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An anti-C3b/iC3b monoclonal antibody (Mab) as an adjuvant to rituximab killing of non-Hodgkin's lymphoma (NHL) and chronical lymphocytic leukemia (CLL) cells.

2621 Background: Complement-dependent cytotoxicity (CDC) is a key mechanism of Rituximab action in killing NHL cells both in vitro and in vivo. Here we present the studies of a mouse/human chimeric Mab (ETI-210) specific for human complement C3 cleavage products, C3b and iC3b, in enhancing Rituximab ability to kill NHL cells in vitro and ex vivo.


METHODS
In the CDC assay, Raji cells, DB cells, primary NHL and CLL cells were treated with Rituximab and the anti-C3b/iC3b in the presence of normal human serum at 37 degrees for 1 hour or longer. Cell death, determined by propidium iodide staining, was measured by a flow cytometric method.


RESULTS
The anti-C3b/iC3b Mab increased the cell killing of NHL cell lines tested in the one-hour treatment of Rituximab plus anti-C3b/iC3b Mab in the presence of human complement. The difference in cell killing between Rituximab plus anti-C3b/iC3b and Rituximab alone was 40%-70%. The enhancing effect of the anti-C3b/iC3b was also seen in long-term treatment (1 - 2 days). In the absence of human serum, the cell killing by Rituximab plus the anti-C3b/iC3b Mab was much lower than in the presence of serum. The addition of excess purified iC3b to the CDC assay under the experimental conditions only caused a minimal inhibition of cell killing. The anti-C3b/iC3b Mab was also tested ex vivo against primary cells from 11 NHL and 10 CLL patients. In 3 NHL samples, the anti-C3b/iC3b Mab enhanced Rituximab-mediated killing; in the remaining samples enhancement was observed but was not significant since Rituximab alone already caused above 90% killing. The antibody also increased Rituximab-mediated killing in 6 out of 10 CLL samples.


CONCLUSIONS
The anti-C3b/iC3b Mab is able to substantially enhance Rituximab-mediated killing of lymphoma cells via complement-mediated lysis. This Mab has therapeutic applications in NHL and CLL treatment. No significant financial relationships to disclose.