Belimumab, a Neutralizing BAFF (B Cell Activating Factor) Antibody, Enhances the Susceptibility of Chronic Lymphoid Leukemia (CLL) Cells to Abt-199 Treatment

Abt-199 is a small molecule BCL-2 inhibitor which has recently been approved for treatment of CLL and mediates its effects by induction of apoptosis in the leukemic cells. The TNF family member B cell activating factor (BAFF) contributes to disease pathophysiology in mature B cell malignancies including CLL by sustaining survival and preventing apoptosis of the malignant B cells. BAFF also plays a prominent role in autoimmune diseases, and accordingly a BAFF-neutralizing antibody termed Belimumab (Benlysta^®) has been developed and is approved for treatment of systemic lupus erythematosus. Notably, elevated levels of BAFF have also been detected in sera of B cell lymphoma patients. We demonstrated recently that BAFF protects CLL cells from NK cell cytotoxicity including Rituximab-induced antibody-dependent cellular cytotoxicity (ADCC), the major mechanism by which this CD20-antibody mediates its therapeutic effects. In turn, susceptibility of CLL cells to both direct and Rituximab-induced NK cell killing could be restored by BAFF neutralization with Belimumab (Wild et al, Leukemia 2015). Here we studied whether Belimumab could also serve to increase the susceptibility of CLL cells to Abt-199 treatment. As no information on Abt-199 plasma peak levels in CLL patients is available, we first exposed primary CLL cells of leukemia patients to varying concentrations of Abt-199 and identified 5 nM as in vitro LC₅₀ concentration in analyses of leukemia cell metabolic activity. Next we studied how BAFF influenced the therapeutic efficacy of Abt-199. Analyses of CLL cell metabolic activity and apoptosis/cell death revealed that BAFF concentration-dependently protected primary CLL cells from the therapeutic effects of Abt-199. Notably, CLL cell susceptibility to Abt-199 could be restored by neutralization of BAFF by Belimumab. Together, our findings demonstrate that BAFF contributes to CLL cell resistance to Abt-199 treatment. BAFF neutralization by Belimumab may in turn constitute a promising strategy to increase/restore the therapeutic efficacy of Abt-199, which warrants future clinical studies of combinatorial approaches to improve CLL treatment.