RT Journal Article
SR Electronic
T1 Targeting Rat Anti-Mouse Transferrin Receptor Monoclonal Antibodies through Blood-Brain Barrier in Mouse
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1048
OP 1052
VO 292
IS 3
A1 Lee, Hwa Jeong
A1 Engelhardt, Britta
A1 Lesley, Jayne
A1 Bickel, Ulrich
A1 Pardridge, William M.
YR 2000
UL http://jpet.aspetjournals.org/content/292/3/1048.abstract
AB Drug targeting through the brain capillary endothelium, which forms the blood-brain barrier (BBB) in vivo, may be achieved with peptidomimetic monoclonal antibodies that target peptide transcytosis systems on the BBB in vivo. Murine monoclonal antibodies to the rat transferrin receptor, such as the OX26 monoclonal antibody, are targeted through the BBB on the transferrin receptor in the rat. However, the present studies show the OX26 monoclonal antibody is not an effective brain delivery vector in mice. The emergence of transgenic mouse models creates a need for brain drug-targeting vectors for this species. Two rat monoclonal antibodies, 8D3 and RI7-217, to the mouse transferrin receptor were evaluated in the present studies. Both the RI7-217 and the 8D3 antibody had comparable permeability-surface area products at the mouse BBB in vivo. However, owing to a higher plasma area under the concentration curve, the mouse brain uptake of the 8D3 antibody was higher, 3.1 ± 0.4% of injected dose [(ID)/g] compared with the brain uptake of the RI7 antibody, 1.6 ± 0.2% ID/g, at 60 min after i.v. injection. Conversely, the mouse brain uptake of the OX26 antibody, which does not recognize the mouse transferrin receptor, was negligible, 0.06 ± 0.01% ID/g. The RI7-127 antibody was more selective for brain because this antibody was not measureably taken up by liver. The capillary depletion technique demonstrated transcytosis of the RI7-217 antibody through the mouse BBB in vivo. The brain uptake of the 8D3 antibody was saturable, consistent with a receptor-mediated transport process. In conclusion, these studies indicate rat monoclonal antibodies to the mouse transferrin receptor may be used for brain drug-targeting studies in mice such as transgenic mouse models. The American Society for Pharmacology and Experimental Therapeutics