Advertisement

Antibody targeting of ovarian cancer: recombinant single-chain fragments and the role of internalization

  • M. A. Bookman
  • B. J. Giantonio
  • J. Schultz

Abstract

Among the factors that have hindered development of antibody based therapy are the heterogeneity of tumor antigen expression, the Hmited penetration of bulk tumor masses by macromolecules, cross reactivity between tumor and normal host antigens and unfavourable patterns of antibody internalization [1]. With greater understanding of these obstacles and the ability to engineer changes within the antibody molecule itself, there has been renewed enthusiasm for development and evaluation of immunoconjugates. Improved molecular and functional characterization of tumor antigens has influenced the design of targeting strategies and contributed to the analysis of normal tissue distribution and potential for host toxicity. Furthermore, the choice of specific radionuclide, toxin or drug conjugate has been influenced by increased knowledge of antibody internalization and processing pathways. Thus, a new generation of reagents is being prepared for clinical trial that takes full advantage of past experiences and recent advances in molecular and cellular biology.

Keywords

Ovarian Cancer Epidermal Growth Factor Receptor SKBR3 Cell Flow Cytometric Assay Antibody Target 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bookman, M.A. (1993) Biologic therapy in the management of refractory ovarian cancer. Gynecol Oncol, 51,113–26.PubMedCrossRefGoogle Scholar
  2. 2.
    Slamon, D.J., Godophin, W., Jones, L.A. et al. (1989) Studies of HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 244, 707–12.PubMedCrossRefGoogle Scholar
  3. 3.
    Berchuck, A., Kamel, A., Whitaker, R. et al. (1990) Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res., 50, 4087–91.PubMedGoogle Scholar
  4. 4.
    Drebin, J.A., Link, V.C., Stern, D.F. et al. (1985) Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell, 41, 695–706.CrossRefGoogle Scholar
  5. 5.
    Drebin, J.A. Link, V.C., Greene, M.I. (1988) Monoclonal antibodies specific for the neu oncogene product directly mediate anti-tumor effects in vivo. Oncogene, 2, 387–94.PubMedGoogle Scholar
  6. 6.
    Stewart, J.S.W., Hird, V., Snook, D. et al. (1990) Intraperitoneal yttrium-90-labeled monoclonal antibody in ovarian cancer, J. Clin. Oncol, 8, 1941–50.PubMedGoogle Scholar
  7. 7.
    Woo, D.V., Li, D., Mattis, J.A. and Steplewski, Z. (1989) Selective chromosomal damage and cytotoxicity of 125I-labeled monoclonal antibody 17-la in human cancer cells. Cancer Res., 49, 2952–8.PubMedGoogle Scholar
  8. 8.
    Braslawsky, G.R., Kadow, K., Knipe, J. et al. (1991) Adriamycin(hydrazone)-antibody conjugates require internalization and intracellular acid hydrolysis for antitumor activity.Cancer Immunol Immunother., 33, 367–74.PubMedCrossRefGoogle Scholar
  9. 9.
    Trail, P.A., Willner, D., Lasch, S.J. et al. (1993) Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science, 261,212–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Van Leeuwen, F., van de Vijver, M.J., Lomans, J. et al. (1990) Mutation of the human neu protein facilitates down-modulation by monoclonal antibodies. Oncogene, 5,497–503.PubMedGoogle Scholar
  11. 11.
    Huang, S.S., Koh, H.A., Konish, Y. et al. (1990) Differential processing and turnover of the oncogenically activated neu/erb B2 gene product and its normal cellular counterpart. J. Biol Chem., 265,3340–6.PubMedGoogle Scholar
  12. 12.
    Bookman, M.A. (1992) Immunotoxin therapy in ovarian cancer. In Ovarian Cancer 2: Biology, Diagnosis and Management, (eds P. Mason, F. Sharp and W. Creasman), Chapman & Hall, London, pp. 153–60.Google Scholar
  13. 13.
    Paganelli, G., Magnani, P., Zito, F. et al. (1991) Three-step monoclonal antibody tumor targeting in carcinoembryonic antigen-positive patients. Cancer Res., 51, 5960–6.PubMedGoogle Scholar
  14. 14.
    Huston, J.S., Levinson, D., Mudgett-Hunter, M. et al. (1988) Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in E. coll Proc. Natl Acad. Sci USA, 85, 5879–83.CrossRefGoogle Scholar
  15. 15.
    Skerra, A. and Pluckthun, A. (1988) Assembly of a functional immunoglobulin Fv fragment in Escherichia coli. Science, 240,1038–41.Google Scholar
  16. 16.
    Milenic, D.E., Yokota, T., Filpula, D.R. et al. (1991) Construction, binding properties, metabolism, and tumor targeting of a single- chain Fv derived from the pancarcinoma monoclonal CC49. Cancer Res., 51, 6363–71.PubMedGoogle Scholar
  17. 17.
    Yokota, T., Milenic, D.E., Whitlow, M. and Schlom, J. (1992) Rapid tumor penetration of a single-chain Fv and comparison with the immunoglobulin forms. Cancer Res., 52, 3402–8.PubMedGoogle Scholar
  18. 18.
    Kelley, R.F., O’Connell, M.P., Carter, P. et al. (1992) Antigen binding thermodynamics and antiproliferative effects of chimeric and humanized anti-pl85HER2 antibody Fab fragments. Biochemistry, 31, 5434–41.PubMedCrossRefGoogle Scholar
  19. 19.
    Chaudhary, V.K., Queen, C., Junghans, R.P. et al. (1989) A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature, 339, 394–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Tai, M.-S., Mudgett-Hunter, M., Levinson, D. et al. (1990) A bifunctional fusion protein containing Fc-binding fragment B of staphylococcal protein A amino terminal to antidigoxin single-chain Fv. Biochemistry, 29, 8024–30. 24.Google Scholar
  21. 21.
    Batra, J.K., Kasprzyk, P.G., Bird, R.E. et al. (1992) Recombinant anti-erbB2 immunotoxins containing Pseudomonas exotoxin. Proc. Natl Acad. Sci. USA, 89,5867–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Wels, W., Harwerth, I.-M., Mueller, M. et al. (1992) Selective inhibition of tumor cell growth by a recombinant single-chain antibody-toxin specific for the erbB-2 receptor. Cancer Res., 52,6310–17.PubMedGoogle Scholar
  23. 23.
    McCartney, J.E., Tai, M.-S., Opperman, H. et al. (1993) Refolding of single-chain Fv with C-terminal cystein (sFv’); formation of disulfide-bonded homodimers of anti-c-erbB2 and anti-digoxin sFv’. Miami Short Reports, 3, 91.Google Scholar
  24. 24.
    Cumber, A.J., Ward, E.S., Winter, G. et al. (1992) Comparative stabilities in vitro and in vivo of a recombinant mouse antibody FvCys fragment and a bisFvCys conjugate, J.Immunol, 149,120–6.PubMedGoogle Scholar
  25. 25.
    Adams, G.P., McCartney, J.E., Tai, M.-S. et al. (1993) Highly specific in vivo tumor targeting by monovalent and divalent forms of 741F8 sFv, an anti-c-erbB2 single-chain Fv molecule. Cancer Res., 53, 4026–34.PubMedGoogle Scholar

Copyright information

© Chapman & Hall 1995

Authors and Affiliations

  • M. A. Bookman
  • B. J. Giantonio
  • J. Schultz

There are no affiliations available

Personalised recommendations