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In vitro and in vivo hematopoietic effect of mutant human granulocyte
colony-stimulating factor [see comments]
M Okabe, M Asano, T Kuga, Y Komatsu, M Yamasaki, Y Yokoo, S Itoh, M Morimoto and T Oka
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co, Ltd, Shizuoka,
Japan.
About 100 derivatives of human recombinant granulocyte colony- stimulating
factor (rhG-CSF) were created by various gene-mutagenic techniques, and
KW-2228, in which amino acids were replaced at five positions of N-terminal
region of intact rhG-CSF, was picked up and evaluated for its biologic and
physicochemical properties in comparison with intact rhG-CSF. KW-2228
showed two to four times higher specific activity than that of intact
rhG-CSF in mouse and/or human bone marrow progenitor cells by
colony-forming unit assay in soft agar, and by cell- proliferation assay in
liquid culture. KW-2228 showed a potency to increase peripheral neutrophil
counts when it was administered to normal C3H/He mice by single intravenous
injection. Increase of total leukocyte count and neutrophils was observed,
with peak level at 8 to 12 hours at low doses (0.5 to 1.0
micrograms/mouse), and the highest level was maintained for 24 to 30 hours
at high doses (5 to 10 micrograms/mouse). The granulopoietic effect of
KW-2228 was examined by several doses of single course (once daily for 10
days) or multiple courses (twice daily injection for 5 days followed by
cessation for 9 days on one cycle, 3 cycles in total) of treatment. KW-2228
showed higher activity than that of rhG-CSF, especially at sub-optimal
doses of multiple courses of treatment. Furthermore, KW-2228 was found to
be more stable physicochemically and biologically than intact rhG-CSF,
especially under thermal conditions at 56 degrees C and in the human plasma
at 37 degrees C, suggesting a protease resistancy. Pharmacokinetic study
showed that plasma concentration of KW-2228 assayed for its bioactivity
maintained a higher level than that of intact rhG-CSF for 60 minutes after
intravenous injection of this protein to normal mice. Those results suggest
that KW-2228 might show a superior in vivo hematopoietic effect to intact
rhG-CSF due to its high specific activity to progenitor cells, and also due
to its improved physicochemical, biologic, and pharmacokinetic stability in
host animals.
Volume 75,
Issue 9,
pp. 1788-1793,
05/01/1990
Copyright © 1990 by The American Society of Hematology
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