Abstract 3337: Targeting acute myeloid leukemia via anti-IL1RAP antibodies

Abstract

Abstract The current standard of care for Acute Myeloid Leukemia (AML) is largely ineffective in terms of achieving long term remission. This is mostly due to inability to remove all of the leukemic cells, and there is accumulating evidence to support the remaining leukemic cells are Leukemic Stem Cells (LSC) which are resistant to standard chemotherapy. We and others (Barreyro L. et. al. 2012) have discovered that IL-1 receptor accessory protein (IL1RAP) is overexpressed on LSC and their progenitors, but not on normal hematopoietic stem cells (HSC). Moreover, knockdown/knockout of IL1RAP expression greatly decreases growth/survival of AML cells. Thus, we have screened anti-IL1RAP therapeutic antibodies by applying FACS based analysis and Complement-Dependent Cytotoxicity (CDC) assays on both AML cell lines and primary patient samples. In a parallel effort, we also applied a functional IL-1β-induced NF-κB signaling assay to identify function-blocking anti-IL1RAP antibodies. Colony Formation Cell (CFC) assay results demonstrated that lead IL1RAP antibodies can significantly impede growth of both AML blast cells and leukemic stem cell-like cells. In contrast, normal HSCs are unaffected by these antibodies. Lead anti-IL1RAP antibodies also showed tumor growth inhibition in an established EOL-1 orthotopic tumor model. One major challenge of targeting IL1RAP by an antibody is that a large amount of IL1RAP protein is secreted into human serum, serving as a potential “sink” that inhibits IL1RAP antibody efficacy. We addressed this by developing a novel IL1RAP antibody that binds preferentially to the membrane-bound IL1RAP protein as compared to the secreted form. We will discuss different therapeutic development strategies to further advance the utilization of these lead anti-IL1RAP therapeutic antibodies for treating AML and other myeloid leukemic indications. Citation Format: Ping Jiang, Bob Y. Liu, Jen Huang, Jennifer Lu, Sharmili Roy, Madhavi Mishra, Xiaoxian Zhao, Jeffrey Lin, Eric D. Hsi, Jagath R. Junutula. Targeting acute myeloid leukemia via anti-IL1RAP antibodies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3337.