Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies

CD20 is a nonglycosylated 33 to 37 kD phosphoprotein involved in B-cell signaling that subserves important functions in the regulation of B-cell proliferation and differentiation. In addition, this B-cell surface antigen has been shown recently to be an effective target for immunotherapy of B-cell m...

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Bibliographic Details
Published in:Blood 1998-03, Vol.91 (5), p.1644-1652
Main Authors: DAMING SHAN, LEDBETTER, J. A, PRESS, O. W
Format: Article
Language:English
Subjects:
Animals
Antibodies, Anti-Idiotypic - pharmacology
Antibodies, Monoclonal - pharmacology
Antigens, CD20 - immunology
Antigens, CD20 - physiology
Antineoplastic agents
Apoptosis
B-Lymphocytes - immunology
B-Lymphocytes - physiology
Biological and medical sciences
Burkitt Lymphoma - pathology
Calcium - metabolism
Cell Cycle
Cell Division
Chelating Agents - pharmacology
Cross-Linking Reagents
Egtazic Acid - analogs & derivatives
Egtazic Acid - pharmacology
Goats
Humans
Immunotherapy
Medical sciences
Mice
Pharmacology. Drug treatments
Receptors, Fc - physiology
Tumor Cells, Cultured
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Summary:CD20 is a nonglycosylated 33 to 37 kD phosphoprotein involved in B-cell signaling that subserves important functions in the regulation of B-cell proliferation and differentiation. In addition, this B-cell surface antigen has been shown recently to be an effective target for immunotherapy of B-cell malignancies using chimeric (mouse/human) or radiolabeled murine monoclonal anti-CD20 antibodies. In this report we show that extensive crosslinking of CD20 with murine anti-CD20 monoclonal antibodies (MoAbs) in the presence of either goat anti-mouse IgG or Fc receptor (FcR)-expressing cells directly inhibits B-cell proliferation, induces nuclear DNA fragmentation, and leads to cell death by apoptosis. The apoptotic effects of these MoAbs can be inhibited by chelation of extracellular or intracellular Ca2+ by EGTA or Bapta AM, indicating that anti-CD20-mediated apoptosis may be related to changes in Ca2+ concentration. These findings suggest that ligation of CD20 in vivo by anti-CD20 antibodies in the presence of FcR-expressing cells may initiate signal transduction events that induce elevation of [Ca2+]i and lead to apoptosis of malignant B cells, thereby contributing to the impressive tumor regressions observed in mouse models and clinical trials using anti-CD20 MoAbs.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.v91.5.1644