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J. Biol. Chem., Vol. 263, Issue 29, 15064-15070, 10, 1988
MJ Knauf, DP Bell, P Hirtzer, ZP Luo, JD Young and NV Katre
We have examined the effects of a variety of chemical modifications to
recombinant human interleukin-2 (rIL-2) on its pharmacokinetic behavior in
rats. Unmodified rIL-2 is cleared from plasma with half-lives of 3 and 44
min for the alpha and beta phases. Modification of rIL-2 with monomethoxy
polyethylene glycol or polyoxyethylated glycerol increased the half-lives
as much as 20-fold, although the volume of distribution remained unchanged
at 88 +/- 13 ml/kg. The clearance rates correlated with the effective
molecular size of the modified protein determined by size exclusion
chromatography. Clearance decreased rapidly as the effective molecular size
increased from 19.5 to 70 kDa, whereas above 70 kDa the clearance decreased
more slowly. This abrupt change at 70 kDa may be related to the
permeability threshold of the kidney glomerular membrane which retains
proteins larger than albumin in the plasma. Using the relationship between
clearance and effective molecular size, the clearance rates of mixtures of
modified rIL-2 could be predicted based on their average effective
molecular size. Since the effectiveness of rIL-2 therapy is likely to be
related to its pharmacokinetic behavior, the ability to design a molecule
with a predictable time course in plasma provides a means to study this
relationship.
Relationship of effective molecular size to systemic clearance in rats of recombinant interleukin-2 chemically modified with water-soluble polymers
Department of Process/Product Development, Cetus Corporation, Emeryville, California 94608.
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