The delivery to the brain of nonlipophilic therapeutic compounds, especially proteins, is severely hindered by the presence of the blood-brain barrier, which is formed by the tightly apposed brain capillary endothelial cells. However, brain endothelial cells do possess specific receptor-mediated transport mechanisms so that substances required by the brain can cross the blood-brain barrier. By use of monoclonal antibodies that bind to the transferrin receptor present on the luminal surface of brain capillary endothelial cells, we have taken advantage of the transport system responsible for the delivery of iron to the brain to deliver recombinant human soluble CD4 (rsCD4), a potential anti-HIV therapeutic, across the blood-brain barrier. Anti-transferrin receptor antibody-rsCD4 conjugates were synthesized with a disulfide linkage and characterized in vitro. Experiments that use immunohistochemistry to localize these conjugates after intravenous administration into the tail vein of rats have shown that both the carrier antibody and the protein "passenger" accumulate in brain capillaries. The carrier-mediated delivery of radiolabeled protein across the blood-brain barrier in vivo was also examined in both rodents and primates. With use of the technique of capillary depletion in rats, the amount of rsCD4 in the capillary fraction of the brain, which reaches a maximal value within 1 hr postinjection, was shown to decrease with time, whereas the amount in the brain parenchyma increased, which suggests that the protein was delivered across the blood-brain barrier. In primates rsCD4 levels in the brain were increased 5-fold when the protein was administrated intravenously in the form of an anti-transferrin receptor antibody-rsCD4 conjugate.