Cytotoxins Directed at Interleukin-4 Receptors as Therapy for Human Brain Tumors

  • Raj K. Puri
Part of the Methods in Molecular Biology™ book series (MIMB, volume 166)


Interleukin-4 (IL-4) is a pleiotropic immune regulatory cytokine that has been extensively studied in the last decade. Activated T-lymphocytes, mast cells, and basophils (1, 2, 3) produce it. Consistent with the pleiotropic nature of this molecule, the receptors for IL-4 have been identified on many different cell types, including hematopoietic and nonhematopoietic cells (2, 3, 4). We have reported that a variety of solid tumor cells express a greater number of highaffinity IL-4 receptors (IL-4R) than normal cells (5, 6, 7, 8, 9, 10, 11, 12). We were first to report that murine solid cancer cells expressed high affinity IL-4R (4). We later reported that human renal-cell carcinoma and other solid tumor cells expressed functional IL-4R (6, 7). These receptors are functional because IL-4 can cause signal transduction, inhibit growth of some tumor cell lines, and increase expression of major histocompatibility antigens and the intercellular adhesion molecule-1 (ICAM-1) on some tumor cell lines (11, 12, 13, 14, 15, 16, 17). IL-4R is also expressed, although in low numbers, in normal immune cells such as T-cells, B-cells, monocytes, other blood cells such as eosinophils, basophils, and fibroblasts, and endothelial cells (1, 2, 3).


Glioma Cell Glioblastoma Cell Cerebral Spinal Fluid Cynomolgus Monkey Normal Brain Tissue 
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  1. 1.
    Paul, W. E. (1990) Interleukin-4, A prototypic immunoregulatory lymphokine. Blood 77, 1859–1870.Google Scholar
  2. 2.
    Puri, R. K. and Siegel, J. P. (1993) Interleukin-4 and cancer therapy. Cancer Invest. 11, 473–486.PubMedCrossRefGoogle Scholar
  3. 3.
    Puri, R. K. (1995) Structure and function of interleukin-4 and its receptors, in Cytokines: Interleukins and Their Receptors (Kurzrock, R. and Talpaz, M., eds.), Kluwer Academic Publishers, Norwell, MA, pp. 143–186.Google Scholar
  4. 4.
    Idzerda, R. L., March, C. J., Mosley, B., Lyman, S. D., Bos, T. V., Girupel, S. D., et al. (1990) Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily. J. Exp. Med. 171, 861–873.PubMedCrossRefGoogle Scholar
  5. 5.
    Puri, R. K., Ogata, M., Leland, P., Feldman, G. M., and Pastan, I. (1991) Expression of high affinity IL4 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.PubMedGoogle Scholar
  6. 6.
    Obiri, N. I., Hillman, G., Haas, G. P., Sud, S., and Puri, R. K. (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.PubMedCrossRefGoogle Scholar
  7. 7.
    Obiri, N. I., Siegel, J. P., Varricchio, F., and Puri, R. K. (1994) Expression and function of high affinity interleukin-4 receptors on human melanoma, ovarian and breast carcinoma cells. Clin. Exp. Immunol. 95, 148–155.PubMedCrossRefGoogle Scholar
  8. 8.
    Obiri N. I. and Puri, R. K. (1994) Characterization of interleukin-4 receptors expressed on human renal cell carcinoma cells. Oncology Res. 6, 419–427.Google Scholar
  9. 9.
    Varricchio, V., Obiri, N. I., Haas, G. P., and Puri, R. K. (1993) Immunostaining of interleukin-4 receptor on human renal cell carcinoma. Lymphokine Cytokine Res. 12, 465–469.PubMedGoogle Scholar
  10. 10.
    Varricchio, F., Husain, R., Dover, P. Gill, P., and Puri, R. K. (1997) Interleukin-4 receptor expression in vivo on human AIDS-related Kaposi’s sarcoma. Oncology Res. 9, 495–503.Google Scholar
  11. 11.
    Murata, T., Noguchi, P. D., and Puri, R. K. (1995) Receptors for Interleukin (IL)-4 do not associate with the common γ chain, and IL-4 induces the phosphorylation of JAK2 tyrosine kinase in human colon carcinoma cells. J. Biol. Chem. 270, 30,829–30,836.PubMedCrossRefGoogle Scholar
  12. 12.
    Mehrotra, R., Varricchio, F., Husain, S. R., and Puri, R. K. (1998) Head and neck cancers but not benign lesions express interleukin-4 receptors in situ. Oncology Reports 5, 45–48.Google Scholar
  13. 13.
    Obiri, N. I., Tandon, N., and Puri, R. K. (1995) Upregulation of intercellular adhesion molecule-1 on human renal cell carcinoma cells by interleukin-4. Int. J. Cancer 61, 635–642.PubMedCrossRefGoogle Scholar
  14. 14.
    Leland, P., Obiri, N. I., Aggarwal, B. B., and Puri, R. K. (1995) Suramin blocks binding of interleukin-4 to its receptors and interleukin-4 induced mitogenic response. Oncology Res. 7, 227–235.Google Scholar
  15. 15.
    Murata, T., Obiri, N. I., and Puri, R. K. (1998) Structure of and signal transduction through interleukin 4 and interleukin 13 receptors. Int. J. Mol. Med. 1, 551–557.PubMedGoogle Scholar
  16. 16.
    Murata, T., Taguchi, J., and Puri, R. K. (1998) Interleukin-13 receptor γ′ chain but not α chain: A functional component of interleukin-4 receptor. Blood 91, 3884–3891.PubMedGoogle Scholar
  17. 17.
    Husain, S. R., Leland, P., Aggarwal, B. B., and Puri, R. K. (1996) Transcriptional up-regulation of interleukin 4 receptors by human immunodeficiency virus type 1 tat gene. AIDS Res. Human Retroviruses 12, 1349–1359.CrossRefGoogle Scholar
  18. 18.
    Aman, M. J., Tayebi, N., Obiri, N. I., Puri, R. K., Modi, W. S., and Leonard, W. J. (1996) cDNA cloning and characterization of the human interleukin-13 receptor α chain. J. Biol. Chem. 271, 29,265–29,270.PubMedCrossRefGoogle Scholar
  19. 19.
    Russell, S. M., Keegan, A. D., Harada, N., Nakamura, Y., Noguchi, M., Leland, P., et al. (1993) Interleukin-2 receptor gamma chain: A functional component of the interleukin-4 receptor. Science 262, 1880–1883.PubMedCrossRefGoogle Scholar
  20. 20.
    Kondo, M., Takeshita, T., Ishi, N., Nakamura, M., Watanabe, S., Arai, K., and Sugamura, K. (1993) Sharing of interleukin-2 (IL-2) receptor γc chain between receptors for IL-2 and IL-4. Science 262, 1874–1877.PubMedCrossRefGoogle Scholar
  21. 21.
    Noguchi, M., Nakamura, Y., Russell, S. M., Ziegler, S. F., Tsang, M., Cao, X., et al. (1993) Interleukin-2 receptor γ chain: A functional component of interleukin-7 receptor. Science 262, 1877–1880.PubMedCrossRefGoogle Scholar
  22. 22.
    Russell, S. M., Johnston, M., Noguchi, M., Kawamura, M., Bacon, C., Friedman, M., et al. (1994) Interaction of IL-2 receptor beta and gamma chain with Jak 1 and Jak 3, implications for XSCID and XCID. Science 266, 1042–1045.PubMedCrossRefGoogle Scholar
  23. 23.
    Giri, J. G., Ahdieh, M., Eisenman, J., Snanebeck, K., Grabstein, K., Kumaki, S., et al. (1994) Utilization of beta and gamma chains of the IL-2 receptor by novel cytokine IL-15. EMBO J. 13, 2822–2830.PubMedGoogle Scholar
  24. 24.
    Obiri, N. I., Leland, P., Murata, T., Debinski, W., and Puri, R. K. (1997) The interleukin-13 receptor structure differs on various cell types and may share more than one component with interleukin 4 receptor. J. Immunol. 158, 756–764.PubMedGoogle Scholar
  25. 25.
    Murata, T. and Puri, R. K. (1997) Comparison of IL-13 and IL-4 induced signalling in EBV-immortalized human B cells. Cell. Immunol. 175, 33–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Murata, T., Obiri, N. I., and Puri, R. K. (1997) Human ovarian carcinoma cell lines express IL-4 and IL-13 receptors: comparison between IL-4 and IL-13 signaling. Int. J. Cancer 70, 230–240.PubMedCrossRefGoogle Scholar
  27. 27.
    Murata, T., Taguchi, J., Puri, R. K., and Mohri, H. (1999) Sharing of receptor subunits and signal transduction pathway between the IL-4 and IL-13 receptor system. Int. J. Hematol. 69, 13–20.PubMedGoogle Scholar
  28. 28.
    Obiri, N. I., Murata, T., Debinski, W., and Puri, R. K. (1997) Modulation of interleukin-13 binding and signaling in human renal cell carcinoma cells by the γc chain of the IL-2 receptor. J. Biol. Chem. 272, 20,251–20,258.PubMedCrossRefGoogle Scholar
  29. 29.
    Debinski, W., Puri, R. K., Kreitman, R. J., 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, 14,065–14,070.PubMedGoogle Scholar
  30. 30.
    Puri, R. K., Leland, P, Obiri, N. I., Husain, S. R., Mule, J., Pastan, I., et al. (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.PubMedCrossRefGoogle Scholar
  31. 31.
    Puri, R. K., Mehrotra, P. T., Leland, L., Kreitman, R, Siegel, J. P., and Pastan, I. (1994) Chimeric protein comprised of IL-4 and Pseudomonas exotoxin (IL4-PE4E) is cytotoxic for activated human lymphocytes. J. Immunol. 152, 3693–3700.PubMedGoogle Scholar
  32. 32.
    Debinski, W., Puri, R. K., and Pastan, I. (1994) Chimeric toxin composed of human Interleukin 4 and derivatives of Pseudomonas exotoxin A are potent antitumor agents in mice. Int. J. Cancer 58, 744–748.PubMedCrossRefGoogle Scholar
  33. 33.
    Kreitman, R. J., Puri, R. K., and Pastan, I. (1994) A circularly permutated recombinant interleukin-4 toxin with increased activity. Proc. Natl. Acad. Sci. USA 91, 6889–6893.PubMedCrossRefGoogle Scholar
  34. 34.
    Puri, R. K., Leland, P., Kreitman, R. J., and Pastan, I. (1994) Human neurological cancer cells express interleukin-4 (IL-4) receptors which are targets for the cytotoxic effect of IL4-Pseudomonas exotoxin chimeric protein. Int. J. Cancer 58, 574–581.PubMedCrossRefGoogle Scholar
  35. 35.
    Kreitman, R. J., Puri, R. K., Leland, P., Lee, B., and Pastan, I. (1994) Site directed mutagenesis of IL-4, Improved binding and cytotoxicity of mutant IL4-Toxins by conjugation through cysteine substitutions in IL-4. Biochemistry 33, 11,637–11,644.PubMedCrossRefGoogle Scholar
  36. 36.
    Kreitman, R. J., Puri, R. K., 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.PubMedGoogle Scholar
  37. 37.
    Puri, R. K., Hoon, D. S., Leland, P., Snoy, P., Rand, R. W., Pastan, I., et al. (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.PubMedGoogle Scholar
  38. 38.
    Husain, S. R., Gill, P., Kreitman, R. J., Pastan, I., and Puri, R. K. (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.PubMedGoogle Scholar
  39. 39.
    Husain, S. R., Bihari, N., Kreitman, R. J., Pastan, I., and Puri, R. K. (1998) Complete regression of established glioblastoma tumor xenografts by interleukin-4 toxin therapy. Cancer Res. 58, 3649–3653.PubMedGoogle Scholar
  40. 40.
    Husain, S. R., Kreitman, R. J., Pastan, I., and Puri, R. K. (1999) Interleukin-4 receptor directed cytotoxin therapy of AIDS-associated Kaposi’s sarcoma tumors in xenograft model. Nature Med. 5, 817–822.PubMedCrossRefGoogle Scholar
  41. 41.
    Pastan, I. and FitzGerald, D. (1991) Recombinant toxins for cancer treatment. Science 254, 1173.PubMedCrossRefGoogle Scholar
  42. 42.
    Pastan, I., Chaudhary, V. K., and FitzGerald, D. J. (1992) Recombinant toxins as novel therapeutic agents. Annu. Rev. Biochem. 61, 331.PubMedCrossRefGoogle Scholar
  43. 43.
    Joshi, B., Plautz, G., and Puri, R. K. (2000) Interleukin-13 receptor α chain: A novel tumor associated antigen on malignant glioma cells. Cancer Res. (Advances in Brief). 60, 1168–1172.PubMedGoogle Scholar
  44. 44.
    Morrison, B. and Leder, P. (1992) A receptor binding domain of mouse interleukin-4 defined by a solid phase binding assay and in vitro mutagenesis. J. Biol. Chem. 267, 11,957–11,963.PubMedGoogle Scholar
  45. 45.
    Gossett, K. A., Barbolt, T. A., Cornacoff, J. B., Zelinger, D. J., and Dean, J. H. (1993) Clinical pathologic alterations associated with subcutaneous administration of recombinant interleukin-4 to cynomolgus monkeys. Toxicol. Pathol. 21, 46–53.PubMedCrossRefGoogle Scholar
  46. 46.
    Cornacoff, J. B., Gossett, K. A., Barbolt, T. A., and Dean J. H. (1992) Preclinical evaluation of recombinant interleukin-4. Toxicol. Lett. 64/65, 299–310.CrossRefGoogle Scholar
  47. 47.
    Laske, D. W., Youle, R. J., and Oldfield, E. H. (1997) Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nature Med. 3, 1362–1368.PubMedCrossRefGoogle Scholar
  48. 48.
    Murata, T., Obiri, N. I., Debinski, W., and Puri, R. K. (1997) Structure of IL-13 receptor: Analysis of subunit composition in cancer and immune cells. Biochem. Biophys. Res. Commun. 238, 90–94.PubMedCrossRefGoogle Scholar
  49. 49.
    Rand, R. W., Kreitman, R. J. Patronas, N., Varrichio, F., Pastan, I., and Puri, R. K. (2000) Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high grage glioma. Clin. Cancer Res. 6, 2157–2165.PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2001

Authors and Affiliations

  • Raj K. Puri
    • 1
  1. 1.Laboratory of Molecular Tumor Biology, Division of Cellular and Gene TherapyCenter for Biologics Evaluation and Research, Food and Drug AdministrationBethesda

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