Experimental and theoretical models have been developed to describe the in vivo transport of macromolecules such as protein toxins, immunotoxins, and monoclonal antibodies (MAbs). These have led to quantitative measurements of influx and efflux rates, as well as binding parameters, of these compounds in solid tumors. Quantitative autoradiography has been employed to assess the spatial distribution of intravenously administered immunotoxins in solid tumors. Two quantitative measures were devised that permit comparisons of the spatial distributions among immunotoxins that vary in molecular weight and degree of binding. The spatial heterogeneity observed in these experiments supports the use of spatially distributed models to describe macromolecular transport. We have developed such models for two-step protocols that use MAbs to achieve targeted delivery of a radionuclide. The theoretical results are being compared to experimental data obtained in a lung metastasis model. An immunotoxin injected directly into the cerebrospinal fluid has been evaluated for treatment of leptomeningeal neoplasia in a Phase I trial. A pharmacokinetic analysis of immunotoxin transport in the CSF has been performed and compared to preclinical experiments in rats and monkeys. These studies provide a basis for interspecies comparisons that will be applicable to future studies of CSF injection of macromolecules.
