Receptors for
interleukin 4 (IL-4R) are overexpressed on the surface of various human solid
tumors including
renal cell carcinoma,
glioblastoma,
Kaposi's sarcoma, and
head and neck squamous cell carcinoma (SCCHN). On the basis of this preferential receptor overexpression, a novel IL-4R-targeted
cytotoxin,
IL-4 (38-37)-PE38KDEL, was developed in which circularly permuted
IL-4 [IL-4 (38-37)] was fused to mutated form of Pseudomonas
exotoxin (PE38KDEL). Despite the recognized expression of the IL-4R on SSCHN, the utility of a receptor-specific fusion
protein for the treatment of this disease remains unknown. The purpose of this study was to establish the utility of
IL-4 (38-37)-PE38KDEL for the treatment of established SSCHN in animal models of human disease. Expression of IL-4R in SCCHN was confirmed by immunohistochemistry with eight of eight tissue sections expressing IL-4R.
Protein synthesis inhibition assays demonstrated growth inhibition of two cell lines in
IL-4 (38-37)-PE38KDEL in a dose-dependent fashion. In two SCCHN s.c. xenografted nude mouse models, i.p. and intratumoral injection of
IL-4 (38-37)-PE38KDEL mediated
tumor regression with no visual toxicity observed in any of the animals. Subcultured
tumor cells after intratumoral treatment with
IL-4 toxin did not develop resistance to the
drug. These data demonstrate that
IL-4 (38-37)-PE38KDEL is effective in mediating significant antitumor effects in SCCHN and may represent an attractive therapeutic option for patients with advanced
cancers of the upper aerodigestive tract.