Evidence-Based Reviews

Vaccine for cocaine addiction: A promising new immunotherapy

Current Psychiatry. 2010 September;9(9):16-A

References

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2. Jertborn M, Svennerholm AM, Holmgren J. Safety and immunogenicity of an oral recombinant cholera B subunit-whole cell vaccine in Swedish volunteers. Vaccine. 1992;10:130-132.

3. Fox BS, Kantak KM, Edwards MA, et al. Efficacy of a therapeutic cocaine vaccine in rodent models. Nat Med. 1996;2:1129-1132.

4. Martell BA, Orson FM, Poling J, et al. Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. Arch Gen Psychiatry. 2009;66(10):1116-1123.

5. Haney M, Gunderson EW, Jiang H, et al. Cocaine-specific antibodies blunt the subjective effects of smoked cocaine in humans. Biol Psychiatry. 2010;67(1):59-65.

6. Kosten TR, Rosen M, Bond J, et al. Human therapeutic cocaine vaccine: safety and immunogenicity. Vaccine. 2002;20:1196-1204.

7. Grabenstein JD. ImmunoFacts: vaccines and immunological drugs. St. Louis, MO: Facts and Comparisons, Inc.; 1994:487b.

8. Pani PP, Trogu E, Vacca R, et al. Disulfiram for the treatment of cocaine dependence. Cochrane Database Syst Rev. 2010;(1):CD007024.-

9. Dackis CA, Kampman KM, Lynch KG, et al. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology. 2005;30(1):205-211.

10. Anderson AL, Reid MS, Li SH, et al. Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend. 2009;104(1-2):133-139.

11. Winhusen T, Somoza E, Ciraulo DA, et al. A double-blind, placebo-controlled trial of tiagabine for the treatment of cocaine dependence. Drug Alcohol Depend. 2007;91 (2-3):141-148.

12. Kahn R, Biswas K, Childress AR, et al. Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals. Drug Alcohol Depend. 2009;103 (1-2):59-64.

13. Johnson BA, Roache JD, Ait-Daoud N, et al. A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of cocaine dependence. Drug Alcohol Depend. 2006;84(3):256-263.

14. Norman AB, Tabet MR, Norman MK, et al. A chimeric human/murine anticocaine monoclonal antibody inhibits the distribution of cocaine to the brain in mice. J Pharmacol Exp Ther. 2007;320:145-153.

15. Norman AB, Norman MK, Buesing WR, et al. The effect of a chimeric human/murine anti-cocaine monoclonal antibody on cocaine self-administration in rats. J Pharmacol Exp Ther. 2009;328:873-881.

16. Cornuz J, Zwahlen S, Jungi WF, et al. A vaccine against nicotine for smoking cessation: a randomized controlled trial. PLoS One. 2008;3(6):e2547.-

17. Wagena EJ, de Vos A, Horwith G, et al. The immunogenicity and safety of a nicotine vaccine in smokers and nonsmokers: results of a randomized, placebo-controlled phase 1/2 trial. Nicotine Tob Res. 2008;10(1):213-218.

18. Hatsukami DK, Rennard S, Jorenby D, et al. Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Clin Pharmacol Ther. 2005;78(5):456-467.

19. Maurer P, Bachmann MF. Vaccination against nicotine: an emerging therapy for tobacco dependence. Expert Opin Investig Drugs. 2007;16(11):1775-1783.

20. Volkow ND. Message from the director on ARRA funding for the development of a nicotine vaccine. National Institute on Drug Abuse Web site. Available at: http://drugabuse.gov/about/welcome/nicotinevaccine909.html. Accessed August 13, 2010.

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DR. ANTHENELLI: What other kinds of research are going on as far as vaccines for cocaine?

DR. SOMOZA: There is a strain of transgenic mice that when stimulated produce human, as well as mice, antibodies. At the University of Cincinnati, Andrew Norman, PhD, was able to immunize these mice and they generated human antibodies against cocaine (Box 1).^14,15 Then you’ll have vials of monoclonal antibodies that you can administer to your patient. However, this is still in early testing.

DR. ANTHENELLI: We’ve talked about immunotherapy and how it might work for the treatment of cocaine addiction. How might these types of vaccines be used for treating other substances of abuse?

DR. SOMOZA: Investigators are currently working on a vaccine for nicotine dependence (Box 2)^4,16-20 and there’s a vaccine being developed for methamphetamine,²¹ but it is not as advanced as cocaine. A similar methodology has been used for some time to treat digitalis overdose. There is no antidote for digitalis toxicity, so researchers have developed an antibody—digoxin immune fab—that attaches to the drug, which is then excreted through the kidneys. I fully expect that this methodology eventually will work for cocaine, meth-amphetamine, and nicotine dependence. My hunch is that producing human antibody in industrial quantities would be the most sensible way to eventually make this work.

Table

Pharmacotherapy for cocaine dependence: Most evidence is weak

Study	Design	Results
Disulfiram
Pani et al, 2010⁸	Meta-analysis of 7 studies with 492 cocaine-dependent patients	Researchers found ‘low evidence’ supporting disulfiram for treating cocaine dependence
Modafinil
Dackis et al, 2005⁹	62 cocaine-dependent patients randomized to modafinil, 400 mg/d, or placebo for 8 weeks	Patients receiving modafinil provided significantly more BE-negative urine samples and were significantly more likely to achieve ≥3 weeks of cocaine abstinence
Anderson et al, 2009¹⁰	210 cocaine-dependent patients randomized to modafinil, 200 mg/d or 400 mg/d, or placebo for 12 weeks	Modafinil significantly reduced cocaine craving but did not significantly improve the average weekly percentage of cocaine non-use days
Tiagabine
Winhusen et al, 2007¹¹	141 cocaine-dependent patients randomized to tiagabine, 20 mg/d, or placebo for 12 weeks	No significant changes in cocaine use vs placebo as measured by self-report and urine BE
Baclofen
Kahn et al, 2009¹²	Cocaine-dependent patients randomized to baclofen, 60 mg/d, or placebo for 8 weeks	No significant difference between groups in cocaine use as measured by urine BE
Ondansetron
Johnson et al, 2006¹³	63 cocaine-dependent patients randomized to ondansetron, 0.25 mg, 1 mg, or 4 mg twice daily, or placebo for 10 weeks	The odansetron 4 mg group had a significantly greater rate of improvement in percentage of patients with a cocaine-free week compared with the placebo group
BE: benzoylecgonine

Box 1

Next step in addiction vaccines: A human anti-cocaine monoclonal antibody

Promising clinical trials of therapy for addiction–cocaine addiction (TA-CD) and nicotine conjugate vaccines show that immunotherapy may be effective for addictive disorders. However, immune response varies among patients and the vaccines are effective only in those who produce high concentrations of anti-drug antibodies. Our multidisciplinary translational research project has generated a predominantly human sequence monoclonal antibody (mAb) with high affinity (K_d = 4 nM) for cocaine and specificity over cocaine’s inactive metabolites. This mAb (preclinical designation, 2E2) is at an advanced stage of preclinical development for preventing relapse in treatment-seeking cocaine abusers.

Development of 2E2 has met several key safety and efficacy milestones. Because the structure of mAb is mostly human, repeated treatments should be safe and should confer long-term efficacy. 2E2 binds to and sequesters cocaine in the peripheral circulation and dramatically lowers brain cocaine concentrations in mice.¹⁴ Furthermore, 2E2 decreases the effect of cocaine in a rat model of relapse.¹⁵ In FDA-required safety tests, there was no apparent cross-reactivity of 2E2 with an extensive panel of human tissues in vitro, indicating that 2E2 likely is safe for patients. The genes encoding the mAb have been cloned and slightly re-engineered to make them even closer to a human sequence and the expressed recombinant protein retains the identical affinity and specificity for cocaine. We continue to work with our industry collaborator, Vybion Inc., to develop a stably transfected mammalian cell line capable of high-level production of 2E2, which is necessary to support in vivo toxicology studies required for an FDA Investigational New Drug application and subsequent clinical trials. This anti-cocaine mAb should be a useful adjunct to TA-CD by supplementing concentrations of vaccine-generated anti-cocaine antibodies.

Andrew B. Norman, PhD
Department of psychiatry and behavioral neuroscience

William J. Ball, PhD
Department of pharmacology and cell biophysics
University of Cincinnati College of Medicine
Cincinnati, OH

Box 2

Vaccines for nicotine: Another tool to help patients break the habit

Dependence on nicotine—the main addictive agent in cigarette smoke and other tobacco products—also is being targeted with vaccines. Like cocaine, the nicotine molecule is too small to provoke an immune response by itself. Therefore, nicotine derivatives linked to virus-like particles¹⁶ or detoxified bacteria-derived proteins¹⁷ are immunogenic enough to stimulate an antibody response. With once-monthly vaccinations of these conjugated nicotine compounds, patients can produce sufficient antibodies to sequester nicotine in the peripheral bloodstream before it crosses the blood-brain barrier to produce its rewarding effects.

Animal and human studies have found proof that this concept may work. These immunotherapies do not seem to provoke acute nicotine withdrawal and patients do not increase their smoking rates to try to counteract the antibodies’ nicotine-scavenging effects.^16-19 As was the case with the cocaine trial,⁴ smoking cessation efficacy is positively correlated with the individual’s antibody titer response. Published phase I and II trials indicate that these vaccines may be safe and well-tolerated; mild reactions at the intramuscular injection site are the most commonly reported adverse event.^16-18 Larger phase III clinical trials are underway.²⁰

Robert M. Anthenelli, MD