers. Treatment with GNC92H2 resulted in a 69% decrease in crossovers compared with baseline. This effect persisted across two additional challenges over 11 days with decreases of 46 -47%. In contrast, the control group showed increases of up to 28%. Significant differences between groups were observed in the stereotypic measure in all three challenges. The results indicate that these immunopharmacotherapeutic agents have significant cocaine-blockade potential and therefore may offer an effective strategy for the treatment of cocaine abuse.T he abuse of cocaine (structure 1 in Fig. 1) has reached epidemic proportions in the United States, representing a major and increasing threat to public health (1). At present, there is no suitable medication for the treatment of this illness. Despite the many advances in the understanding of the biochemistry of action of cocaine, the development of antagonists, agonists, and antidepressants for pharmacotherapeutic and psychotherapeutic interventions has had limited success in both animal models and clinical studies (2-4). Because these therapeutic means are designed to block the central neurochemical effects of cocaine, their actions are nonselective and thus generate unwanted secondary effects (5). Immunopharmacotherapy, wherein antibodies are used to neutralize the drug, offers a possible alternative. Rather than targeting the receptors in the brain, antibodies obstruct partitioning of cocaine from the blood. This approach has the advantage of operating by means of an endogenous response that is independent of the central nervous system, thus circumventing the problem of neurotoxicity.Earlier studies showed that anti-morphine (6) and anti-heroin (7) antibodies could suppress opiate-induced effects. In the last decade, this strategy has been explored as a possible treatment for cocaine abuse. Work from this laboratory demonstrated that active immunization with a keyhole limpet hemocyanin (KLH) immunoconjugate derived ...

Identification and Characterization of Single Chain Anti-cocaine Catalytic Antibodies

“…E-mail address of the corresponding author: kdjanda@scripps.edu nopharmacological approach, our laboratory [6][7][8][9] and others, 10,11 have demonstrated that anti-cocaine antibodies can prevent the psychomotor effects attributable to cocaine. Passive immunization of rats with monoclonal antibody (mAb) GNC92H2 impeded the entry of cocaine into the brain and thus led to a significant decrease in stereotypic behavior.…”

Immunization prevents DDT buildup in mouse tissues

“…The majority of work in this area has been conducted with vaccines directed against cocaine [24][25][26] and nicotine [27][28][29][30][31]. In addition, vaccines for heroin [32], phencyclidine [33], methamphetamine [34] have also been developed.…”

Molecular cloning and characterization of a single-chain variable fragment antibody specific for benzoylecgonine expressed in Escherichia coli

“…The studies have focused on the ability of mAb to affect drug discrimination and relapse to drug use. In rats, passive immunization reduced reinforcing effects, and reinstatement of cocaine self-administration after low-dose cocaine (Carrera et al, 2000;Carrera et al, 2001). The recombinant of a humanized anti-cocaine mAb was reported with a modest KD value for cocaine of about 200 nM (Redwan et al, 2003).…”

“…Drug vaccines induce drug-specific antibodies in the bloodstream, which bind to the drug of abuse and prevent it from entering the brain. Several studies demonstrated that immunization against cocaine can reduce drug intake and drug-seeking behavior in rats and mice (Carrera et al, 1995;Kantak et al, 2000;Carrera et al, 2001). Vaccines for cocaine and nicotine can generally offer long-term protection with minimal treatment compliance.…”