Cocaine abuse is a serious social and medical problem that has proven intractable to conventional pharmacological interventions. It may well be that novel alternative approaches can be used to generate an agent that circumvents that problems normally encountered in using drug derivatives for drug abuse treatment. Serum antibodies which selectively bind to cocaine, and significantly reduce the levels of cocaine reaching the brain dopamine transporters have the potential for diminishing its euphoric effects thus assisting treatment seeking individuals in reducing their cocaine usage. In Project 1 of this SPIRCAP Program Project grant our specific research aims are to immunize transgenic mice, developed recently by GenPharm International, homozygous, or hemizygous for the human heavy (mu and gamma) and light chain (kappa) immunoglobulin transgenes (with inactivated mouse JH and Jk genes) with benzoylecgonine-carrier protein conjugates in order to generate a matured anti-cocaine human IgG immune response. Standard mouse spleen cell-myeloma cell hybridoma technology will then be used to generate, identify and isolate hybridoma cell lives secreting individual human anti-cocaine antibodies. These monoclonal antibodies will be characterized in order to identify those with high affinity and specificity for cocaine and which may be suitable for use in high affinity and specificity for cocaine and which may be suitable for use in a passive immunization approach to the clinical therapy of cocaine abuse. Simultaneously with this work we will be assisting with Project 2 animal trials using the mouse monoclonal antibody B4E10 and rats immunized with the benzoylecgonine (BE)-carrier conjugates in order to establish the ability of antibodies to alter """"""""in vivo"""""""" physiological responses to cocaine. Then, once they are available, we will conduct animal trials with the purified human anti-cocaine monoclonal antibodies. These studies are designed to demonstrate the feasibility of using antibodies to attenuate the central nervous system effects of cocaine. If successful we will then begin conducting initial Phase I safety and pharmacokinetic trials in humans. In addition to experiments detained in this section, Project 1 investigators will be participating in all aspects of this program since they require extensive use of immunochemical techniques. In preliminary work, BE-protein conjugates have been synthesize, characterized and anti- hapten responses elicited in both transgenic mice and normal rats.
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