| One of the continuing challenges of modern pharmaceutical sciences is to devise ways to keep potent drugs, especially biomolecules, active in the circulation for longer periods of time. Among the approaches that have been investigated is the use of antibodies as specific carrier proteins.; The goal of this research was to assess the feasibility of a novel strategy that would make use of pre-existing endogenous antibodies as drug carriers. If a suitable universally recognized hapten could be identified, this hapten would be monovalently conjugated to drugs so that when administered, the conjugate would bind to the patient's own antibodies, and they would act as carriers for it. A second, but no less important, goal was to better understand and model the pharmacokinetics of antibody-binding compounds in general.; In the first phase of the research, low molecular weight conjugates of fluorescein were injected into mice actively immunized against fluorescein. Antibody titer, antibody binding affinity, and hapten dose were varied. Total conjugate clearance decreased dramatically with increasing titer and affinity, although this effect tapered off above a threshold level. Antibody binding appeared to prolong circulation both by blocking clearance and by slowing re-distribution. The data was consistent with a two-compartment model with antibody binding in each compartment, but parameter estimates from the model were not consistent among mouse groups.; In the next phase, two fluorescein-protein conjugates were synthesized with molecular weights of 25,000 and 11,000 daltons. Circulation of these conjugates was substantially prolonged in fluorescein-immunized mice, but they were cleared more rapidly than the low molecular weight conjugates. Results of affinity measurements and of the pharmacokinetic experiments supported a hypothesis that binding affinity would drop off with increasing conjugate size.; In the last phase of the research, the effect of antibody binding on the development of a further antibody response was assessed. Fluorescein-immunized and mock-immunized mice were given repeat doses of the fluorescein-light chain conjugate, and the development of antibodies against the human light chain portion of the conjugate was monitored. In two experiments, the fluorescein immunized mice tended to develop higher titers, but the difference between the groups was not significant. |
