Therapeutic (high) doses of rituximab activate calcium mobilization and inhibit B-cell growth via an unusual mechanism triggered independently of both CD20 and Fcgamma receptors
| Autor: | Tammy L. Unruh, Uliana Kanevets, Julie P. Deans, Yan Shi, Jonathan Zuccolo, Stephen A. Beers |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
medicine.medical_specialty medicine.drug_class Cell Survival Immunology Receptors Fc Monoclonal antibody Calcium in biology Cell Line Antibodies Monoclonal Murine-Derived Internal medicine medicine Immunology and Allergy Humans Immunologic Factors Calcium Signaling Receptor B cell Chromatography High Pressure Liquid Cell Proliferation Pharmacology CD20 B-Lymphocytes biology Chemistry Antibodies Monoclonal Antigens CD20 Cell biology medicine.anatomical_structure Endocrinology Monoclonal biology.protein Signal transduction Antibody Rituximab |
| Zdroj: | Journal of immunotherapy (Hagerstown, Md. : 1997). 33(1) |
| ISSN: | 1537-4513 |
| Popis: | Rituximab is a CD20-specific monoclonal antibody that effectively targets and depletes B lymphocytes in vivo, primarily via indirect cytotoxic mechanisms. Direct effects on B cells may also contribute to B-cell depletion but are less clearly defined. In this report, we demonstrate that monomeric rituximab, at the high concentrations found in plasma following infusion of therapeutic doses, induces prolonged low-amplitude release of calcium from thapsigargin-sensitive intracellular stores and reduces the growth of Ramos B cells in culture. Intracellular calcium release was triggered via a signaling pathway distinct from the lipid raft-dependent and src family kinase-dependent pathway that is activated by CD20 hypercrosslinking or B-cell receptor association. The response was independent of both CD20 and Fc receptor binding, and was also triggered by some, but not all, irrelevant monoclonal IgG1 antibodies. The data indicate that unique regions within IgG may contribute to direct effects of therapeutic monoclonal antibodies delivered at suprasaturating concentrations. |
| Databáze: | OpenAIRE |
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