An understanding of the factors that govern in vivo transport of macromolecules such as ribonculeases, protein toxins, immunotoxins, streptavidin, and monoclonal antibodies (MAbs) will facilitate development of strategies for increasing delivery of these kinds of agents to targeted tissues. Experimental studies, supported by mathematical models, are being conducted in tumor- and nontumor-bearing animals. Measurements of influx and efflux rates and binding parameters of these compounds in various tissues have been obtained. Quantitative autoradiography has been used to characterize the spatial distribution of these compounds in solid tumors. A two-step protocol was investigated that involved the combined use of a modified MAb and a rapidly diffusible substance that binds to the Mab. Spatially distributed pharmacokinetic models were developed to simulate the experimental characteristics of such protocols in order to explore the effects of parameters such as dose, binding affinity, interval between injection of the first and second components, and antigen internalization on outcomes such as total radionuclide uptake, spatial heterogeneity, and tumor:nontumor ratios. Simulations permitted comparison of protocols involving directly radiolabeled MAb with those utilizing streptavidin- or biotin-conjugated MAb. Similar models were applied to the study of the effect of receptor modulation on penetration of protein toxins in solid tumors. A flow chamber was developed to examine the effects of membrane permeability, dose, and dose schedule on the cytotoxicity of protein toxins.
