SL-401, a Novel Targeted Therapy Directed to the Interleukin-3 Receptor (IL-3R), Blocks Plasmacytoid Dendritic Cell (pDC)-Triggered Myeloma Cell Growth and Prevents Osteoclastogenesis

IntroductionDespite the advent of novel therapies, relapse of multiple myeloma (MM) is common and the disease remains largely incurable. Our previous studies showed that bone marrow (BM) plasmacytoid dendritic cells (pDCs) play a central role in the immune deficiency characteristic of MM; as well as promote MM cell growth, survival, and drug resistance (Chauhan et al., Cancer Cell 2009, 16:309-323). These findings identify an integral role of pDCs in MM pathogenesis and provide the basis for targeting pDC-MM interactions as a novel therapeutic strategy in MM. In this context, we found that pDCs exhibit a high level of interleukin-3 receptor (IL-3Rα) expression, and pDC-MM interactions trigger secretion of interleukin-3 (IL-3), which in turn, induces MM cell growth and pDC survival, and promotes osteolytic bone disease in MM. These findings identified targeting IL-3R expressed on pDCs as a promising novel therapeutic strategy. Additionally, our preliminary data show that a significant number of clonogenic side population cells in MM (MM-SPs) with characteristic stem cell like features express IL-3R. Here we examined the effect of SL-401, a novel targeted therapy directed against IL-3R, on pDC-induced MM cell growth, osteoclast (OCL) formation, and MM-SPs.