Overexpressed cell surface interleukin-4 receptor molecules can be successfully targeted for antitumor cytotoxin therapy

Crit Rev Immunol. 2001;21(1-3):299-310.

Abstract

A variety of human solid cancer cell lines and primary cell cultures has been reported to overexpress high-affinity receptors (R) for interleukin-4 (IL-4), a pleiotropic immunoregulatory cytokine. The significance of IL-4R expression is not known; however, IL-4 is able to upregulate adhesion molecules, inhibit cell proliferation, and mediate signal transduction in tumor cell lines. To target IL-4R, we produced a chimeric protein composed of a circular 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 CD34+, even though these cells express detectable numbers of IL-4R. The cytotoxicity was specific because excess of recombinant IL-4 neutralized the cpIL4-PE effect. To further develop this molecule, in vivo antitumor activity was tested in animal models of human cancer. This agent showed remarkable antitumor activity in AIDS-Kaposi's sarcoma, glioblastoma multiforme, and breast cancer models in immunodeficient animals. cpIL4-PE caused partial or complete regression of established human tumors. Preclinical efficacy and toxicity studies provided a therapeutic window in which this cancer-targeted agent could be used. On the basis of these studies, we initiated a Phase I clinical trial for the treatment of recurrent glioblastoma multiforme. Our preliminary clinical results suggest that cpIL4-PE has antitumor activity against the deadliest form of brain tumors, without detectable toxicity to normal brain tissues. Thus, IL-4 receptors represent novel targets for cancer cytotoxin therapy.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain Neoplasms / therapy*
  • Clinical Trials, Phase I as Topic
  • Humans
  • Immunotoxins / pharmacokinetics
  • Immunotoxins / therapeutic use*
  • Interleukin-4
  • Receptors, Interleukin-4 / biosynthesis*
  • Tissue Distribution

Substances

  • Immunotoxins
  • Receptors, Interleukin-4
  • interleukin 4 (38-37)-PE38KDEL
  • Interleukin-4