Advertisement

Breast Cancer Research and Treatment

, Volume 38, Issue 1, pp 3–9 | Cite as

Recombinant immunotoxins

  • Ira Pastan
  • Lee H. Pai
  • Ulrich Brinkmann
  • David FitzGerald
Immunotherapy

Summary

Pseudomonas exotoxin has been genetically modified so that it targets cancer cells. This was accomplished by deleting its cell binding domain and replacing it with Fv fragments of antibodies that react with breast, colon, and other cancers. Several recombinant immunotoxins are now in clinical trials.

Key words

breast cancer cancer treatment colon cancer Pseudomonas exotoxin 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Rees AR, Adamson ED, Graham CF: Epidermal growth factor receptors increase during the differentiation of embryonal carcinoma cells. Nature 281: 309–311, 1979.PubMedGoogle Scholar
  2. 2.
    Veale D, Kerr N, Gibson GJ, Harris AL: Characterization of epidermal growth factor receptor in primary human non-small cell lung cancer. Cancer Res 49:1313–1317, 1989.PubMedGoogle Scholar
  3. 3.
    Steck PA, Lee P, Hung MC, Yung WK: Expression of an altered epidermal growth factor receptor by human glioblastoma cells. Cancer Res 48:5433–5439, 1988.PubMedGoogle Scholar
  4. 4.
    Wilding G, Valverius E, Knabbe C, Gelmann EP: Role of transforming growth factor-alpha in human prostate cancer cell growth. Prostate 15:1–12, 1989.PubMedGoogle Scholar
  5. 5.
    Lau JL, Fowler J Jr, Ghosh L: Epidermal growth factor in the normal and neoplastic kidney and bladder. J Urol 139:170–175, 1988.PubMedGoogle Scholar
  6. 6.
    Vitetta ES, Stone M, Amlot P, Fay J, May R, Till M, Newman J, Clark P, Collins R, Cunningham D, et al: Phase I immunotoxin trial in patients with B-cell lymphoma. Cancer Res 51:4052–4058, 1991.PubMedGoogle Scholar
  7. 7.
    Grossbard ML, Lambert JM, Goldmacher VS, Spector NL, Kinsella J, Eliseo L, Coral F, Taylor JA, Blattler WA, Epstein CL, et al: Anti-B4-blocked ricin: a phase I trial of 7-day continuous infusion in patients with B-cell neoplasms. J Clin Oncol 11:726–737, 1993.PubMedGoogle Scholar
  8. 8.
    Chang K, Pastan I, Willingham MC: Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int J Cancer 50:373–381, 1992.PubMedGoogle Scholar
  9. 9.
    Pastan I, Lovelace E, Rutherford AV, Kunwar S, Willingham MC, Peehl DM: PR1 — a monoclonal antibody that reacts with an antigen on the surface of normal and malignant prostate cells. J Natl Cancer Inst 85:1149–1154, 1993.PubMedGoogle Scholar
  10. 10.
    Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen C: An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA 270:943–947, 1993.PubMedGoogle Scholar
  11. 11.
    Weiner GJ, Kahn D, Jochimsen PR, Bevering CG, Kisker MA: Radiolabeled antibody imaging of patients with potentially resectable colorectal adenocarcinoma. Cancer Invest 12:111–120, 1994.PubMedGoogle Scholar
  12. 12.
    Hakomori S: Possible functions of tumor-associated carbohydrate antigens. Curr Opin Immunol 3:646–653, 1991.PubMedGoogle Scholar
  13. 13.
    Baeckstrom D, Hansson GC, Nilsson O, Johansson C, Gendler SJ, Lindholm L: Purification and characterization of a membrane-bound and a secreted mucintype glycoprotein carrying the carcinoma-associated sialyl-LEA epitope on distinct core proteins. J Biol Chem 266:21537–21547, 1991.PubMedGoogle Scholar
  14. 14.
    Allured VS, Collier RJ, Carroll SF, McKay DB: Structure of exotoxin A of Pseudomonas aeruginosa at 3.0 Angstrom. Proc Natl Acad Sci USA 83:1320–1324, 1986.PubMedGoogle Scholar
  15. 15.
    Kounnas MZ, Morris RE, Thompson MR, FitzGerald DJ, Strickland DK, Saelinger CB: The alpha-2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J Biol Chem 267:12420–12423, 1992.PubMedGoogle Scholar
  16. 16.
    Chiron MF, Fryling CM, FitzGerald DJ: Cleavage of pseudomonas exotoxin and diphtheria toxin by a furin-like enzyme prepared from beef liver. J Biol Chem 269:18167–18176, 1994.PubMedGoogle Scholar
  17. 17.
    Moehring JM, Inocencio NM, Robertson BJ, Moehring TJ: Expression of mouse furin in a Chinese hamster cell resistant to Pseudomonas exotoxin A and viruses complements the genetic lesion. J Biol Chem 268: 2590–2594, 1993.PubMedGoogle Scholar
  18. 18.
    Chaudhary V, Jinno Y, FitzGerald D, Pastan I: Pseudomonas exotoxin contains a specific sequence at the carboxyl terminus that is required for cytotoxicity. Proc Natl Acad Sci USA 87:308–312, 1990.PubMedGoogle Scholar
  19. 19.
    Pastan I, Willingham MC, Gottesman M: Molecular manipulations of the multidrug transporter: a new role for transgenic mice. FASEB J 5:2523–2528, 1991.PubMedGoogle Scholar
  20. 20.
    Pai LH, Pastan I: Immunotoxin therapy for cancer [clinical conference]. JAMA 269:78–81, 1993.PubMedGoogle Scholar
  21. 21.
    Brinkmann U, Pai LH, FitzGerald DJ, Willingham M, Pastan I: B3(Fv)-PE38KDEL, a single-chain immunotoxin that causes complete regression of a human carcinoma in mice. Proc Natl Acad Sci USA 88:8616–8620, 1991.PubMedGoogle Scholar
  22. 22.
    Batra JK, Kasprzyk PG, Bird RE, Pastan I, King CR: Recombinant anti-erbB2 immunotoxins containing Pseudomonas exotoxin. Proc Natl Acad Sci USA 89: 5867–5871, 1992.PubMedGoogle Scholar
  23. 23.
    Debinski W, Karlsson B, Lindholm L, Siegall CB, Willingham MC, FitzGerald D, Pastan I: 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, 1992.PubMedGoogle Scholar
  24. 24.
    Buchner J, Pastan I, Brinkmann U: A method for increasing the yield of properly folded recombinant fusion proteins: single-chain immunotoxins from renaturation of bacterial inclusion bodies. Anal Biochem 205:263–270, 1992.PubMedGoogle Scholar
  25. 25.
    Renkin EM: Multiple pathways of capillary permeability. Circ Res 41:735–743, 1977.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Ira Pastan
    • 1
  • Lee H. Pai
    • 1
  • Ulrich Brinkmann
    • 1
  • David FitzGerald
    • 1
  1. 1.Laboratory of Molecular Biology, Division of Cancer Biology, Diagnosis and CentersNational Cancer Institute, National Institutes of HealthBethesdaUSA

Personalised recommendations