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Internalization Property of Interleukin-4 Receptor Chain Increases Cytotoxic Effect of Interleukin-4 Receptor-targeted Cytotoxin in Cancer Cells¹

Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Although the receptor for interleukin-4 (IL-4R) is highly expressed on solid human cancer cells, its significance and internalization function is still unclear. To address these issues, we reconstituted Chinese hamster ovarian (CHO-K1) cells with various components of the IL-4R by transient transfection and performed internalization assays using radiolabeled IL-4. Radiolabeled IL-4 internalized through the IL-4R chain in a time-dependent manner. When the IL-4R chain was cotransfected with the IL-13R1 or -_c chain, the IL-4 internalization level was identical to IL-4R transfectants, suggesting that the IL-4R chain plays a major role in IL-4 internalization. These results were confirmed by determining the cytotoxicity of a chimeric protein composed of IL-4 and a mutated form of Pseudomonas exotoxin [IL4(38–37)-PE38KDEL] in CHO-K1 cells transfected with increasing concentrations of IL-4R cDNA. To use the internalization property of the IL-4R chain in the context of IL-4R-targeted cytotoxin therapy, we transiently transfected pancreatic and brain tumor cells with IL-4R chain. Surprisingly, these tumor cells acquired 4–75-fold higher binding activity to IL-4 compared with control cells. Consequently, the cytotoxic activity of IL-4 toxin to these cancer cells was enhanced 5–13-fold compared with control cells as assessed by protein synthesis inhibition and clonogenic assays. Taken together, a combination approach that involves transfer of the IL-4R gene and IL-4R-targeted cytotoxin therapy may serve as a novel approach for cancer therapy.

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