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Role of antennary structure of N-linked sugar chains in renal handling of
recombinant human erythropoietin
T Misaizu, S Matsuki, TW Strickland, M Takeuchi, A Kobata and S Takasaki
Pharmaceutical Development Laboratory, Kirin Brewery, Gunma, Japan.
To elucidate the role of the branched structure of sugar chains of human
erythropoietin (EPO) in the expression of in vivo activity, the
pharmacokinetic profile of a less active recombinant human EPO sample
(EPO-bi) enriched with biantennary sugar chains was compared with that of a
highly active control EPO sample enriched with tetraantennary sugar chains.
After an intravenous injection in rats, 125I-EPO-bi disappeared from the
plasma with 3.2 times greater total body clearance (Cltot) than control
125I-EPO. Whole-body autoradiography after 20 minutes of administration
indicated that the overall distribution of radioactivity is similar, but
125I-EPO-bi showed a higher level of radioactivity in the kidneys than
control 125I-EPO. Quantitative determination of radioactivity in the
tissues also indicated that radioactivity of 125I-EPO-bi in the kidneys was
two times higher than that of control 125I-EPO. The difference in plasma
disappearance between 125I-EPO-bi and control 125I-EPO was not observed in
bilaterally nephrectomized rats. The distribution of 125I-EPO-bi to bone
marrow and spleen was similarly inhibited by simultaneous injection of
excess amounts of either the nonlabeled EPO-bi or control EPO. These
results indicate that the low in vivo biologic activity of EPO-bi results
from rapid clearance from the systemic circulation by renal handling. Thus,
the well-branched structure of the N-linked sugar chain of EPO is suggested
to play an important role in maintaining its higher plasma level, which
guarantees an effective transfer to target organs and stimulation of
erythroid progenitor cells.
Volume 86,
Issue 11,
pp. 4097-4104,
12/01/1995
Copyright © 1995 by The American Society of Hematology
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