Analysis of antitumor activity of an interleukin-13 (IL-13) receptor-targeted cytotoxin composed of IL-13 antagonist and Pseudomonas exotoxin.

Abstract

We have shown previously that a chimeric fusion protein composed of human interleukin-13 (IL-13) and Pseudomonas exotoxin (PE), termed IL-13 cytotoxin (IL13-PE38), is specifically cytotoxic to various cancer cell lines and primary cell cultures derived from a variety of solid cancers. In addition, we have shown that IL-13 mutant IL-13E13K, in which glutamic acid (E) residue at position 13 of IL-13 molecule was substituted by a lysine (K), is a powerful antagonist of IL-13 and binds to IL-13 receptor with a higher affinity compared with wild-type IL-13. In this study, we have generated an IL-13 cytotoxin IL13E13K-PE38, in which IL-13 antagonist is fused to PE to determine whether this molecule has improved cytotoxicity to tumor cells compared with wild type (wt)IL13-PE38. Highly purified IL13E13K-PE38 was tested in various tumor cell lines including seven glioblastoma multiforme cell lines to compare its binding to the cells, in vitro cytotoxicity, in vivo antitumor activity, and safety in mouse model with wtIL13-PE38. IL13E13K-PE38 bound to U251MG and IL-13Ralpha2 chain-transfected tumor cell lines with 3 to 10 times higher affinity compared with wtIL13-PE38. However, IL13E13K-PE38 did not show higher cytotoxicity compared with wtIL13-PE38 in glioblastoma multiforme or any other cell lines tested. The antitumor activity of IL13E13K-PE38, when administered intraperitoneally to nude mice bearing U251 tumors, was also similar to wtIL13-PE38. Some improvement in antitumor activity was observed when lower doses of IL13E13K-PE38 were injected intratumorally in subcutaneous tumors. These results indicate that in general, IL13E13K-PE38 mediates similar cytotoxicity and antitumor activity to wtIL13-PE38 despite its improved binding affinity to IL-13 receptors.

• Authors: Mitomu Kioi, Koji Kawakami, Raj K Puri
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 18 Pt 1 Pg. 6231-8 (Sep 15 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15448012 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Bacterial Toxins
• Cytotoxins
• Exotoxins
• IL13-PE38
• IL13E13K-PE38 protein
• IL13RA1 protein, human
• Il13ra1 protein, mouse
• Interleukin-13
• Interleukin-13 Receptor alpha1 Subunit
• Receptors, Interleukin
• Receptors, Interleukin-13
• Recombinant Fusion Proteins

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Bacterial Toxins (pharmacology)
• Binding, Competitive
• Cell Line, Tumor
• Cell Proliferation
• Cytotoxins (metabolism)
• Dose-Response Relationship, Drug
• Exotoxins (chemistry, pharmacology)
• Female
• Glioblastoma (drug therapy)
• Humans
• Interleukin-13 (analogs & derivatives, chemistry, pharmacology)
• Interleukin-13 Receptor alpha1 Subunit
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Neoplasm Transplantation
• Protein Binding
• Pseudomonas (metabolism)
• Receptors, Interleukin (metabolism)
• Receptors, Interleukin-13
• Recombinant Fusion Proteins (chemistry, pharmacology)
• Time Factors