Development and Activities of the BR96-Doxorubicin Immunoconjugate

  • Ingegerd Hellström
  • Karl Erik Hellström
  • Peter D. Senter
Part of the Methods in Molecular Biology™ book series (MIMB, volume 166)


The use of antibodies to selectively destroy tumors has attracted attention since Paul Ehrlich’s dream about “magic bullets,” and it gained support from the demonstration by Pressman in the 1950s that antibodies can be employed to deliver radioisotopes to tumors in rodents. The promise of this approach received a strong boost when Köhler and Milstein introduced monoclonal antibody (MAb) technology in the 1970s (1). However, the clinical success of unmodified MAbs or MAbs conjugated to drugs, radioisotopes, or toxins in the treatment of tumors has been modest so far. The primary exceptions are the use of MAbs targeting the HER2 growth factor receptor in breast carcinomas (2) and MAbs to treat B-cell lymphomas (3, 4). Encouraging results have also been obtained when a MAb reacting with a differentiation antigen expressed on colorectal carcinomas was given to patients who were at high risk of tumor recurrence following primary surgery (5).


Athymic Mouse Human Carcinoma Anthracycline Antibiotic Free Doxorubicin Labile Bond 
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.


  1. 1.
    Hellström, I., Hellström, K. E., Siegall, C., and Trail, P. A. (1995) Immunoconjugates and immunotoxins for therapy of carcinomas, in Ad. Pharmacol. (August, J. T., Anders, M. W., Murad, F., and Coyle, J. T., eds.), Academic Press, San Diego, pp. 349–388.Google Scholar
  2. 2.
    Slamon, D., Leyland-Jones, B., Shak, S., Paton, V., Bajamonde, A., Fleming, T., et al. (1998) Addition of herceptin (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: a randomized, multinational controlled phase III trial. Proc. of ASCO (Abstract) 17, 98A.Google Scholar
  3. 3.
    Kaminski, M., Zasadny, K., Francis, I., Milik, A., Ross, C., Moon, S., Crawford, et al. (1993) Radioimmunotherapy of B-cell lymphoma with 131 I anti-B1 (anti-CD20) antibody. N. Engl. J. Med. 329, 459–465.PubMedCrossRefGoogle Scholar
  4. 4.
    Press, O. W., Eary, J. F., Appelbaum, F. R., Martin, P. J., Badger, C. C., Nelp, W. B., et al. (1993) Radiolabeled-antibody therapy of B cell lymphoma with autologous bone marrow support. N. Engl. J. Med. 329, 1219–1268.PubMedCrossRefGoogle Scholar
  5. 5.
    Riethmüller, G., Schneider-Gadicke, E., Schlimok, G., Schmiegel, W., Raab, R., Hoffken, K., Gruber, R., Pechlmaier, H., Hirche, H., Piehlmayr, R., Buggisch, P., Witte, J., et al. (1994) Randomized trial of monoclonal antibody for adjuvant therapy of resected Dukes C colorectal carcinoma. Lancet 343, 1177–1183.PubMedCrossRefGoogle Scholar
  6. 6.
    Pietersz, G. A., Krauer, K., and McKenzie, I. F. (1994) The use of monoclonal antibody immunoconjugates in cancer therapy. Adv. Exp. Med. Biol. 353, 169–179.PubMedGoogle Scholar
  7. 7.
    Senter, P. D., Wallace, P. M., Svensson, H. P., Vrudhula, V. M., Kerr, D. E., Hellström, I., et al. (1993) Generation of cytotoxic agents by targeted enzymes. Bioconjugate Chem. 4, 3–9.CrossRefGoogle Scholar
  8. 8.
    Carter, S. K. (1975) Adriamycin-a review. J. Nat. Cancer Inst. 55, 1265–1274.PubMedGoogle Scholar
  9. 9.
    Young, R. C., Ozols, R. F., and Myers, C. E. (1981) The anthracycline antineoplastic drugs. New Engl. J. Med. 305, 139–153.PubMedCrossRefGoogle Scholar
  10. 10.
    Hurwitz, E., Levy, R., Maron, R., Wilchek, M., Arnon, R., and Sela, M. (1975) The covalent binding of daunomycin and adriamycin to antibodies, with retention of both drug and antibody activities. Cancer Res. 35, 1175–1181.PubMedGoogle Scholar
  11. 11.
    Levy, R., Hurwitz, E., Maron, R., Arnon, R., and Sela, M. (1975) The specific cytotoxic effects of daunomycin conjugated to antitumor antibodies. Cancer Res. 35, 1182–1186.PubMedGoogle Scholar
  12. 12.
    Hurwitz, E., Wilchek, M., and Pitha, J. (1980) Soluble macromolecules as carriers for daunorubicin. J. Appl. Biochem. 2, 25–35.Google Scholar
  13. 13.
    Shen, W. C. and Ryser, H. J. (1981) Cis-aconityl spacer between daunomycin and macromolecular carriers: a model of pH-sensitive linkage releasing drug from a lysosomotropic conjugate. Biochem. Biophys. Res. Commun. 102, 1048–1054.PubMedCrossRefGoogle Scholar
  14. 14.
    Diener, E., Diner, U. E., Sinha, A., Xi, S., and Vergidis, R. (1986) Specific immunosuppression by immunotoxins containing daunomycin. Science 231, 148–150.PubMedCrossRefGoogle Scholar
  15. 15.
    Yang, H. Y. and Reisfeld, R. A. (1988) Doxorubicin conjugated with a monoclonal antibody directed to a human melanoma-associated proteoglycan suppresses the growth of established tumor xenografts in nude mice. Proc. Natl. Acad. Sci. 85, 1189–1193.PubMedCrossRefGoogle Scholar
  16. 16.
    Dillman, R. O., Johnson, D. E., Shawler, D. L., and Koziol, J. A. (1988) Superiority of an acid-labile daunorubicin-monoclonal antibody immunoconjugate compared to free drug. Cancer Res. 48, 6097–6102.PubMedGoogle Scholar
  17. 17.
    Lavie, E., Hirschberg, D. L., Schreiber, G., Thor, K., Hill, L., Hellström, I., et al. (1991) Monoclonal antibody L6-daunomycin conjugates constructed to release free drug at the lower pH of tumor tissue. Cancer Immunol. Immunother. 33, 223–230.PubMedCrossRefGoogle Scholar
  18. 18.
    Poznansky, M. J. and Juliana, R. L. (1984) Biological approaches to the controlled delivery of drugs: a critical review. Pharmacol. Rev. 36, 277–336.PubMedGoogle Scholar
  19. 19.
    Braslawsky, G. R., Edson, M. A., Pearce, W., Kaneko, T., and Greenfield, R. S. (1990) Antitumor activity of adriamycin (hydrazone-linked) immunoconjugates compared with free adriamycin and specificity of tumor cell killing. Cancer Res. 50, 6608–6614.PubMedGoogle Scholar
  20. 20.
    Mattes, M. J., Griffiths, G. L., Diril, H., Goldenberg, D. M., Ong, G. L, and Shih, L. B. (1994) Processing of antibody-radioisotope conjugates after binding to the surface of tumor cells. Cancer 73, 787–793.PubMedCrossRefGoogle Scholar
  21. 21.
    Gerweck, L. E., and Seetharaman, K. (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res. 56, 1194–1198.PubMedGoogle Scholar
  22. 22.
    Kaneko, T., Willner, D., Monkovic, I., Knipe, J. O., Braslawsky, G. R., Greenfield, R. S., and Vyas, D. M. (1991) New hydrazone derivatives of adriamycin and their immunoconjugates-a correlation between acid stability and cytotoxicity. Bioconjug. Chem. 2, 133–141.PubMedCrossRefGoogle Scholar
  23. 23.
    Trail, P. A., Willner, D., Knipe, J., Henderson, A. J., Lasch, S. J., Zockler, M. E., et al. (1997) Effect of linker variation on the stability, potency, and efficacy of carcinoma-reactive BR64-doxorubicin immunoconjugates. Cancer Res. 57, 100–105.PubMedGoogle Scholar
  24. 24.
    Hellström, I., Garrigues, H. J., Garrigues, U., and Hellström, K. E. (1990) Highly tumor-reactive, internalizing, mouse monoclonal antibodies to Ley related cell surface antigen. Cancer Res. 50, 2183–2190.PubMedGoogle Scholar
  25. 25.
    Garrigues, J., Garrigues, U., Hellström, I., and Hellström, K. E. (1993) Ley specific antibody with potent anti-tumor activity is internalized and degraded in lysosomes. Am. J. Pathol. 142, 607–622.PubMedGoogle Scholar
  26. 26.
    Firestone, R. A., Willner, D., Hoffstead, S. J., King, H. D., Kaneko, T., Braslawsky, G. R., et al. (1996) Synthesis and antitumor activity of the immunoconjugate BR96-Dox. J. Controlled Release 39, 251–259.CrossRefGoogle Scholar
  27. 27.
    Trail, P. A., Willner, D., Lasch, S. J., Henderson, A. J., Hofstead, S., Casazza, A. M., et al. (1993) Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science 261, 212–215.PubMedCrossRefGoogle Scholar
  28. 28.
    Sjögren, H. O., Isaksson, M., Willner, D., Hellström, I., Hellström, K. E., and Trail, P. A. (1997) Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats. Cancer Res. 57, 4530–4536.PubMedGoogle Scholar
  29. 29.
    Mosure, K. W., Henderson, A. J., Klunk, L. J., and Knipe, J. O. (1997) Disposition of conjugate-bound and free doxorubicin in tumor-bearing mice following administration of a BR96-doxorubicin immunoconjugate (BMS 182248) Cancer Chemother. Pharmacol. 40, 251–258.PubMedCrossRefGoogle Scholar
  30. 30.
    Yarnold, S. and Fell, H. P. (1994) Chimerization of anti-tumor antibodies via homologous recombination “conversion vectors.” Cancer Res. 54, 1–7.Google Scholar
  31. 31.
    Slichenmyer, W. J., Saleh, M. N., Bookman, M. A. et al (1996) Phase I studies of BR96 doxorubicin in patients with advanced solid tumors that express the Lewis Y antigen. Anti-Cancer Treatment, Sixth International Congress (Abstract) 95, 6–9.Google Scholar
  32. 32.
    Saleh, M. N., LoBuglio, A. F., and Trail, P. A. (1998) Immunoconjugate therapy of solid tumors: studies with BR96-doxorubicin, in Basic and Clinical Oncology, vol. 15: Monoclonal Antibody-Based Therapy of Cancer (Grossbard, M., ed.), Marcel Dekker, New York, pp. 397–416.Google Scholar
  33. 33.
    Tolcher, A. W., Sugarman, S., Gelmon, K. A., Cohen, R., Saleh, M., Isaacs, C., et al. (1999) Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J. Clin. Oncol. 17, 478–484.PubMedGoogle Scholar
  34. 34.
    Trail, P. A., Slichenmyer, W. J., Birkhofer, M. J., Warner, G., Knipe, J., Willner, D., et al. (1996) BR96-doxorubicin immunoconjugate for treatment of patients with carcinoma. Proc. Am. Assoc. Cancer Res. (Abstract) 37, 626.Google Scholar
  35. 35.
    Trail, P. A., Bianchi, A. B., Henderson, A. J., TrailSmith, M. D., Willner, D., Girit, E., et al. (1999a) Enhanced antitumor activity of paclitaxel in combinaiton with the anti-carcinoma immunoconjugate BR96-Dox Orubicin. Clin. Cancer Res. 5, 3632–3638.PubMedGoogle Scholar
  36. 36.
    Jain, R. (1994) Barriers to drug delivery in solid tumors. Sci. Am. 271, 58–65.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2001

Authors and Affiliations

  • Ingegerd Hellström
    • 1
  • Karl Erik Hellström
    • 1
  • Peter D. Senter
    • 2
  1. 1.Pacific Northwest Research InstituteSeattle
  2. 2.Seattle GeneticsBothell

Personalised recommendations