The development of pharmacotherapies for the treatment of cocaine dependence has been a high priority in addiction research for more than three decades, yet no medication has been approved in the USA or in other countries for this disease. The absence of efficacious treatments remains a significant problem since, for example, the National Survey on Drug Use and Health statistics from 2010 show that approximately 1.5 million individuals were current cocaine users. Cocaine use is also associated with significant medical and psychiatric morbidity. It has been estimated that over 500,000 drug misuse or abuse visits were the result of recent cocaine exposure. In view of the misuse and a lack of treatment for cocaine addiction we have sought an alternative treatment strategy that targets the drug itself aiming to keep drug below its effective concentration rather than try to modulate or disrupt the effects of the drug at sites of action in the brain. We have termed this strategy immunopharmacotherapy. The current proposal has been tailored to investigate immunopharmacotherapy from two vantage points;the first will explore antibody manifolds as an approach to attenuate cocaine toxicity while the second will examine active vaccination as a means to curb cocaine abuse. Based on this general semblance we have crafted a set of specific aims including: (1) Implementing a domain deleted recombinant fragment (scFv-Fc) design to understand antibody manifold requirements for the treatment of immediate as well as long-term cocaine toxicity effects. (2) How hapten, carrier and adjuvant formulations impact a vaccines performance. A systematic study will be conducted wherein each of these three components will be varied. A vaccine's success will be graded based upon antibody-cocaine affinity/total antibody produced as well as kinetic parameters defining the degradation of cocaine. (3) To engage endogenous antibodies as a means to overcome the weak immunogenicity of drug of abuse vaccines. The underlying principle to a successful vaccine is a potent immune response. This has also been an Achilles heel as drug-immune responses have been widely variable. Anti-Gal is the most abundant natural antibody in humans;a vaccine expressing ?-epitopes that can be targeted to antigen presenting cells (APCs) would readily increase the immunogenicity of the vaccine. We will exploit ?-Gal to target our cocaine haptens to APCs for a superior vaccine. (4) A metric to test our most promising active cocaine vaccine formulations will be conducted in a rodent model examining cocaine dependence and re-escalation. The importance of this model is that trying to break physical dependence through re-escalation studies is extraordinarily difficult to disrupt by any medications mean and will pose a real test to our vaccine development. The research we have planned both highlight the promise of immunopharmacotherapy and will also strive to overcome the deficiencies of this approach in our quest for developing vaccines for the treatment of cocaine abuse and its toxicity.

Public Health Relevance

The currently available medications for the treatment of cocaine abuse and its related toxicity have had limited success. Anti-addiction vaccines aimed at engaging antibodies that block the pharmacological effects of the drug have great potential for treating drug abuse. We present a series of studies for addressing both challenges and deficiencies in the development of immunopharmacotherapy for the treatment of cocaine abuse.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DA008590-19A1
Application #
8839167
Study Section
(DDNS)
Program Officer
Shih, Ming L
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Eubanks, Lisa M; Ellis, Beverly A; Cai, Xiaoqing et al. (2014) A human recombinant monoclonal antibody to cocaine: Preparation, characterization and behavioral studies. Bioorg Med Chem Lett 24:4664-6
Collins, K C; Schlosburg, J E; Lockner, J W et al. (2014) Lipid tucaresol as an adjuvant for methamphetamine vaccine development. Chem Commun (Camb) 50:4079-81
Hicks, Martin J; Kaminsky, Stephen M; De, Bishnu P et al. (2014) Fate of systemically administered cocaine in nonhuman primates treated with the dAd5GNE anticocaine vaccine. Hum Gene Ther Clin Dev 25:40-9
Collins, Karen C; Janda, Kim D (2014) Investigating hapten clustering as a strategy to enhance vaccines against drugs of abuse. Bioconjug Chem 25:593-600
Maoz, Anat; Hicks, Martin J; Vallabhjosula, Shankar et al. (2013) Adenovirus capsid-based anti-cocaine vaccine prevents cocaine from binding to the nonhuman primate CNS dopamine transporter. Neuropsychopharmacology 38:2170-8
De, Bishnu P; Pagovich, Odelya E; Hicks, Martin J et al. (2013) Disrupted adenovirus-based vaccines against small addictive molecules circumvent anti-adenovirus immunity. Hum Gene Ther 24:58-66
Cai, Xiaoqing; Whitfield, Timothy; Moreno, Amira Y et al. (2013) Probing the effects of hapten stability on cocaine vaccine immunogenicity. Mol Pharm 10:4176-84
Cai, Xiaoqing; Whitfield, Timothy; Hixon, Mark S et al. (2013) Probing active cocaine vaccination performance through catalytic and noncatalytic hapten design. J Med Chem 56:3701-9
Cai, Xiaoqing; Tsuchikama, Kyoji; Janda, Kim D (2013) Modulating cocaine vaccine potency through hapten fluorination. J Am Chem Soc 135:2971-4
Wee, Sunmee; Hicks, Martin J; De, Bishnu P et al. (2012) Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects. Neuropsychopharmacology 37:1083-91

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