K. Kawakami et al., Overexpressed cell surface interleukin-4 receptor molecules can be successfully targeted for antitumor cytotoxin therapy, CR R IMMUN, 21(1-3), 2001, pp. 299-310
A variety of human solid cancer cell lines and primary cell cultures has be
en reported to overexpress high-affinity receptors (R) for interleukin-4 (I
L-4), a pleiotropic immunoregulatory cytokine. The significance of IL-4R ex
pression is not known; however, IL-4 is able to upregulate adhesion molecul
es, inhibit cell proliferation, and mediate signal transduction in tumor ce
ll lines. To target IL-4R, we produced a chimeric protein composed of a cir
cular permuted IL-4 and a mutated form of Pseudomonas exotoxin [termed IL4(
38-37)PE38KDEL or cpIL4-PE]. The recombinant cpIL4-PE was highly cytotoxic
to cancer cells, but not toxic to normal B cells, T cells, monocytes, and C
D34(+), even though these cells express detectable numbers of IL-4R. The cy
totoxicity was specific because excess of recombinant IL-4 neutralized the
cpIL4-PE effect. To further develop this molecule, in vivo antitumor activi
ty was tested in animal models of human cancer. This agent showed remarkabl
e antitumor activity in AIDS-Kaposi's sarcoma, glioblastoma multiforme, and
breast cancer models in immunodeficient animals. cpIL4-PE caused partial o
r complete regression of established human tumors. Preclinical efficacy and
toxicity studies provided a therapeutic window in which this cancer-target
ed agent could be used. On the basis of these studies, we initiated a Phase
I clinical trial for the treatment of recurrent glioblastoma multiforme. O
ur preliminary clinical results suggest that cpIL4-PE has antitumor activit
y against the deadliest form of brain tumors, without detectable toxicity t
o normal brain tissues. Thus, IL-4 receptors represent novel targets for ca
ncer cytotoxin therapy.