HUMAN INSULIN-RECEPTOR MONOCLONAL-ANTIBODY UNDERGOES HIGH-AFFINITY BINDING TO HUMAN BRAIN CAPILLARIES IN-VITRO AND RAPID TRANSCYTOSIS THROUGH THE BLOOD-BRAIN-BARRIER IN-VIVO IN THE PRIMATE

Purpose. The ability of monoclonal antibodies against the human insuli n receptor to undergo transcytosis through the blood-brain barrier (BB B) was examined in the present studies. Methods. Two murine monoclonal antibodies (MAb83-7 and MAb83-14) which bind different epitopes withi n the alpha-subunit of the human insulin receptor were examined using isolated human brain capillaries, frozen sections of primate brain, an d in vivo pharmacokinetic studies in anesthetized Rhesus monkeys. Resu lts. Both antibodies strongly illuminated capillary endothelium in imm unocytochemical analysis of frozen sections of brain from Rhesus monke y but not squirrel monkey. Both monoclonal antibodies, in the iodinate d forms, bound to human brain microvessels, although the binding and e ndocytosis of MAb83-14 was approximately 10-fold greater than MAb83-7. The active binding of MAb83-14 to the human insulin receptor was para lleled by a very high rate of transport of this antibody through the B BB in vivo in two anesthetized Rhesus monkeys. The BBB permeability-su rface area (PS) product in neocortical gray matter was 5.4 +/- 0.6 mu L/min/g, which is severalfold greater than previous estimates of the P S 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, th ere was no brain uptake of the mouse IgG(2a) isotype control antibody. Conclusions. These studies demonstrate an unexpected high degree of t ranscytosis of a monoclonal antibody through the primate BBB in vivo.