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Toxicologic Pathology of Cytokines, Cytokine Receptors, and Other Recombinant Human ProteinsDevelopment of a Recombinant Interleukin-4-Pseudomonas Exotoxin for Therapy of Glioblastoma
Raj K. Puri
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892
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  100 µg/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.
Key Words: Interleukin-4 receptors • recombinant chimeric protein • interleukin-4-Pseudomonas exotoxin • glioblastoma • cytotoxicity • antitumor activity • toxicology
References
- Debinski W., Puri RK, Kreitman RJ, and Pastan I. (1993). A wide range of human cancers express IL-4 receptors that can be targeted with chimeric toxin composed of IL-4 and Pseudomonas exotoxin. J. Biol. Chem. 268: 14065-14070.[Abstract/Free Full Text]
- Giri JG, Ahdieh M., Eisenman J., Snanebeck K., Grabstein K., Kumaki S., Naman A., Park LS, Cosman D., and Anderson D. (1994). Utilization of β and
 chains of the IL-2 receptor by novel cytokine IL-15. EMBO J. 13: 2822-2830.[Web of Science][Medline]
[Order article via Infotrieve] - Husain SR, Bihari N., Kreitman RJ, Pastan I., and Puri RK (1998). Complete regression of established glioblastoma tumor xenografts by interleukin-4 toxin therapy. Cancer Res. 58: 3649-3653.[Abstract/Free Full Text]
- Husain SR, Gill P., Kreitman RJ, Pastan I., and Puri RK (1997). Interleukin-4 receptor expression on AIDS-associated Kaposi's sarcoma cells and their targeting by a chimeric protein comprised of circularly permuted interleukin-4 and Pseudomonas exotoxin. Mol. Med. 3: 327-338.[Web of Science][Medline]
[Order article via Infotrieve]
- Idzerda RL, March CJ, Mosley B., Lyman SD, Bos TV, Gimpel SD, Din WS, Grabstein KH, Widmer MB, Park LS, Cosman D., and Beckmann MP (1990). Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily. J. Exp. Med. 171: 861-873.[Abstract/Free Full Text]
- Kondo M., Takeshita T., Ishi N., Nakamura M., Watanabe S., Arai K., and Sugamura K. (1993). Sharing of interleukin-2 (IL-2) receptor chain between receptors for IL-2 and IL-4. Science 262: 1874-1877.[Abstract/Free Full Text]
- Kreitman RJ, Puri RK, and Pastan I. (1994). A circularly permutated recombinant interleukin-4 toxin with increased activity. Proc. Natl. Acad. Sci. USA 91: 6889-6893.[Abstract/Free Full Text]
- Kreitman RJ, Puri RK, and Pastan I. (1995). Increased antitumor activity of a circularly permuted IL4-toxin in mice with IL-4 receptor bearing human carcinoma. Cancer Res. 55: 3357-3363.[Abstract/Free Full Text]
- Murata T., Noguchi PD, and Puri RK (1995). Receptors for interleukin (IL)-4 do not associate with the common chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. J. Biol. Chem. 270: 30829-30836.[Abstract/Free Full Text]
- Murata T., Obiri NI, Debinski W., and Puri RK (1997). Structure of IL-13 receptor: Analysis of subunit composition in cancer and immune cells. Biochem. Biophys. Res. Commun. 238: 90-94.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Murata T., Obiri NI, and Puri RK (1998). Structure of and signal transduction through interleukin 4 and interleukin 13 receptors. Int. J. Mol. Med. 1: 551-557.[Web of Science][Medline]
[Order article via Infotrieve]
- Murata T., Taguchi J., and Puri RK (1998). Interleukin-13 receptor
 ' but not chain: A functional component of interleukin-4 receptor. Blood 91: 3884-3891.[Abstract/Free Full Text] - Noguchi M., Nakamura Y., Russell SM, Ziegler SF, Tsang M., Cao X., and Leonard WJ (1993). Interleukin-2 receptor chain: A functional component of interleukin-7 receptor. Science 262: 1877-1880.[Abstract/Free Full Text]
- Obiri NI, Hillman G., Haas GP, Sud S., and Puri RK ( 1993). Expression of high affinity interleukin-4 receptors on human renal cell carcinoma cells and inhibition of tumor cell growth in vitro by interleukin-4. J. Clin. Invest. 91: 88-93.[Web of Science][Medline]
[Order article via Infotrieve]
- Obiri NI, Leland P., Murata T., Debinski W., and Puri RK (1997). The IL-13 receptor structure differs on various cell types and may share more than one component with IL-4 receptor. J. Immunol. 158: 756-764.[Abstract]
- Obiri NI, Siegel JP, Varricchio F., and Puri RK (1994). Expression and function of high affinity interleukin-4 receptors on human melanoma, ovarian and breast carcinoma cells. Clin. Exp. Immunol. 95: 148-155.[Web of Science][Medline]
[Order article via Infotrieve]
- Pastan I., Chaudahry VK, and FitzGerald DJ (1992). Recombinant toxins as novel therapeutic agents. Annu. Rev. Biochem. 61: 331—354.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Pastan I. and FitzGerald D. (1991). Recombinant toxins for cancer treatment. Science 254: 1173-1177.[Abstract/Free Full Text]
- Paul WE (1990). Interleukin-4: A prototypic immunoregulatory lymphokine. Blood 77: 1859-1870.[Web of Science]
- Puri RK ( 1995). Structure and function of interleukin 4 and its receptors. In: Cytokines: Interleukins and Their receptors, R Kurzrock and M Talpaz (eds). Kluwer, Norwell, Massachusetts, pp. 143-186.
- Puri RK, Debinski W., Obiri N., Kreitman R., and Pastan I. (1994). Human renal cell carcinoma cells are sensitive to the cytotoxic effect of a chimeric protein comprised of human interleukin-4 and Pseudomonas exotoxin. Cell. Immunol. 154: 369-379.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Puri RK, Hoon DS, Leland P., Snoy P., Rand RW, Pastan I., and Kreitman RJ (1996). Preclinical development of a recombinant toxin containing circularly permuted interleukin-4 and truncated Pseudomonas exotoxin for therapy of malignant astrocytoma. Cancer Res. 56: 5631-5637.[Abstract/Free Full Text]
- Puri RK, Leland P., Kreitman RJ, and Pastan I. (1994). Human neurological cancer cells express interleukin-4 (IL-4) receptors which are targets for the cytotoxic effect of IL-4—Pseudomonas exotoxin chimeric protein. Int. J. Cancer 58: 574-581.[Web of Science][Medline]
[Order article via Infotrieve]
- Puri RK, Leland P., Obiri NI, Husain SR. Mule J., Pastan I., and Kreitman RJ (1996). An improved circularly permutated interleukin 4-toxin is highly cytotoxic to human renal cell carcinoma cells: Introduction of c chain in RCC cells does not improve sensitivity. Cell. Immunol. 171: 80-86.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Puri RK, Ogata M. Leland P, Feldman GM, FitzGerald D., and Pastan 1 ( 1991). Expression of high affinity IL-4 receptors on murine sarcoma cells and receptor mediated cytotoxicity of tumor cells to chimeric protein between IL-4 and Pseudomonas exotoxin. Cancer Res. 51: 3011-3017.[Abstract/Free Full Text]
- Puri RK and Siegel JP (1993). Interleukin-4 and cancer therapy. Cancer Invest. 11: 473-486.[Web of Science][Medline]
[Order article via Infotrieve]
- Russell SM, Johnston JA, Noguchi M., Kawamura M., Bacon CM, Friedmann M., Berg M., McVicar DW, Witthuhn BA, Silvennoinen O., Goldmann AS, Schmalstieg FC, Ihle JN, O'Shea JJ, and Leonard WJ (1994). Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: Implications for XSCID and XCID. Science 266: 1042-1045.[Abstract/Free Full Text]
- Russell SM, Keegan AD, Harada N., Nakamura Y., Noguchi M., Leland P., Friedmann MC, Miyajima A., Puri RK, Paul WE, and Leonard WJ (1993). Interleukin-2 receptor gamma chain: A functional component of the interleukin-4 receptor. Science 262: 1880—1883.[Abstract/Free Full Text]
Toxicologic Pathology, Vol. 27, No. 1,
53-57 (1999)
DOI: 10.1177/019262339902700111
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