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Cancer Immunology, Immunotherapy

, Volume 48, Issue 12, pp 673–683 | Cite as

Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells

  • Daming Shan
  • Jeffrey A. Ledbetter
  • Oliver W. Press
ORIGINAL ARTICLE

Abstract

Anti-CD20 monoclonal antibodies have been successfully employed in the clinical treatment of non-Hodgkin's lymphomas in both unmodified and radiolabeled forms. Previous publications have demonstrated that the antitumor effects of unmodified anti-CD20 mAb are mediated by several mechanisms including antibody-dependent cellular cytotoxicity, complement-mediated cell lysis, and induction of apoptosis by CD20 cross-linking. In this report, we demonstrate induction of apoptosis by three anti-CD20 monoclonal antibodies [1F5, anti-B1, and C2B8 (Rituximab)]. The magnitude of apoptosis induction was greater with the chimeric Rituximab antibody than with the murine 1F5 and anti-B1 antibodies. Apoptosis could be enhanced with any of the antibodies by cross-linking with secondary antibodies (or Fc-receptor-bearing accessory cells). The signaling events involved in anti-CD20-induced apoptosis were investigated, including activation of protein tyrosine kinases, increases in intracellular Ca2+ concentrations, caspase activation, and cleavage of caspase substrates. Our results indicate that anti-CD20-induced apoptosis can be attenuated by PP1, an inhibitor of protein tyrosine kinases Lck and Fyn, chelators of extracellular or intracellular Ca2+, and inhibitors of caspases, suggesting that anti-CD20-induced apoptosis may involve modulation of these signaling molecules. We also demonstrated that varying the expression of Bcl-2 did not affect the magnitude of anti-B1-induced apoptosis, possibly because of the sequestering effects of other Bcl-2 family members, such as Bad. These studies identify several of the signal-transduction events involved in the apoptosis of malignant B cells that transpire following ligation of CD20 by anti-CD20 antibodies in the presence of Fc-receptor-expressing cells or secondary goat anti-(mouse Ig) antibodies and which may contribute to the tumor regressions observed in mouse models and clinical trials.

Key words CD20 Apoptosis Mechanisms Lymphomas Immunotherapy 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • Daming Shan
    • 1
  • Jeffrey A. Ledbetter
    • 2
  • Oliver W. Press
    • 1
  1. 1.Department of Biological Structure, University of Washington Medical Center, Division of Medical Oncology, Box 356043, Seattle, WA 98195-6043, USA e-mail: dmshan@u.washington.edu Tel.: +1-206-543-7140 Fax: +1-206-598-4509US
  2. 2.Xcyte Therapies, Seattle, Washington, USAUS

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