Rl. Alexander et al., In vitro interleukin-3 binding to leukemia cells predicts cytotoxicity of a diphtheria toxin/IL-3 fusion protein, BIOCONJ CHE, 11(4), 2000, pp. 564-568
Patients with acute myeloid leukemia frequently develop chemotherapy resist
ant blasts. To overcome multidrug resistance, a diphtheria toxin fusion pro
tein (DTIL3) was engineered by fusing the catalytic and translocation domai
ns of diphtheria toxin (DT) to human interleukin-3 (IL-3). However, when bl
asts were isolated from patients and tested for colony growth inhibition by
DTIL3, only a third of the samples showed sensitivity to the fusion protei
n. Prior to clinical development, we need to be able to identify which pati
ents are likely to respond to therapy with DTIL3. In this report, we compar
ed the inhibition of thymidine incorporation in human leukemia cell lines b
y DTIL3 to the IL-3 receptor number and affinity. We found DTIL3 was cytoto
xic to four of the eight cell lines tested with half-maximal inhibition of
thymidine incorporation (IC50) from 1 to 50 pM. The IL-3 receptor density f
or these cell lines ranged from 0 to 2635 receptors per cell. The dissociat
ion constant for an IL-3 high-affinity receptor agonist was 0.5 nM for cell
lines with receptors. We found a correlation for the cell lines between th
e presence of high-affinity IL-3 receptors and sensitivity to DTIL3 (p = 0.
03). These results suggest the variability in sensitivity of patient leukem
ic progenitors to DTIL3 may be due in part to the presence or absence of hi
gh-affinity IL-3 receptors.