SL-501, a Next-Generation Targeted Therapy Directed to the IL-3 Receptor (IL-3R), Possesses Preclinical Anti-Tumor Activity Against Hodgkin’s and Non-Hodgkin’s Lymphoma

While Hodgkin’s lymphoma (HL) is among the most curable lymphomas, a significant percentage of patients relapse after frontline therapy or have primary refractory disease. Patients that remain resistant after second or third line chemotherapy or autologous stem cell transplantation (ASCT) have very limited treatment options. Non-Hodgkin’s lymphoma (NHL) comprises a wide array of clinical subtypes, which have indolent to aggressive clinical courses. Multiple lines of chemotherapy and ASCT are part of the NHL treatment strategy, but indolent forms frequently recur, and patients can develop resistance to therapies that were previously effective. The prognosis for patients with HL and NHL who fail to achieve durable remission with approved therapeutics or transplantation is poor. Therefore, new treatment strategies for such patients are desperately needed.

The interleukin-3 receptor (IL-3R) alpha chain (CD123) is overexpressed on the tumor bulk and cancer stem cells (CSCs) of multiple hematologic malignancies. In particular, CD123 has been shown to be upregulated on a variety of leukemias and lymphomas, including HL and certain NHLs. We previously showed that SL-401, a novel IL-3R-targeted therapy comprised of IL-3 fused to a truncated diphtheria toxin payload, possesses cytotoxic activity against IL-3R-expressing HL and NHL cells. SL-501 is a next-generation IL-3R targeted therapy with increased binding affinity for the IL-3R and enhanced potency against both tumor bulk and CSCs of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Here, the anti-tumor activity of SL-501 against HL and NHL cells was investigated.

Our flow cytometry assessment of CD123 showed that the receptor was expressed on two nodular sclerosing HL cell lines (L-428 and HDLM2), one mixed cellularity HL line (L-1236), and two mantle cell lymphoma lines (Mino and JeKo-1). CD123 was expressed to varying extents, ranging from high expression in HDLM-2 (99.5%) and L-428 (89.1%), to moderate-to-low expression in Mino (25.4%), L-1236 (19.5%) and JeKo-1 (2.9%). In this study, the activity of SL-501 was tested against this panel of cell lines. Cell were treated with SL-501 (range: 6.3 pM – 1.5 mM) for 48 hours and then assessed for viability using the CellTiter Glo® in vitro cytotoxicity assay. We found that SL-501 reduced the viability of all cell lines tested in a dose-dependent fashion. In particular, SL-501 showed very high potency against the HDLM2 and L-1236 lines, with IC50 values in the sub-nanomolar range (0.139 nM and 0.191 nM, respectively). SL-501 was also cytotoxic against L-428, JeKo-1, and Mino cell lines, with IC50s of 91 nM, 97 nM, and 116 nM, respectively.

Taken together, these findings demonstrate that SL-501, a novel next-generation IL-3R-targeted therapeutic, possesses potent in vitro anti-cancer activity against a variety of HL and NHL cell lines. Additional functional studies are ongoing. These promising results provide a rationale for further development of SL-501 in HL and NHL.