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Blood, 1 February 2001, Vol. 97, No. 3, pp. 752-758
NEOPLASIA
Interleukin-4 variant (BAY 36-1677) selectively induces
apoptosis in acute lymphoblastic leukemia cells
Kleebsabai Srivannaboon,
Armen B. Shanafelt,
Elisabetta Todisco,
Carla P. Forte,
Frederick G. Behm,
Susana
C. Raimondi,
Ching-Hon Pui, and
Dario Campana
From the Departments of Hematology-Oncology and
Pathology, St Jude Children's Research Hospital, and the University of
Tennessee College of Medicine, Memphis, TN; and Molecular Technologies,
Bayer Biotechnology, Berkeley, CA.
Interleukin 4 (IL-4) suppresses the growth of acute lymphoblastic
leukemia (ALL) cells, but its clinical usefulness is limited by
proinflammatory activity due mainly to the interaction of cytokine with
endothelial cells and fibroblasts. Stroma-supported cultures of
leukemic lymphoblasts were used to test the antileukemic activity of an
IL-4 variant, BAY 36-1677, in which the mutations Arg 121 to Glu and
Thr 13 to Asp ensure high affinity for IL-4R /IL-2R receptors
expressed by lymphoid cells, without activation of the IL-4R/IL-13R receptors mainly expressed by other cells. BAY 36-1677 (25 ng/mL) was cytotoxic in 14 of 16 cases of B-lineage ALL;
the median reduction in cell recovery after 7 days of culture was 85%
(range, 17%-95%) compared to results of parallel cultures not exposed
to the cytokine. Twelve of the 14 sensitive cases had t(9;22) or 11q23
abnormalities; 3 were obtained at relapse. BAY 36-1677 induced
apoptosis in leukemic lymphoblasts but did not substantially affect the
growth of normal CD34+ cells, thus conferring a growth
advantage to normal hematopoietic cells over leukemic lymphoblasts in
vitro. BAY 36-1677 had antileukemic activity equal or superior to that
produced by native IL-4, but it lacked any effects on the growth of
endothelial cells and fibroblasts. The molecular manipulation of IL-4
to abrogate its proinflammatory activity has generated a novel and
therapeutically promising cytokine for the treatment of high-risk ALL.
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