Single-Chain Fusion Toxins for the Treatment of Breast Cancer: Antitumor Activity of BR96 sFv-PE40 and Heregulin-PE40

  • C. B. Siegall
Conference paper
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 140)

Abstract

Many commonly used anti-cancer drugs have been identified through massive screenings of natural products and chemical compounds. Unfortunately, these screens have resulted in the selection of compounds that are not only cytotoxic to cancer cells, but to most actively proliferating cells as well. The small degree of selectivity usually lies in the fact that cancer cells are amongst the most rapidly proliferating of all cell types in the body. A different approach to the development of anti-cancer therapeutics is through rational design of targeted cytotoxic agents. These molecules are delivered to specific cell-surface receptors or antigens, usually by monoclonal antibodies (MAbs) or growth factor/cytokines, and have been appended to a variety of cytotoxic agents. These molecules include drug-immunoconjugates (Trail et al. 1993), enzyme-prodrugs (Senter et al. 1988), radiolabeled-antibodies (Press et al. 1993), and immunotoxins (Chaudhary et al. 1989) and have been used in vitro, in vivo, and clinically to target cancer cells for elimination. This article will focus on two recently developed immunotoxins, BR96 sFv-PE40 and HAR-TX ß2, and will describe their component structure, expression, purification, and preclinical characterization.

Keywords

Toxicity Fermentation Albumin Carbohydrate Codon 

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References

  1. Allured VS, Collier RJ, Carroll SF, McKay DB (1986) Structure of exotoxin A of Pseudomonas aeruginosa at 3.0-A resolution. Proc Natl Acad Sci USA 83: 320–324CrossRefGoogle Scholar
  2. Brinkmann U, Pastan I (1994) Immunotoxins against cancer. Biochim Biophys Acta 1198: 27–45PubMedGoogle Scholar
  3. Carraway KL III, Sliwkowski MX, Akita RW, Platko JV, Guy PM, Nuijens A, Diamonti AJ, Vandlen RL, Cantley LC, Cerione RA (1994) The erbB3 gene product is a receptor for heregulin. J Biol Chem 269: 14303–14306PubMedGoogle Scholar
  4. Chaudhary VK, Queen C, Junghans RP, Waldmann TA, FitzGerald DJ, Pastan I (1989) A recombinant immunotoxin consisting of two antibody variable domains fused to Pseudomonas exotoxin. Nature 339: 394–397PubMedCrossRefGoogle Scholar
  5. Frankel AE (1993) Immunotoxin therapy of cancer. Oncology 7: 69–86PubMedGoogle Scholar
  6. Friedman PN, McAndrew Si, Gawlak SL, Chace D, Trail PA, Brown JP, Siegall CB (1993a) BR96 sFv-PE40, a potent single-chain immunotoxin that selectively kills carcinoma cells. Cancer Res 53: 334–339PubMedGoogle Scholar
  7. Friedman PN, Chace DF, Trail PA, Siegall CB (1993b) Anti-tumor activity of the single-chain immunotoxin BR96 sFv-PE40 against established breast and lung tumor xenografts. J Immunol 150: 3054–3061PubMedGoogle Scholar
  8. Garrigues J, Garrigues U, Hellström I, Hellström KE (1993) Ley specific antibody with potent anti-tumor activity is internalized and degrade in lysosomes. Am J Pathol 2: 607–622Google Scholar
  9. Ghetie V, Vitetta E (1994) Immunotoxins in the therapy of cancer: from bench to clinic. Pharmacol Ther 63: 209–234PubMedCrossRefGoogle Scholar
  10. Hellström I, Garrigues HJ, Garrigues U, Hellström KE (1990) Highly tumor-reactive, internalizing, mouse monoclonal antibodies to LeY-related cell-surface antigens. Cancer Res 50: 2183–2190PubMedGoogle Scholar
  11. Hwang J, FitzGerald DJP, Adhya S, Pastan I (1987) Functional domains of Pseudomonas exotoxin identified by deletion analysis of the gene expressed in E. coli. Cell 48: 129–136Google Scholar
  12. Kondo T, FitzGerald D, Chaudhary VK, Adhya S, Pastan I (1988) Activity of immunotoxins constructed with modified Pseudomonas exotoxin A lacking the cell recognition domain. J Biol Chem 263: 9470–9475PubMedGoogle Scholar
  13. Plowman GD, Green JM, Culouscou JM, Carlton GW, Rothwell VM, Buckley S (1993) Heregulin induces tyrosine phosphorylation of HER4/p180erbB4 Nature 366: 473–475PubMedCrossRefGoogle Scholar
  14. Press OW, Eary JF, Appelbaum FR, Martin PJ, Badger CC, Nelp WB, Glenn S, Butchko G, Fisher D, Porter B, Matthews DC, Fisher LD, Bernstein ID (1993) Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. N Engl J Med 329: 1219–1224PubMedCrossRefGoogle Scholar
  15. Senter PD, Saulnier MG, Schreiber GJ, Hirschberg DL, Brown JP, Hellström I, Hellström KE (1988) Antitumor effects of antibody-alkaline phosphatase conjugates in combination with etoposide phosphate. Proc Natl Acad Sci USA 85: 4842–4846PubMedCrossRefGoogle Scholar
  16. Siegall CB, Chace D, Mixan B, Garrigues U, Wan H, Paul L, Wolff E, Hellström I, Hellström KE (1994a) In vitro and in vivo characterization of BR96 sFv-PE40. J Immunol 152: 2377–2384PubMedGoogle Scholar
  17. Siegall CB, Liggitt D, Chace D, Tepper MA, Fell HP (1994b) Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitumor activity. Proc Natl Acad Sci USA 91: 9514–9518PubMedCrossRefGoogle Scholar
  18. Siegall CB, Wolff EA, Gawlak SL, Paul L, Chace D, Mixan B (1995a) Immunotoxins as cancer chemotherapeutic agents. Drug Dev Res 34: 210–219CrossRefGoogle Scholar
  19. Siegall CB, Mixan B, Chace D, Bacus SS, Cohen BD, Greene J, Goetze A, Plowman GD, Hellström I, Hellström KE, Fell HP (1995b) HER4 expression correlates with cytotoxicity directed by a heregulin-toxin fusion protein. J Biol Chem 270: 7625–7630PubMedCrossRefGoogle Scholar
  20. Trail PA, Willner D, Lasch Si, Henderson AJ, Hofstead SJ, Casazza AM, Firestone RA, Hellström I, Hellström KE (1993) Cure of xenografted human carcinomas by BR96-Doxorubicin immunoconjugates. Science 261: 212–215PubMedCrossRefGoogle Scholar
  21. Tzahar E, Levkowitz G, Karunagaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D, Yarden Y (1994) ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all neu differentiation factor/heregulin isoforms. J Biol Chem 269: 25226–25233PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • C. B. Siegall
    • 1
  1. 1.Molecular Immunology DepartmentBristol-Myers Squibb, Pharmaceutical Research InstituteSeattleUSA

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