Abstract
3039 Background: Given the success of treating CLL with antibody therapies, interest in those directed at alternative B-cell antigens remains high. Lumiliximab is a chimeric macaque and human anti-CD23 monoclonal antibody whose antigen is expressed on almost all CLL cells. Methods: We examined lumiliximab’s ability to mediate direct apoptosis, antibody-dependent cellular cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) against primary CLL cells and CD23+ B-cell lines. Apoptosis was measured with a flow-cytometry based assay for active caspase-3. ADCC was determined by 51Cr-release assay. CDC assays were performed in the presence of 30% autologous plasma from patients and quantified by propidium iodide staining. Western blotting analysis was used to monitor protein expression before and after treatment with lumiliximab. The CD23+ human lymphoma SKW6.4 cell line was used for in vivo evaluation of lumiliximab in a disseminated human lymphoma model. Results: Lumiliximab mediates apoptosis, ADCC, and CDC in CD23+ B-cell lines. However, in primary CLL cells, the primary mechanism of cell killing appears to be mediated via apoptosis. Apoptosis induced by lumiliximab occurs mainly through the intrinsic pathway used by other CLL therapies. Lumiliximab decreased expression of Bcl-2 and XIAP and inhibited Akt activation in CLL cells. Lumiliximab when combined in vitro or in vivo with rituximab or fludarabine effectively mediates synergistic cytotoxicity against primary CLL cells and CD23+ B-cell lines. Significant antitumor activity was also observed with lumiliximab vs a control antibody in a SCID mouse model of human B-cell lymphoma (P <.01). More importantly, lumiliximab + rituximab or lumiliximab + fludarabine results in prolonged survival vs lumiliximab, rituximab, or fludarabine single-agent treatment. Conclusions: These results indicate that lumiliximab induces apoptosis by activating caspases and downregulating antiapoptotic proteins, and suggest that in combination with rituximab or chemotherapy, lumiliximab synergistically enhances antitumor activity in CLL or other B-cell malignancies in which this antigen is overexpressed. No significant financial relationships to disclose.
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