Induction of Protective and Specific Antibodies against Cocaine by Intranasal Immunisation Using a Glyceride Adjuvant

Hrafnkelsdottir, Kolbrun; Valgeirsson, Jon; Gizurarson, Sveinbjörn

doi:10.1248/bpb.28.1038

Cited by 17 publications

(12 citation statements)

References 23 publications

(25 reference statements)

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“…Cocaine, norcocaine, and benzoylecgonine were obtained from the National Institute on Drug Abuse, Baltimore MD. BSA-SNC conjugates were prepared using the method described by Hrafnkelsdottir et al 2005 (19). The purity of the compounds was checked by thin layer chromatography and NMR.…”

Section: Methodsmentioning

confidence: 99%

Hapten Optimization for Cocaine Vaccine with Improved Cocaine Recognition

et al. 2014

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In the absence of any effective pharmacotherapy for cocaine addiction, immunotherapy is being actively pursued as a therapeutic intervention. While several different cocaine haptens have been explored to develop anti-cocaine antibodies, none of the hapten was successfully designed which had a protonated tropane nitrogen as is found in native cocaine under physiological conditions, including the succinyl norcocaine (SNC) hapten that has been tested in phase II clinical trials. Herein, we discuss three different cocaine haptens: hexyl-norcocaine (HNC), bromoacetamido butyl- norcocaine (BNC), and succinyl-butyl- norcocaine (SBNC), each with a tertiary nitrogen structure mimicking that of native cocaine which could optimize the specificity of anti-cocaine antibodies for better cocaine recognition. Mice immunized with these haptens conjugated to immunogenic proteins produced high titer anti-cocaine antibodies. However, during chemical conjugation of HNC and BNC haptens to carrier proteins, the 2β methyl ester group is hydrolyzed and immunizing mice with these conjugate vaccines in mice produced antibodies that bound both cocaine and the inactive benzoylecgonine metabolite. While in the case of the SBNC conjugate vaccine hydrolysis of the methyl ester did not appear to occur, leading to antibodies with high specificity to cocaine over BE. Though we observed similar specificity with a SNC hapten, the striking difference is that SBNC carries a positive charge on the tropane nitrogen atom, and therefore it is expected to have better binding of cocaine. The 50% cocaine inhibitory concentration (IC50) value for SBNC antibodies (2.8 μM) was significantly better than the SNC antibodies (9.4 μM) when respective hapten-BSA was used as a substrate. In addition, antibodies from both sera had no inhibitory effect from BE. In contrast to BNC and HNC, the SBNC conjugate was also found to be highly stable without any noticeable hydrolysis for several months at 4°C and 2-3 days in pH 10 buffer at 37°C.

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Section: Methodsmentioning

confidence: 99%

Hapten Optimization for Cocaine Vaccine with Improved Cocaine Recognition

et al. 2014

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“…Nabi Biopharmaceuticals collaborated with Aktiv-Dry (Boulder, CO USA) to reformulate its NicVAX® antinicotine vaccine into particles 1–3 µm in diameter that form a stable, dry powder suitable for inhalation [108]. Lyfjathroun Biopharmaceuticals (Reykjavik, Iceland) developed a mucosal adjuvant (RhinoVax®) that allows effective intranasal vaccine administration [41]. When used in conjunction with an anticocaine vaccine (cocaine conjugated to keyhole limpet hemocyanin), two doses of intranasal vaccine generated specific anticocaine antibodies in mice, albeit at a fivefold lower serum level than after subcutaneous vaccination.…”

Section: Antidrug Vaccinesmentioning

confidence: 99%

Pharmacokinetic Strategies for Treatment of Drug Overdose and Addiction

Gorelick

2012

Future Med. Chem.

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The pharmacokinetic treatment strategy targets the drug molecule itself, aiming to reduce drug concentration at the site of action, thereby minimizing any pharmacodynamic effect. This approach might be useful in the treatment of acute drug toxicity/overdose and in the long-term treatment of addiction. Phase IIa controlled clinical trials with anticocaine and antinicotine vaccines have shown good tolerability and some efficacy, but Phase IIb and III trials have been disappointing because of the failure to generate adequate antibody titers in most participants. Monoclonal antibodies against cocaine, methamphetamine and phencyclidine have shown promise in animal studies, as has enhancing cocaine metabolism with genetic variants of human butyrylcholinesterase, with a bacterial esterase, and with catalytic monoclonal antibodies. Pharmacokinetic treatments offer potential advantages in terms of patient adherence, absence of medication interactions and benefit for patients who cannot take standard medications.

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“…At about the same time, Landry treated 3 rhesus monkeys with a succinyl norcocaine-BSA vaccine and reported that the level of antibodies in the blood corresponded to suppression of operant responding to a food reward, and that there were no side effects resulting from the vaccination (39). In 2005, Hrafnkelsdottir vaccinated mice with a succinyl norcocaine –KLH vaccine both by an intranasal route using a glyceride adjuvant (RhinoVax) and by a subcutaneous route (40). After a challenge with cocaine, the levels of cocaine in the serum, brain and olfactory bulb were measured, and the amount of cocaine found in the brain was less for all cocaine immunized groups as compared to controls.…”

Section: Anti-cocaine Vaccinesmentioning

confidence: 99%

Anti-cocaine vaccine development

Kinsey¹,

Kosten²,

Orson³

2010

Expert Review of Vaccines

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Cocaine abuse is an ongoing and serious problem which has lead to the growth of a brutal criminal enterprise, particularly in the Americas and Europe. At present, there are no effective pharmacological agents available to treat the addiction by blocking cocaine or reversing its effects. In order to help motivated addicts conquer their addiction, vaccines against cocaine are being developed, and one has progressed to clinical trials. This review will discuss the concept of anti-drug vaccines in general, the successes and limitations of the various anti-cocaine vaccine approaches, the results of the clinical trials with an anti-cocaine vaccine, and some new vaccine-mediated approaches to combat cocaine addiction. KeywordsSubstance Abuse; Vaccination; Cocaine; Immunotherapy HistoryCocaine is one of the oldest known drugs. The leaves of the coca plant have been chewed by the indigenous peoples of South America for thousands of years to increase stamina for high altitude work and to afford feelings of well-being. In 1859, the active ingredient in coca was isolated and named cocaine, and it was considered a rather benign drug until the beginning of the 20 th century, when the negative aspects of its use became widely recognized (1). The sale and distribution of opium, coca leaves, and their derivatives was restricted in the United States under the 1914 Harrison Narcotics Tax Act to the practice of medicine, dentistry, and veterinary medicine. However, the law was not strictly enforced for cocaine, and there was open use of the drug for a number of years, although this was generally limited to the minority and low income urban populations, artists, and musicians (2). The addictive properties of cocaine were again gradually recognized, but in spite of this and increased efforts to enforce drug laws, the use of cocaine, particularly the smoked free base form known as crack, exploded during the 1970's and 80's. There is some light on the horizon, however, as data gathered by SAMSHA, the Substance Abuse and Mental Health Services Administration of the US Department of Health and Human Services shows that admissions to substance abuse treatment for cocaine decreased from 1995 to 2005, and the age of those admitted went up substantially (3). Even though there was a decrease in admissions among African-Americans, there was an increase Anti-drug VaccinesIt has been known and studied for at least 50 years that small molecules (haptens) will not usually elicit an immune response unless they are covalently attached to an immunogenic protein (6,7). This results in the body's tolerance for most medications and chemical exposures without significant harmful immune reactions. Allergic reactions to medicines like penicillin occur when the immune system recognizes the chemical or its metabolic products after they have been bound to native proteins, allowing for antigen presentation and initiation of the immune response (8). Therefore, to produce an anti-drug vaccine, the hapten is covalently attached to a foreign carrier prote...

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Induction of Protective and Specific Antibodies against Cocaine by Intranasal Immunisation Using a Glyceride Adjuvant

Cited by 17 publications

References 23 publications

Hapten Optimization for Cocaine Vaccine with Improved Cocaine Recognition

Hapten Optimization for Cocaine Vaccine with Improved Cocaine Recognition

Pharmacokinetic Strategies for Treatment of Drug Overdose and Addiction

Anti-cocaine vaccine development

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