The IL-3Rα-Targeted Drug SL-401 Selectively Kills Blastic Plasmacytoid Dendritic Cell Neoplasm Cells

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive neoplasm derived from plasmacytoid dendritic cell precursors that involves the skin and invariably leads to aggressive leukemic dissemination (Garnache Ottou et al., 2007). The incidence is more frequent in men and elderly subjects, but BPDCN may occur in young adults and even in children. Current treatment options are not codified, and although conventional chemotherapy often induces an initial response, relapse is frequent and rapid. The prognosis is poor, with a median overall survival of 9–13 months whatever the initial presentation was. Allogeneic hematopoietic transplantation is currently the only potentially curative treatment, but this is not an option for most elderly patients. Therefore, there is an urgent need to develop novel therapies that can specifically target this tumor type. Since BPDCN cells express high levels of the interleukin-3 receptor (IL-3R) α-chain (CD123), we tested SL-401, a novel biologic conjugate that targets IL-3Rα (Konopleva et al. 2010 and Frolova et al. 2010), against 2 BPDCN cell lines (GEN2.2 and CAL-1) and 6 primary BPDCN cells isolated from 5 patients (P#1-5). Cells from P#2 were tested at diagnosis (#2d) and at relapse (#2r). A CD123+ cell line (TF-1/H-ras) sensitive to SL-401 and a CD123⁻ cell line (Daudi) were used as controls. Cytotoxicity was assessed by MTT assay as well as flow cytometry (FC) after Annexin-V (AV) and 7-AAD staining. Primary BPDCN cells were cultured with IL-3 alone (to maintain survival) or IL-3 in combination with SL-401 for 24 h (FC) or 48 h (MTT) (Figure 1). All BPDCN cell lines and primary cells were found to be sensitive to SL-401 by MTT assay (Figure 1A). These results were confirmed by FC with a dose-dependent decrease in cell viability observed for the GEN2.2 and CAL-1 lines, (47 ± 10 to 2 ± 2%, n = 4, and 90 ± 7 to 11 ± 5%, n = 4, respectively) when treated with SL-401 compared to untreated cells (48 ± 9% and 88 ± 5%, for GEN2.2 and CAL-1 respectively). Cell viability decreased for all the 6 primary cells tested by FC (Figure 1B). The Daudi negative control cell line was resistant to SL-401 (Figure 1A), which confirmed SL-401 specificity.