TARGETING OF INTERLEUKIN-13 RECEPTOR ON HUMAN RENAL-CELL CARCINOMA-CELLS BY A RECOMBINANT CHIMERIC PROTEIN COMPOSED OF INTERLEUKIN-13 AND ATRUNCATED FORM OF PSEUDOMONAS EXOTOXIN-A (PE38QQR)

We have previously shown that human renal cell carcinoma (RCC) cells e xpress large numbers of interleukin-13 receptors (IL-13R), a newly des cribed hemopoietic growth factor receptor. To target tumor cells that express IL-13R. we have produced a chimeric protein composed of human IL-13 and a derivative of Pseudomonas exotoxin A, termed PE38QQR. We r eport here that IL13-PE38QQR is highly cytotoxic to many human RCC cel l lines. IL-13R-negative cell lines or cell lines expressing low numbe rs of IL-13R (<300 sites/cell) that include human bone marrow-derived cells were not susceptible to the cytotoxic effect of IL13-PE38QQR. Th e sensitivity of RCC cells to IL13-PE38QQR correlated positively with the density of IL-13R. The cytotoxic activity of IL13-PE38QQR was comp eted by an excess of IL-13 in a protein synthesis inhibition assay and confirmed by a clonogenic assay. Even though IL-13 and IL-4 are homol ogues and IL-4R and IL-13R have been proposed to share a receptor subu nit, IL-4 did not compete for the cytotoxicity mediated by IL13-toxin on RCC. IL13-PE38QQR competes for [I-125]-lL-13 binding sites on RCC c ells, although at a lower affinity than the wild-type recombinant cyto kine. Human T-cell, B-cell, and monocytic cell lines are unresponsive to the cytotoxic action of IL13-PE38QQR. Thus, our results indicate th at IL13-PE38QQR is highly cytotoxic to human RCC cells, although it is not cytotoxic to a variety of normal hematopoietic cells. IL13-PE38QQ R should be further investigated preclinically for the treatment of hu man RCCs. This is a US government work. There are no restrictions on i ts use.