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Vol. 292, Issue 3, 1048-1052, March 2000
Department of Medicine, UCLA School of Medicine, Los Angeles,
California (H.J.L., W.M.P.); Max Planck Institute, Bad Nauheim, Germany
(B.E.); The Salk Institute, La Jolla, California (J.L.); and Texas Tech
University, Amarillo, Texas (U.B.)
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.
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