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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-03-0876.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 1071-1079
NEOPLASIA
An anti-C3b(i) mAb enhances complement activation, C3b(i)
deposition, and killing of CD20+ cells by
rituximab
Adam D. Kennedy,
Michael D. Solga,
Theodore A. Schuman,
Amos W. Chi,
Margaret A. Lindorfer,
William M. Sutherland,
Patricia
L. Foley, and
Ronald P. Taylor
From the Department of Biochemistry and Molecular
Genetics, the Department of Cell Biology, and the Center for
Comparative Medicine, University of Virginia Health Sciences Center,
Charlottesville.
We investigated deposition of the complement protein fragment C3b
and its breakdown products (collectively designated as C3b(i)) on
CD20-positive cells treated with rituximab (RTX) in the presence of
normal human serum (NHS). Radioimmunoassay (RIA) demonstrates that about 500 000 C3b(i) molecules deposit per cell, and
fluorescence microscopy reveals that C3b(i) colocalizes with bound RTX.
Use of mAb 3E7, specific for C3b(i) bound to substrates, enhances C3b(i) deposition; > 1 million C3b(i) deposit when cells are incubated with NHS, RTX and mAb 3E7. Treatment of Raji cells in NHS plus RTX
leads to robust cell killing (95%) after 24 to 48 hours, and mAb 3E7
significantly enhances RTX-mediated killing of Raji and DB cells. A
cynomolgus monkey model based on intravenous infusion of RTX followed
by mAb 3E7 demonstrated that RTX rapidly binds to B cells and promotes
complement activation and C3b(i) deposition; fluorescence microscopy
analyses revealed the same pattern of colocalization of C3b(i) on
cell-bound RTX in vivo as observed in vitro. Preliminary in vitro
studies with blood samples from patients with chronic lymphocytic
leukemia lead to similar findings. These experiments suggest that
complement plays a key role in the mechanism of action of RTX;
moreover, the in vivo molecular form of RTX (and possibly other
antitumor mAbs) in the circulation or in tissues may include C3b(i)
molecules covalently bound to the therapeutic mAb, thus allowing it to
interact with cells containing both Fc and complement receptors.
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