Therapies based upon catalytic antibodies hold great potential for the treatment of human afflictions like drug addiction. This stems from the fact that catalytic antibodies constitute exquisitely specific reagents which can permanently alter and inactivate drugs. Moreover, since they exhibit turnover, each catalytic antibody will continuously destroy many target molecules rather than just binding stoichiometrically. Presently, most catalytic antibodies are obtained by immunizing mice with a transition state analog antigen and then selecting those rare clones which have the appropriate activity. Murine catalytic antibodies however will present problems for use in the treatment of human disease because as foreign proteins they will elicit an inhibitory antibody response. Additionally, the primary catalyic antibodies obtained by this approach are often inadequate because of their low catalytic activity. That fact indicates the need to develop compatable vaccines to elicit second generation antibodies with improved catalytic activity. This project tests the hypothesis that antibodies against the binding site of catalytic antibodies can be used to circumvent these problems. These anti-idiotypes can provide vaccines that elicit new, high specific activity catalytic antibodies using the patient's own immune system. The essence of this anti-idiotype strategy is to generate monoclonal antibodies that are complementary to the combining site of a conventional anti-cocaine catalytic antibody. By forming an internal image of that combining site, this anti- idiotype will, in effect, replicate the true transition state with higher fidelity than the original chemically synthesized cocaine transition state analog. As such it can be used as an antigen to elicit a whole new repertoire of anti-cocaine catalytic antibodies. Such transition state-mimicking anti- idiotype antibodies or genetically engineered replicas will form the basis of potent vaccines for generating therapeutic anti- cocaine catalytic antibodies in humans. This avoids the clinical use of chemically synthesized transition state analog antigens or the need for passive administration of catalytic antibodies derived from other species. To test this hypothesis active site-specific anti-idiotype monoclonal antibodies will be produced by immunizing mice with murine anti-cocaine catalytic antibodies. Those anti-idiotype antibodies, which simulate the true transition state, will be used to immunize other mice and generate new catalytic antibodies. These will be screened for anti-idiotype reactivity by measuring binding to the original transition state antigen using ELISA. They will then be isolated and tested for improved catalytic activity in comparison to the original anti-cocaine catalytic antibody.
