We plan to utilize a unique proprietary transgenic mouse line engineered to produce human immunoglobulins in order to generate human monoclonal anti-cocaine antibodies. These human antibodies should prove suitable for passive immunotherapy of cocaine dependent patients resulting in an effective treatment for cocaine addiction. The use of human monoclonal anti-cocaine antibodies should negate the problem of species incompatibility which has to date restricted the use of passive immunotherapy. Investigators actively working on the development and assessment of cocaine pharmacotherapy as part of our NIDA sponsored Medication Development Research Unit are collaborating with a group of academic and industrial investigators actively developing novel immunotherapy techniques. The overall goals of this SPIRCAP proposal are: 1) Generate in the transgenic mice an anti-cocaine human IgG immune response. Then produce, identify and isolate spleen cell-mouse myeloma hybridomas secreting individual human anti-cocaine monoclonal antibodies. 2) Characterize the purified antibodies with respect to their affinity and specificity for cocaine binding relative to cocaine metabolites and related compounds. 3) Determine the effects of selected human anti-cocaine antibodies on the behavioral effects and on the pharmacokinetics of cocaine in rats and select the best candidate for advancement. 4) Scale-up production of the anti-cocaine monoclonal antibody to FDA-required purity standards in sufficient quantities for animal toxicity studies and then phase 1 human safety trials. 5) Assess animal toxicity of a characterized anti-cocaine antibody in a GLP facility and file and IND application with the FDA to proceed into phase 1 clinical trials. 6) Determine any toxicity and measure the pharmacokinetics of the antibody in humans. The success of this SPIRCAP program will be defined by the ability of a human anti- cocaine antibody to safely modify the pharmacokinetics of cocaine and significantly decrease CSF concentrations of cocaine. These studies will form the basis for an application to the FDA for advancement of an identified human monoclonal anti-cocaine antibody to Phase II clinical trials to determine the efficacy of a passive immunotherapy of cocaine abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19DA012043-04
Application #
6378809
Study Section
Special Emphasis Panel (ZDA1-KXA-N (06))
Program Officer
Chiang, Nora
Project Start
1998-09-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$1,671,351
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Norman, Andrew B; Tabet, Michael R; Norman, Mantana K et al. (2007) A chimeric human/murine anticocaine monoclonal antibody inhibits the distribution of cocaine to the brain in mice. J Pharmacol Exp Ther 320:145-53
Norman, Andrew B; Tsibulsky, Vladimir L (2006) The compulsion zone: a pharmacological theory of acquired cocaine self-administration. Brain Res 1116:143-52
Tsibulsky, Vladimir L; Norman, Andrew B (2005) Real time computation of in vivo drug levels during drug self-administration experiments. Brain Res Brain Res Protoc 15:38-45
Paula, Stefan; Tabet, Michael R; Farr, Carol D et al. (2004) Three-dimensional quantitative structure-activity relationship modeling of cocaine binding by a novel human monoclonal antibody. J Med Chem 47:133-42
Norman, Andrew B; Buesing, William R; Norman, Mantana K et al. (2004) The self-administration of WIN 35,428 and cocaine: comparisons of satiety threshold and elimination half-life in rats. Eur J Pharmacol 483:281-7
Cabovska, B; Norman, A B; Stalcup, A M (2003) Separation of cocaine stereoisomers by capillary electrophoresis using sulfated cyclodextrins. Anal Bioanal Chem 376:134-7
Paula, Stefan; Tabet, Michael R; Keenan, Susan M et al. (2003) Three-dimensional structure-activity relationship modeling of cocaine binding to two monoclonal antibodies by comparative molecular field analysis. J Mol Biol 325:515-30
Norman, Andrew B; Welge, Jeffrey A; Tsibulsky, Vladimir L (2002) Characterization of the distribution of the cocaine priming threshold and the effect of SCH23390. Brain Res 946:253-61
Norman, A B; Tsibulsky, V L (2001) Satiety threshold regulates maintained self-administration: comment on Lynch and Carroll (2001). Exp Clin Psychopharmacol 9:151-4; discussion 160-2
Tsibulsky, V L; Norma, A B (2001) Satiety threshold during maintained cocaine self-administration in outbred mice. Neuroreport 12:325-8

Showing the most recent 10 out of 13 publications