Pharmacokinetics and saturable blood-brain barrier transport of biotin bound to a conjugate of avidin and a monoclonal antibody to the transferrin receptor.
The delivery of biotinylated therapeutics through the blood-brain barrier (BBB) may be facilitated by the use of avidin-based chimeric peptide conjugates. The latter are formed by conjugating avidin to a BBB drug delivery vector, which is a protein that undergoes receptor-mediated transcytosis through the BBB. The murine OX26 monoclonal antibody to the rat transferrin receptor undergoes receptor-mediated transport through the BBB, and previous studies have shown that a [3H]biotin/avidin-OX26 conjugate is effectively transported through the BBB. However, avidin is a cationic protein, which causes a marked increase in the systemic clearance of avidin-based conjugates from the plasma compartment. The present studies describe attempts to elevate the reduced plasma area under the curve (AUC) of [3H]biotin/avidin-OX26 by preloading or coloading with unconjugated OX26 antibody or unconjugated avidin. Both systemic clearance and BBB transport of avidin-OX26 were equally affected by OX26 preloading or coloading; this had inverse effects on the plasma AUC and the BBB permeability surface area product with no resulting change in the fractional delivery of [3H]biotin to brain. Conversely, avidin coloading preferentially reduced brain clearance of the [3H]biotin/avidin-OX26 conjugate, without substantial alteration in the plasma AUC and greatly reduced the fractional delivery of [3H]biotin to brain. In summary, these studies show that the use of avidin-based vectors results in rapid systemic clearance, which causes a reduction in the delivery of [3H]biotin to brain, despite a comparable BBB permeability coefficient for either the unconjugated OX26 antibody or the avidin-OX26 conjugate.
Kang
Y S
YS
Department of Medicine and Brain Research Institute, UCLA School of Medicine 90024.
Bickel
U
U
Pardridge
W M
WM
D000818:Animals; D000911:Antibodies, Monoclonal; D001360:Avidin; D001692:Biological Transport; D001710:Biotin / Q000097:blood / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000502:physiology*; D004337:Drug Carriers; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D011990:Receptors, Transferrin; D001360:Avidin; D001710:Biotin