Expression of interleukin-6 receptors by pediatric acute lymphoblastic leukemia cells with the t(4;11) translocation: a possible target for therapy with recombinant IL6-Pseudomonas exotoxin.
We have detected expression of interleukin-6 receptors (IL-6R) by primary leukemic cells from three of six patients with t(4;11)+ ALL. Scatchard analysis revealed from 960 to 2100 high-affinity IL-6R/cell on these cells (median, 1560; mean, 1540). All three IL-6R+ cases also expressed CD33, which was not expressed on IL-6R-negative cases. To determine if these receptors could serve as a target for a recombinant ligand-toxin, we examined the sensitivity of primary IL-6R+ ALL cells to a recombinant IL6-Pseudomonas exotoxin (IL6-PE4E) fusion protein, in which the toxicity and specificity of the chimeric toxin was enhanced by substitution of four glutamine residues for naturally occurring amino acids in PE domain I. Primary cells from IL-6R+ cases were sensitive to IL6-PE4E in a 48-h cytotoxicity assay, with ID50 values (concentrations causing 50% decrease in viability) ranging from 23 ng/ml to 92 ng/ml (median, 61; mean, 58). Furthermore, incubation of these cells with 10(3) ng/ml IL6-toxin for 24 h prevented their subsequent engraftment in SCID mice. Thus, IL6-PE4E may be useful for ex vivo purging of IL-6R+ leukemic cells in an autologous bone marrow transplantation setting and possibly for therapy of residual, chemotherapy-resistant disease.
Gu
L
L
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Zhou
M
M
Jurickova
I
I
Yeager
A M
AM
Kreitman
R J
RJ
Phillips
C N
CN
Findley
H W
HW
D036002:ADP Ribose Transferases; D000818:Animals; D002648:Child; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D005098:Exotoxins / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D005098:Exotoxins; C064195:IL-6-PE40 protein, chimeric; D015850:Interleukin-6; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; D036002:ADP Ribose Transferases