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
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.
30-39
Unruh, Tammy L.
9cb4fc19-e510-458b-9e65-a29c91280901
Zuccolo, Jonathon
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Beers, Stephen A.
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Kanevets, Uliana
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Shi, Yan
abf0deef-c7b0-4a20-9e09-eab0a6303be0
Deans, Julie P.
62e76126-7d87-42d7-88bf-cfae6be40f28
January 2010
Unruh, Tammy L.
9cb4fc19-e510-458b-9e65-a29c91280901
Zuccolo, Jonathon
0bf61d6b-9ece-42bb-8d31-ea498d7a7d49
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Kanevets, Uliana
bc838838-b422-4f7f-a1c7-27a1049712a3
Shi, Yan
abf0deef-c7b0-4a20-9e09-eab0a6303be0
Deans, Julie P.
62e76126-7d87-42d7-88bf-cfae6be40f28
Unruh, Tammy L., Zuccolo, Jonathon, Beers, Stephen A., Kanevets, Uliana, Shi, Yan and Deans, Julie P.
(2010)
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.
Journal of Immunotherapy, 33 (1), .
(doi:10.1097/CJI.0b013e3181b290f1).
Abstract
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.
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Published date: January 2010
Identifiers
Local EPrints ID: 148239
URI: http://eprints.soton.ac.uk/id/eprint/148239
ISSN: 1524-9557
PURE UUID: cc4b2933-a619-45a4-94db-7095ddbf5f95
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Date deposited: 27 Apr 2010 13:59
Last modified: 14 Mar 2024 02:45
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Author:
Tammy L. Unruh
Author:
Jonathon Zuccolo
Author:
Uliana Kanevets
Author:
Yan Shi
Author:
Julie P. Deans
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