Skip to main content
SpringerLink
Log in

Antitumor activity of combinations of antibodies directed against different epitopes on the extracellular domain of the human EGF receptor

  • Published:
Cell Biophysics Aims and scope Submit manuscript

Abstract

The receptor (EGFR) for epidermal growth factor (EGF) and transforming growth alpha (TGFα) is often overexpressed in certain types of human malignancy and high levels of expression of the receptor and/ or coexpression of growth factors. EGF and TGFα have also been correlated with poor prognosis in many patients. We have produced a number of rat monoclonal antibodies (MAbs) against four distinct epitopes on the external domain of the EGF receptor and are currently evaluating their potential for therapeutic use. Nine of these of MAbs were found to inhibit the binding of TGF and EGF to the receptor on tumor cells and these MAbs were able to inhibit the growth in vitro and in vivo of tumor cells that overexpress the EGF receptor. Here, we describe the results of experiments to determine the antitumor activity of combination treatment with two antibodies directed against separate epitopes on the external domain of human EGFR. Our results showed that treatment of human tumor xenografts with a combination of two anti-EGFR MAbs that bind to two distinct epitopes on the external domain of EGF receptor was not as effective as treatment with ICR62 alone, which binds to epitope C on the EGFR and is of IgG2b isotype. A phase I clinical trial with antibody ICR62 is currently underway in Royal Marseden Hospital (UK) in patients with head and neck and lung carcinomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Salomon, D. S. and Perroteau, I. (1986) Growth factors in cancer and their relationship to oncogenes.Cancer Investigation 4(4), 43–60.

    Article  PubMed  CAS  Google Scholar 

  2. Waterfield, M. D. (1991) The role of growth factors in cancer, inIntroduction to the Cellular and Molecular Biology of Cancer, 2nd ed. (Franks L. M. and Teich, N. M., eds.), Oxford University Press, Oxford, UK, pp. 296–329.

    Google Scholar 

  3. Cross, M. and Dexter, M. (1991) Growth factors in development, transformation and tumorigenesis.Cell 64, 271–280.

    Article  PubMed  CAS  Google Scholar 

  4. Harris, A. L. and Neal, D. E. (1987) Epidermal growth factor and its receptor in human cancer, inGrowth Factors and Oncogenes in Breast Cancer. Camelot, Southampton, UK, pp. 60–90.

    Google Scholar 

  5. Gullick, W. J. (1991) Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers.Br. Med. Bull. 47(1), 87–98.

    PubMed  CAS  Google Scholar 

  6. Das, M., Mikyawa, T., Fox, C. F., Pruss, R. M., Aharonov, A., and Hershaman, H. R. (1977) Specific radiolabelling of cell surface receptor for EGF.Proc. Natl. Acad. Sci. USA 74 2790–2794.

    Article  PubMed  CAS  Google Scholar 

  7. Cohen, S., Ushiro, H., Stocheck, C., and Chinkers, M. (1982) A native 170,000 epidermal growth factor receptor-kinase complex from shed membrane vesicles.J. Biol. Chem. 257, 1523–1531.

    PubMed  CAS  Google Scholar 

  8. Carpenter, G. (1983) The biochemistry and physiology of the receptor-kinase for epidermal growth factor.Mol. Cell Endocrinol. 31, 1–9.

    Article  PubMed  CAS  Google Scholar 

  9. Carpenter, G. (1987) Receptor for epidermal growth factor and other polypeptide mitogens.Ann. Rev. Biochem. 56, 881–914.

    Article  PubMed  CAS  Google Scholar 

  10. Ullrich, A. and Schlessinger, J. (1990) Signal transduction by receptors with tyrosine kinase activity.Cell 61, 203–212.

    Article  PubMed  CAS  Google Scholar 

  11. Carpenter, G., King, L., and Cohen, S. (1978) Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro.Nature 276, 409, 410.

    Google Scholar 

  12. Hunter, T. and Cooper, J. A. (1981) Epidermal growth factor induces rapid tyrosine phosphorylation of proteins in A431 human tumor cells.Cell 24, 741–752.

    Article  PubMed  CAS  Google Scholar 

  13. Reynolds, G. J., Todaro, G. J., Fryling, G., and Stephenson, J. R. (1981) Human transforming growth factors induce tyrosine phosphorylation of EGf receptors.Nature 292, 259–262.

    Article  PubMed  CAS  Google Scholar 

  14. Prigent, S. A. and Gullick, W. J. (1992) Type 1 growth factor receptors and their ligands.Cancer Topics 8(12), 141–144.

    Google Scholar 

  15. Sainsbury, J. R. C., Farndon, J. R., Needham, G. K., Malcolm, A. J., and Harris, A. L. (1987) Epidermal growth factor receptor status as predictor of early recurrence of and death from breast cancer.Lancet i, 1398–1402.

    Google Scholar 

  16. Kohler, M., Janz, J., Winze, H. O., Wagner, E., and Bauknecht, T. (1989) The expression of epidermal growth factor receptors. Epidermal growth factor like factor and C-myc in ovarian and cervical carcinoma and their potential clinical significance.Anti-Cancer Res. 4, 1537–1548.

    Google Scholar 

  17. Ozawa, S., Veda, N., Schimizu, N., and Abe, O. (1989) Prognostic significance of epidermal growth factor receptor in oesophageal squamous cell carcinomas.Cancer 63, 2169–2173.

    Article  PubMed  CAS  Google Scholar 

  18. Hendler, F. J., Shun-Siv, A., Oechsli, M., Nanu, L., Richards, C. S., and Ozanne, B. W. (1989) Increased epidermal growth factor-receptor, binding predicts a poor survival in squamous tumours.Cancer Cells 7, 347–351.

    Google Scholar 

  19. Neal, D. E., Sharples, L., Smith, K., Fennelly, J., Hall, R. R., and Harris, A. L. (1990) The epidermal growth factor and the prognosis of the bladder cancer.Cancer 65, 1619–1625

    Article  PubMed  CAS  Google Scholar 

  20. Gorgoulis, V., Aninos, D., Mikou, P., Kanavaros, P., Karameris, A., Joardanoglou, J., Rasidakis, A., Veslemes, M., Ozanne, B., and Spandidos, D. A. (1992) Expression of EGF, TGF-α and EGFR in squamous cell lung carcinomas.Antican. Res. 12, 1183–1188.

    CAS  Google Scholar 

  21. Jaros, E., Perry, R. H., Adam, L., Kelly, P. J., Crawford, P. J., Kalbag, R. M., Mendelow, A. D., Sengupta, R. P., and Pearson, A. D. J. (1992) Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labeling in brain tumours.Br. J. Cancer 66, 373–385.

    PubMed  CAS  Google Scholar 

  22. Mendelsohn, J. (1989) Anti-EGF receptor monoclonal antibodies: biological studies and potential clinical applications.Trans. Amer. Clin. Climatol. Assoc. 100, 31–38.

    CAS  Google Scholar 

  23. Harris, A. L. (1990) The epidermal growth factor receptor as a target for therapy.Cancer Cell 2(2), 321–323.

    CAS  Google Scholar 

  24. Ernis, B. W., Lipman, M. E., and Dickson, R. B. (1991) The EGF receptor system as a target for anti tumour therapy.Cancer Investigation 9(5), 553–562.

    Article  Google Scholar 

  25. Sato, J. D., Le, A. D., and Kawamoto, T. (1987) Derivation and assay of biological effects of monoclonal antibodies to epidermal growth factor receptors.Meth. Enzymol. 146 63–81

    Article  PubMed  CAS  Google Scholar 

  26. Murthy, U., Basu, A., Rodeck, U., Herlyn, M., Ross, A. H., and Das, M. (1987) Binding of an antagonistic monoclonal antibody to an intact and fragmented EGF-receptor polypeptide.Arch. Bio. Biophys. 225(2), 549–560.

    Article  Google Scholar 

  27. Fendly, B. M., Winget, M., Hudziak, R. M., Lipari, M. T., Napier, M. A., and Ullrich, A. (1990) Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product.Cancer Res. 50, 1550–1558.

    PubMed  CAS  Google Scholar 

  28. Gutowski, M. C., Briggs, S. L., and Johnson, D. A. (1991) Epidermal growth factor receptor-reactive monoclonal antibodies: xenograft antitumour activity alone and as drug immunoconjugates.Cancer Res. 51, 5471–5475.

    PubMed  CAS  Google Scholar 

  29. Pellegrini, R., Centis, F., Martignone, Mastroionni, A., Taglibue, E., Tosi, E., Menard, S., and Colnaghi, M. L. (1991) Characterization of a monoclonal antibody directed against the epidermal growth factor receptor binding site.Cancer Immuno. Immunother. 34, 37–42.

    Article  CAS  Google Scholar 

  30. Modjtahedi, H., Styles, J., Box, G., Eccles, S., Gusterson, B., and Dean, C. (1993) Antitumour activity of rat Mabs to the human receptor for EGF, inMutant Oncogenes: Targets for Therapy? (Epenetos, A. A. and Lemoine, N. R., eds.), Chapman Hall, London, pp. 35–47.

    Google Scholar 

  31. Modjtahedi, H., Styles, J., and Dean, C. (1993) The human EGF receptor as a target for cancer therapy: six new rat MAbs against the receptor on the breast carcinoma MDAMB-468.Br. J. Cancer 67, 247–253.

    PubMed  CAS  Google Scholar 

  32. Modjtahedi, H., Eccles, S., Box, G., Styles, J., and Dean, C. (1993) Immunotherapy of human tumour xenografts overexpressing the EGF receptor with rat antibodies that block growth factor-receptor interaction.Br. J. Cancer 67, 254–261.

    PubMed  CAS  Google Scholar 

  33. Cowley, G., Smith, J. A., Gusterson, B., Hendler, F., and Ozanne, B. (1984) The amount of EGF receptor is elevated on squamous cell carcinomas.Cancer Cells 1, 5.

    CAS  Google Scholar 

  34. Filmus, J., Pollak, M. N., Cailleau, R., and Buick, R. N. (1985) MDA-468, a human breast cancer cell line with a high number of epidermal growth factor (EGF) receptors, has an amplified EGF receptor gene and is growth inhibited by EGF.Biochem. Biophysis. Res. Comm. 128(2), 898–905.

    Article  CAS  Google Scholar 

  35. Dyer, M. J. S., Hale, G., Hayhoe, F. G. J., and Waldman, H. (1989) Effect of campath-I antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype.Blood 73, 1431–1439.

    PubMed  CAS  Google Scholar 

  36. Dean, C. J., Styles, J. M., Gyure, L. A., Peppard, J., Hobbs, S. M., Jackson, E., and Hall, J. G. (1984) The production of hybridomas from the gut associated lymphoid tissue of tumour bearing rats. I. Mesenteric nodes as a source of IgG producing cells.Clin. Exp. Immunol. 57, 358–364.

    PubMed  CAS  Google Scholar 

  37. Kohler, G. and Millstein, C. (1975) Continuous culture of fixed cells secreting antibody of predefined specificity.Nature 256, 495–497.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Cancer Research, Secction of Immunology, Sutton, Surrey, UK

    H. Modjtahedi, S. A. Eccles, G. Box, J. Styles & C. J. Dean

Authors
  1. H. Modjtahedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. A. Eccles
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. Box
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Styles
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. J. Dean
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Modjtahedi, H., Eccles, S.A., Box, G. et al. Antitumor activity of combinations of antibodies directed against different epitopes on the extracellular domain of the human EGF receptor. Cell Biophysics 22, 129–146 (1993). https://doi.org/10.1007/BF03033871

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033871

Index Entries

Search

Navigation