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

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.

IL1RAP potentiates multiple oncogenic signaling pathways in AML

“…Because of the low levels of IL1RAP on normal HSPC and its apparent nonessentiality for mammalian organisms given that Il1rap −/− mice have no major steady-state phenotype ( Cullinan et al, 1998 ), IL1RAP is currently emerging as a promising candidate surface target in various myeloid malignancies, including AML, and approaches to target IL1RAP are underway at various preclinical and clinical stages with encouraging initial results ( Ågerstam et al, 2015 , 2016 ; Jiang et al, 2016 ). However, most current strategies rely on recruitment of the immune system and very little is known about possible cell-intrinsic functions of IL1RAP in AML cells.…”

“…We and others previously identified the surface molecule IL-1 receptor accessory protein (IL1RAP) as consistently overexpressed in AML hematopoietic stem and progenitor cells (HSPC) across multiple genetic subtypes of AML ( Barreyro et al, 2012 ; Askmyr et al, 2013 ; Ho et al, 2016 ; Sadovnik et al, 2017 ), as well as in high-risk myelodysplastic syndromes (MDS), hematologic malignancies that often progress to AML. As a result of low IL1RAP expression on normal HSPCs ( Barreyro et al, 2012 ; Ho et al, 2016 ) and apparent dispensability of IL1RAP for the viability of mammalian organisms ( Cullinan et al, 1998 ), IL1RAP has emerged as a promising target for leukemic stem cell (LSC)-directed immunotherapeutic approaches in myeloid malignancies ( Järås et al, 2010 ; Askmyr et al, 2013 ; Herrmann et al, 2014 ; Ågerstam et al, 2015 ; Jiang et al, 2016 ; Landberg et al, 2016 ; Warfvinge et al, 2017 ); however, little is known about whether IL1RAP has a cell-intrinsic role in AML. Current IL1RAP-targeting strategies rely on immune effector cell recruitment, despite most AML patients having compromised immune systems.…”

Targeting Immunophenotypic Markers on Leukemic Stem Cells: How Lessons from Current Approaches and Advances in the Leukemia Stem Cell (LSC) Model Can Inform Better Strategies for Treating Acute Myeloid Leukemia (AML)

“…Jiang and colleagues showed in a xenograft of the AML cell line EOL-1 that several different IL1RAPdirected monoclonal antibodies completely eliminated AML engraftment in BM and blood. These antibodies induced CDC of primary AML blasts when incubated with cells and complement in vitro (Jiang et al 2016). Additionally, an IL1RAP/CD3 bispecific antibody is in development, and both in vivo and in vitro effects on the MV4;11 AML cell line were presented at the 2017 American Society of Hematology meeting (Meng et al 2017).…”