B-cell activating factor (BAFF) belongs to the TNF ligand superfamily of cytokines involved in B cell survival and maturation. BAFF is produced by diverse cell types including innate immune cells like monocytes and dendritic cells as well as T cells, activated B cells, and bone marrow stromal cells. BAFF binds to the BAFF receptor (BAFF-R) with high affinity compared to the other BAFF receptors, BCMA and TACI. While BAFF is known to regulate normal B-cell development and proliferation, it also contributes to survival in chronic lymphocytic leukemia (CLL). We observed expression of BAFF-R on virtually all B cells from CLL patients. B-CLL cells have strong up-regulation of BAFF and BAFF-R compared to normal healthy B cells. We describe here the in-vitro and in-vivo evaluation in CLL of B-1239, a fully human anti-BAFF-R monoclonal IgG1 antibody. B-1239 is devoid of fucose residues in its Fc domain, resulting in enhanced binding to FCgammaRIIIa activating receptor on Natural Killer (NK) cells. While B-1239 failed to induce direct or complement mediated cytotoxicity, binding of B-1239 to CLL cells resulted in enhanced antibody dependent cellular cytotoxicity (ADCC) with allogeneic or autologous NK effector cells in-vitro. Indeed, at a therapeutically relevant concentration of 10 ug/mL B-1239 shows more than 30% increased relative cytotoxic activity over current CLL antibody therapeutic Rituximab. Dilutions of B-1239 down to 0.01 ug/mL showed similar cytotoxicity to the 10 ug/mL concentration. At 0.0001 ug/mL B-1239 has a 40% cytotoxic effect on CLL cells in ADCC assays while antibody therapeutic controls, like Rituximab, show virtually no cytotoxic activity. Furthermore, B-1239 mediated antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages and mediated activation of monocytes and macrophages as detected by TNF-alpha production. Consistent with the cross reactivity to murine BAFF-R, flow cytometric analysis revealed binding of B-1239 to CD5+CD19+ leukemic B cells from Eu-Tcl-1 transgenic mouse CLL cells. A single dose of B-1239 by i.v injection into Eu-Tcl-1 mice resulted in dramatic reduction in circulating CD5+CD19+ leukemic B cells in all three B-1239 injected mice. In contrast, we observed continued increase of leukemic CD5+CD19+ populations in the two vehicle treated mice. Ongoing studies are focused on determining how targeting BAFF-R on CLL B-cells depletes the leukemic population both in-vitro and in-vivo and the downstream effects of targeting through this receptor. Collectively, these results demonstrate that targeting BAFF-R on CLL cells provides a B-cell specific approach for rapid and robust depletion of leukemic CLL cells and provides evidence for a strong therapeutic advantage in BAFF-R targeted therapies in CLL.
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Asterisk with author names denotes non-ASH members.