Development of a recombinant interleukin-4-Pseudomonas exotoxin for therapy of glioblastoma.
About 12,000 Americans are diagnosed with malignant astrocytoma each year. Despite surgery, radiotherapy, and chemotherapy, the prognosis of these patients remains poor. Targeted toxins based on the identification of novel antigens or receptors provide a promising new approach to treating cancer. We have identified one such cell surface protein in the form of interleukin (IL)-4 receptors (IL-4R) on human malignant astrocytoma. Normal brain tissues from frontal cortex and temporal lobe cortex do not express IL-4R. To target IL-4R, we generated a chimeric fusion protein composed of IL-4 and Pseudomonas exotoxin (IL4-PE). This toxin is highly cytotoxic to IL-4R-bearing human brain cancer cells. Preclinical toxicologic experiments were performed in mice, rats, and guinea pigs to determine an maximum tolerated dose. Intrathecal administration in cynomolgus monkeys produced high cerebrospinal fluid levels without any central nervous system or other abnormalities. When IL4-PE was injected into the right frontal cortex of rats, localized necrosis was observed at 1,000 but not < or =100 microg/ml doses. Intravenous administration of this biologic to monkeys produced reversible grade 3 or grade 4 elevations of hepatic enzymes in a dose-dependent manner. These results indicate that localized administration can produce nontoxic levels of IL4-PE that may have significant activity against astrocytoma. In vivo experiments with nude mice have demonstrated that IL4-PE has significant antitumor activity against human glioblastoma tumor model. Intratumor administration of IL4-PE has been initiated for the treatment of malignant astrocytoma in a phase I clinical trial.
Puri
R K
RK
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
D036002:ADP Ribose Transferases; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001427:Bacterial Toxins; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D015195:Drug Design; D005098:Exotoxins / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D015847:Interleukin-4 / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D011549:Pseudomonas / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005098:Exotoxins; D015847:Interleukin-4; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C059989:IL-4-PE40 protein, recombinant