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Novel anti–brain tumor cytotoxins specific for cancer cells

Nature Biotechnology volume 16, pages 449–453 (1998)Cite this article

Abstract

The vast majority of brain cancers (gliomas) express a receptor (R) for interleukin 13 (IL13). In order to achieve specific targeting of the IL13R in gliomas, we have mutagenized human (h) IL13. The mutation was made to alter IL13 interaction with the shared functional IL13/4 normal tissue receptor, but not with the glioma-associated receptor. We have thus produced MIL13.E13K (glutamic acid at position 13 changed to lysine) and fused it to derivatives of Pseudomonas exotoxin A. The hlL13.E13K-based cytotoxins are less active on normal cells and thus less toxic, and are better antitumor agents compared with the cytotoxins containing nonmutagenized hlL13.

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References

  1. Debinski, W., Obiri, N.I., Powers, S.K., Pastan, I. and Puri, R.K. 1995. Human glioma cells overexpress receptor for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin. Clinical Cancer Research 1: 1253–1258.

    CAS  PubMed  Google Scholar 

  2. Debinski, W., Miner, R., Leland, P., Obiri, N.I. and Puri, R.K. 1996. Receptor for IL13 does not interact with IL4 but receptor for IL4 interacts with IL13 on human glioma cells. J. Biol. Chem. 271: 22428–22433.

    Article  CAS  Google Scholar 

  3. Debinski, W., Obiri, N.I., Pastan, I. and Puri, R.K. 1995. A novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin is highly cytotoxic to human carcinoma cells expressing receptors for interleukin 13 and interleukin 4. J. Biol. Chem. 270: 16775–16780.

    Article  CAS  Google Scholar 

  4. Debinski, W., Gibo, D.M. and Puri, R.K. A novel way to identify a human glioblastoma-specific receptor for targeting. Int. J. Cancer. In press.

  5. Obiri, N.I., Debinski, W., Leonard, W.J. and Puri, R.K. 1995. Receptor for interleukin 13: Interaction with interteukin 4 by a mechanism that does not involve the common -y subunit of interleukins 2, 4, 7 and 15 receptor. J. Biol. Chem. 270: 8797–8804.

    Article  CAS  Google Scholar 

  6. Obiri, N.I., Husain, S.R., Debinski, W. and Puri, R.K. 1996. Interleukin 13 inhibits growth of human cell carcinoma cells independently of the p140 interleukin 4 receptor chain. Clin. Cancer Res. 2: 1743–1749.

    CAS  PubMed  Google Scholar 

  7. Puri, R.K., Leland, P., Obiri, N.I., Husain, S.R., Kreitman, R.J., Haas, G.P. et al. 1996. Targeting of interleukin-13 receptor on human renal cell carcinoma cells by a recombinant chimeric protein composed of interleukin 13 and a truncated form of Pseudomonas exotoxin A (PE38QQR). Blood 87: 4333–4339.

    CAS  PubMed  Google Scholar 

  8. Obiri, N.I., Leland, P., Murata, T., Debinski, W. and Puri, R.K. 1997. The IL13 receptor structure differs on various cell types and may share more than one component with IL4 receptor. J. Immunol. 158: 756–764

    CAS  PubMed  Google Scholar 

  9. Husain, S.R., Obiri, N.I., Gill, P., Zheng, T., Pastan, I., Debinski, W. and Puri, R.K. 1997. Receptor for interleukin 13 on AIDS-associated Kaposi's sarcoma cells serves as a new target for a potent Pseudomonas exotoxin-based chimeric toxin protein. Clin. Cancer Res. 3: 151–156.

    CAS  PubMed  Google Scholar 

  10. Pastan, I., Chaudhary, V.K. and Fitzgerald, D. 1992. Recombinant toxins as novel therapeutic agents. Annu. Rev. Biochem. 61: 331–354.

    Article  CAS  Google Scholar 

  11. Youle, R.J. 1996. Immunotoxins for central nervous system malignancy. Semin. Cancer Biol. 7: 65–70.

    Article  CAS  Google Scholar 

  12. Shaw, J.P., Akiyoshi, D.E., Arrigo, D.A., Rhoad, A.E., Sullivan, B., Thomas, J. et al. 1991. Cytotoxic properties of DAB486EGF and DAB389EGF, epidermal growth factor (EGF) receptor-targeted fusion toxins. J. Biol. Chem. 266: 21118–21124.

    CAS  PubMed  Google Scholar 

  13. Phillips, P.C., Levow, C., Catterall, M., Colvin, O.M., Pastan, I. and Brem, H. 1994. Transforming growth factors-α-Pseudbmonas exotoxin fusion protein (TGF-α-PE38) treatment of subcutaneous and intracranial human glioma and medulloblastoma xenografts in athymic mice. Cancer Res. 54: 1008–1015.

    CAS  PubMed  Google Scholar 

  14. Gray, B.L., Smith, D.H., Baldridge, J.S., Harkins, R.N., Vasil, M.L., Chen, E.Y. et al. 1984. Cloning, nucleotide sequence and expression in Escherichia coli of the exotoxin A structural gene of Pseudomonas aeruginosa . Proc. Natl. Acad. Sci. USA 81: 2645–2649.

    Article  CAS  Google Scholar 

  15. Allured, V.S., Collier, R.J., Carroll, S.F. and McKay, D.B. 1986. Structure of exotoxin A of Pseudomonas aeruginosaat 30 Ångstrom resolution. Proc. Natl. Acad. Sci. USA 83: 1320–1324.

    Article  CAS  Google Scholar 

  16. Kounnas, M.Z., Morris, R.E., Thompson, M.R., Fitzgerald, D.J., Strickland, O.K. and Saelinger, C.B. 1992. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J. Biol. Chem. 267: 12420–12423.

    CAS  PubMed  Google Scholar 

  17. Inocencio, N.M., Moehring, J.M. and Moehring, T.J. 1994. Furin activates Pseudomonas exotoxin A by specific cleavage in vivo and in vitro. J. Biol. Chem. 269: 31831–31835.

    CAS  PubMed  Google Scholar 

  18. Ogata, M., Chaudhary, V.K., Pastan, I. and Fitzgerald, D.J. 1990. Processing of Pseudomonas exotoxin by a cellular protease results in the generation of a 37,000-Da toxin fragment that is translocated to the cytosol. J. Biol. Chem. 265: 20678–20686.

    CAS  PubMed  Google Scholar 

  19. Iglewski, B.H. and Kabat, D. 1975. NAD-dependent inhibition of protein synthesis by Pseudomonas aeruginosa toxin. Proc. Natl. Acad. Sci. USA 72: 2284–2288.

    Article  CAS  Google Scholar 

  20. Zurawski, S.M., Vega, F. Jr., Huyghe, B. and Zurawski, G. 1993. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 12: 2663–2670.

    Article  CAS  Google Scholar 

  21. Zurawski, S.M., Chomarat, P., Djossou, O., Bidaud, C., McKenzie, A.N.J., Miossec, P. et al. 1995. The primary binding subunit of the human interleukin-4 receptor is also a component of the interleukin-13 receptor. J. Biol. Chem. 270: 13869–13878.

    Article  CAS  Google Scholar 

  22. Tony, H.-R., Shen, B.-J., Reusch, P. and Sebald, W. 1994. Design of human interleukin-4 antagonists inhibiting interleukin-4-dependent and interleukin-13-dependent responses in T-cells and B-cells with high efficiency. Eur. J. Biochem. 225: 659–665.

    Article  CAS  Google Scholar 

  23. Vita, N., Lefort, S., Laurent, P., Caput, D. and Ferrara, P. 1995. Characterization and comparison of the interleukin 13 receptor with the interleukin 4 receptor on several cell types. J. Biol. Chem. 270: 3512–3517.

    Article  CAS  Google Scholar 

  24. Kruse, N., Tony, H.P. and Sebald, W. 1992. Conversion of human interleukin-4 into a high affinity antagonist by a single amino acid replacement. EMBO J. 11: 3237–3244.

    Article  CAS  Google Scholar 

  25. Kruse, N., Shen, B.J., Arnold, S., Tony, H.-P., Muller, T. and Sebald, N. 1992. Two distinct functional sites of human interleukin 4 are identified by variants impaired in either receptor binding or receptor activation. EMBO J. 12: 5121–5129.

    Article  Google Scholar 

  26. Sohnyder, B., Lugli, S., Feng, N., Etter, H., Lutz, R.A., Ryffel, B. et al. 1996. Interleukin-4 (IL4) and IL13 bind to a shared heterodimeric complex on endothe-lial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common (chain. Blood 87: 4286–4295.

    Google Scholar 

  27. Miloux, B., Laurent, P., Bonnin, O., Lupker, J., Caput, D., Vita, N., Ferrara, P. 1997. Cloning of the human IL13Ra of a functional IL4/IL13 receptor. FEBS Lett. 401: 163–166.

    Article  CAS  Google Scholar 

  28. Idzerda, R.L., March, C.J., Mosley, B., Lyman, S.D., Vanden Bos, T., Gimpel, S.D. et al. 1990. Human interleukin-4 receptor confers biological responsiveness and defines a novel receptor superfamily. J. Exp. Med. 171: 861–873.

    Article  CAS  Google Scholar 

  29. Russell, S.M., Keegan, A.D., Harada, N., Nakamura, Y., Noguchi, M., Leland, P. et al. 1993. lnterleukin-2 receptor -γ chain: a functional component of the interleukin-4 receptor. Science 262: 1880–1883.

    Article  CAS  Google Scholar 

  30. Duschl, A. 1995. An antagonistic mutant of interleukin-4 fails to recruit γ° into the receptor complex. Eur. J. Biochem. 228: 305–310.

    Article  CAS  Google Scholar 

  31. Schnarr, B., Ezernieks, J., Sebald, W. and Duschl, A. 1997. IL4 receptor complexes containing or lacking the γ° chain are inhibited by an overlapping set of antagonistic IL4 mutant proteins. Int. Immunol. 9: 861–868.

    Article  CAS  Google Scholar 

  32. Bochner, B.S., Klunk, D.A., Sterbinsky, S.A., Coffman, R.L. and Schleimer, R.P. 1995. IL13 selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells. J. Immunol. 154: 799–803.

    CAS  PubMed  Google Scholar 

  33. Sironi, M., Sciacca, F.L., Matteucci, C., Conni, M., Vecchi, A., Bernasconi, S. et al. 1994. Regulation of endothelial and mesothelial cell function by interleukin-13: Selective induction of vascular cell adhesion molecule-1 and amplification of interleukin-6 production. Blood 84: 1913–1921.

    CAS  PubMed  Google Scholar 

  34. Caput, D., Laurent, P., Kaghad, M., Lelias, J.-M., Lefort, S., Vita, N. and Ferrara, P. 1996. Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor a chain. J. Biol. Chem. 271: 16921–16926.

    Article  CAS  Google Scholar 

  35. Murata, T., Obiri, N.I., Debinski, W. and Puri, R.K. 1997. Structure of IL13 receptor: analysis of subunit composition in cancer and immune cells. Biochem. Biophys. Res. Common. 238: 92–94.

    Article  Google Scholar 

  36. Seetharam, S., Chaudhary, V.K., FitzGerald, D.J. and Pastan, I. 1991. Increased cytotoxic activity of Pseudomonas exotoxin and two chimeric toxins ending in KDEL. J. Biol. Chem. 266: 17376–17381.

    CAS  PubMed  Google Scholar 

  37. Kreitman, R.J., Puri, R.K. and Pastan, I. 1994. A circularly permuted recombi-nant interleukin 4 toxin with increased activity.Proc. Natl. Acad. Sci. USA 91: 6889–6893.

    Article  CAS  Google Scholar 

  38. Chinnasamy, N., Rafferty, J.A., Hickson, I., Ashby, J., Tinwell, H., Margison, G.P. et al. 1997. O"-benzylguanine potentiates the in vivo toxicity and clasto-genicity of temozolomide and BCNU in mouse bone marrow. Blood 89: 1566–1573.

    CAS  Google Scholar 

  39. Debinski, W., Karlsson, B., Lindhol, L., Siegall, C.B., Willingham, M.C., FitzGerald, D. and Pastan, I. 1992. Monoclonal antibody C242-Pseudomonas exotoxin A: A specific and potent immunotoxin with antitumor activity on a human colon cancer xenograft in nude mice. J. Clin. Invest. 90: 405–411.

    Article  CAS  Google Scholar 

  40. Studier, F.W. and Moffat, B.A. 1986. Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes. J. Mol. Biol. 189: 113–130.

    Article  CAS  Google Scholar 

  41. Debinski, W., Puri, R.K., Kreitman, R.J. and Pastan, I. 1993. A wide range of human cancers express interleukin 4 (IL4) receptors that can be targeted with chimeric toxin composed of IL4 and Pseudomonas exotoxin. J. Biol. Chem. 268: 14065–14070.

    CAS  PubMed  Google Scholar 

  42. Wersall, P., Ohlsson, I., Biberfeld, P., Collins, V., von Krusenstjerna, S., Larsson, S. et al. 1997. Intratumoral infusion of the monoclonal antibody, mAb 425, against the epidermal-growth-factor receptor in patients with advanced malignant glioma. Cancer Immunol. Immunother. 44: 157–164.

    Article  CAS  Google Scholar 

  43. 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. Nat. Med. 3: 1362–1368.

    Article  CAS  Google Scholar 

  44. Rutter, C.M. and Elashoff, R.M. 1994. Analysis of longitudinal data: Random coefficient regression modeling. Stat. Med. 13: 1211–1231.

    Article  CAS  Google Scholar 

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Author notes

  1. Waldemar Debinski: Corresponding author e-mail: wdebinski@psghs.edu

Authors and Affiliations

  1. Section of Neurosurgery, Department of Surgery, Pennsylvania State University College of Medicine, Hershey, PA, 17033-0850

    Waldemar Debinski, Denise M. Gibo & Aynsley Kealiher

  2. Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologies Evaluation and Research, US Food and Drug Administration, Bethesda, MD, 20892-4555

    Nicholas I. Obiri & Raj K. Puri

Authors
  1. Waldemar Debinski
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  4. Aynsley Kealiher
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  5. Raj K. Puri
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Debinski, W., Gibo, D., Obiri, N. et al. Novel anti–brain tumor cytotoxins specific for cancer cells. Nat Biotechnol 16, 449–453 (1998). https://doi.org/10.1038/nbt0598-449

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