Purpose: The ability of monoclonal antibodies against the human insulin receptor to undergo transcytosis through the blood-brain barrier (BBB) was examined in the present studies.

Methods: Two murine monoclonal antibodies (MAb83-7 and MAb83-14) which bind different epitopes within the alpha-subunit of the human insulin receptor were examined using isolated human brain capillaries, frozen sections of primate brain, and in vivo pharmacokinetic studies in anesthetized Rhesus monkeys.

Results: Both antibodies strongly illuminated capillary endothelium in immunocytochemical analysis of frozen sections of brain from Rhesus monkey but not squirrel monkey. Both monoclonal antibodies, in the iodinated forms, bound to human brain microvessels, although the binding and endocytosis of MAb83-14 was approximately 10-fold greater than MAb83-7. The active binding of MAb83-14 to the human insulin receptor was paralleled by a very high rate of transport of this antibody through the BBB in vivo in two anesthetized Rhesus monkeys. The BBB permeability-surface area (PS) product in neocortical gray matter was 5.4 +/- 0.6 microL/min/g, which is severalfold greater than previous estimates of the PS product for receptor-specific monoclonal antibody transport through the BBB. The brain delivery of MAb83-14 to the Rhesus monkey brain was high and 3.8 +/- 0.4% of the injected dose was delivered to 100 g of brain at 3 hours after a single intravenous injection. In contrast, there was no brain uptake of the mouse IgG2a isotype control antibody.

Conclusions: These studies demonstrate an unexpected high degree of transcytosis of a monoclonal antibody through the primate BBB in vivo.