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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1534-1542
CHEMOKINES
Rapid mobilization of murine hematopoietic stem cells
with enhanced engraftment properties and evaluation of hematopoietic
progenitor cell mobilization in rhesus monkeys by a single injection of
SB-251353, a specific truncated form of the human CXC chemokine
GRO
Andrew G. King,
Dan Horowitz,
Susan B. Dillon,
Robert Levin,
Ann M. Farese,
Thomas J. MacVittie, and
Louis M. Pelus
From the Department of Molecular Virology and Host
Defense, SmithKline Beecham Pharmaceuticals, Collegeville, PA, and the
University of Maryland Greenebaum Cancer Center, Baltimore, MD.
SB-251353 is an N-terminal truncated form of the human CXC
chemokine GRO . Recombinant SB-251353 was profiled in murine and rhesus monkey peripheral blood stem cell mobilization and
transplantation models. SB-251353 rapidly and transiently mobilized
hematopoietic stem cells and neutrophils into the peripheral blood
after a single subcutaneous injection. Transplantation of equivalent
numbers of hematopoietic stem cells mobilized by SB-251353 into
lethally irradiated mice resulted in faster neutrophil and platelet
recovery than stem cells mobilized by granulocyte colony-stimulating
factor (G-CSF). A single injection of SB-251353 in combination with 4 days of G-CSF administration resulted in augmented stem and
progenitor cell mobilization 5-fold greater than G-CSF alone. Augmented
stem cell mobilization could also be demonstrated in mice when a single injection of SB-251353 was administered with only one-day treatment with G-CSF. In addition, SB-251353, when used as a single agent or in combination with G-CSF, mobilized long-term repopulating stem
cells capable of hematopoietic reconstitution of lethally irradiated
mice. In rhesus monkeys, a single injection of SB-251353 induced rapid
increases in peripheral blood hematopoietic progenitor cells at a
50-fold lower dose than in mice, which indicates a shift in potency.
These studies provide evidence that the use of SB-251353 alone or in
combination with G-CSF mobilizes hematopoietic stem cells with
long-term repopulating ability. In addition, this treatment may (1)
reduce the number of apheresis sessions and/or amount of G-CSF required
to collect adequate numbers of hematopoietic stem cells for
successful peripheral blood cell transplantation and (2) improve
hematopoietic recovery after transplantation.
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