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.
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.
Unruh
Tammy L
TL
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Zuccolo
Jonathan
J
Beers
Stephen A
SA
Kanevets
Uliana
U
Shi
Yan
Y
Deans
Julie P
JP
D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D011961:Receptors, Fc / Q000378:metabolism; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D007155:Immunologic Factors; D011961:Receptors, Fc; D000069283:Rituximab