Therapeutic (High) Doses of Rituximab Activate Calcium Mobilization and Inhibit B-cell Growth via an Unusual Mechanism Triggered Independently of Both CD20 and Fcγ Receptors

被引:4
作者
Unruh, Tammy L.
Zuccolo, Jonathan
Beers, Stephen A. [3 ]
Kanevets, Uliana [2 ]
Deans, Julie P. [1 ,2 ]
机构
[1] Univ Calgary, Hlth Res Innovat Ctr, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada
[2] Univ Calgary, Dept Microbiol & Infect Dis, Immunol Res Grp, Inst Infect Immun & Inflammat,Fac Med, Calgary, AB T2N 4N1, Canada
[3] Univ Southampton, Sch Med, Gen Hosp, Tenovus Lab,Canc Sci Div, Southampton, Hants, England
基金
加拿大健康研究院;
关键词
B cells; rituximab; IgG; calcium; CD20; ANTI-CD20; MONOCLONAL-ANTIBODY; NON-HODGKINS-LYMPHOMA; SRC-FAMILY KINASE; TYROSINE PHOSPHORYLATION; AUTOIMMUNE-DISEASES; LIPID RAFTS; APOPTOSIS; INDUCTION; ASSOCIATION; PATHWAYS;
D O I
10.1097/CJI.0b013e3181b290f1
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 IgGI antibodies. The data indicate that unique regions within IgG may contribute to direct effects of therapeutic monoclonal antibodies delivered at suprasaturating concentrations.
引用
收藏
页码:30 / 39
页数:10
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