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.
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We have isolated and characterized blast cells and leukemic stem cells (LSCs) enriched from AML patients and identified cell surface targets selectively expressed on AML blast cells and LSCs and not their normal hematopoietic stem cell counterparts. A series of potent, specific, monoclonal antibodies (mAbs) have been generated against one of these AML LSC targets, IL1RAP. IL1RAP mAb clones were characterized for patient binding properties and also evaluated in in vitro cell based assays and in in vivo tumor xenograft models. These monoclonal antibodies demonstrated promising binding profiles in primary AML patients’ samples and robust anti-tumor activity in in vitro cell based assays and in vivo tumor xenograft models. Specifically, select clones have a high degree of specific binding to AML primary patient samples (>90%), and specifically kill primary patient AML cells in complement-dependent cytotoxicity assays. These IL1RAP clones are being evaluated for inhibition of clonogenic potential of AML patient samples in vitro in colony forming assays and against normal clonogenic hematopoietic bone marrow derived stem cells. Select IL1RAP mAb clones evaluated in orthotopic AML tumor xenograft models have shown potent inhibition of tumor engraftment as well as significant tumor growth inhibition effects ranging from 80-90%. Because a key driver of LSC resistance is their quiescence, we also evaluated the antitumor effect of IL1RAP mAbs on quiescent AML cells in vitro. In summary, the patient binding profiles and in vitro and in vivo efficacy against AML cells indicates that targeting IL1RAP is a promising therapeutic approach for the treatment of AML and has the potential for effective eradication of AML LSCs and long term remission in the clinic. Citation Format: Ping Jiang, Sharmili Roy, Jen Huang, Trang Dao-Pick, Jennifer Lu, Madhavi Mishra, Jeffrey Lin, Eric D. Hsi, Robert J. Tressler, Holger Karsunky. Generation and characterization of antibodies specific for IL1RAP antigen to target quiescent and proliferating AML leukemic stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 662. doi:10.1158/1538-7445.AM2014-662
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