Lumiliximab, An Apoptosis Sensitizer to Multiple CLL Therapeutic Agents

Chronic lymphocytic leukemia (CLL) is a B cell malignancy characterized by the accumulation of mature phenotype leukemic B cells in blood, spleen and lymphoid tissues. While many patients respond initially to combination chemotherapy regimens, many become chemoresistant and all will ultimately relapse. Recently the addition of novel monoclonal antibody therapies such as rituximab and alemtuzumab to these treatment regimens has provided additional therapeutic benefit to chemorefractory CLL patients and prompted interest in the evaluation of additional B cell surface antigens as targets. Lumiliximab is a primatized monoclonal antibody directed against CD23, a glycoprotein expressed on the majority of CLL cells, and is currently under investigation in patients with relapsed CLL. It was previously demonstrated that the primary mechanism of action of lumiliximab in both CD23+ lymphoma B cells and CLL patient samples is sensitization to apoptotic cell death and that lumiliximab enhances apoptosis in vivo when combined with either fludarabine or rituximab (Pathan et al., Blood, 2008). In the present study we sought to determine whether lumiliximab could enhance the apoptotic activity of a range of CLL therapies which induce cell death via distinct apoptotic pathways. Our studies demonstrate that the addition of lumiliximab in combination with the alkylating agent chlorambucil resulted in a dose-dependent and significant increase in apoptosis of CD23⁺ lymphoma cells. Lumiliximab also resulted in statistically significantly enhanced apoptosis when combined with alemtuzumab as compared to either single agent alone in both CD23+/CD52⁺ lymphoma cells and CLL patient samples. Examination of the apoptotic pathways induced by these agents revealed that lumiliximab in combination resulted in more dramatic alterations in downstream effectors of apoptosis such as caspase 3, PARP, and DNA fragmentation. Further studies are ongoing to confirm these observations in xenograft models and to delineate the mechanistic basis of the enhanced apoptotic signaling. These data suggest that the use of lumiliximab in combination with current or emerging CLL therapies could be an effective strategy to augment tumor cell killing and may result in new and more effective treatment regimens for the eradication of CLL.