Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell-mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.A cute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by clonal expansion of leukemic cells. Despite an increased understanding of the underlying disease biology in AML, the standard treatment with cytotoxic chemotherapy has remained largely unchanged over the last decades and the overall 5-y survival remains poor, being <30% (1, 2). Hence, there is a pressing need for novel therapies with increased efficacy and decreased toxicity, ideally targeting the AML stem cells because these cells are believed to be critical in the pathogenesis of AML, and their inadequate eradication by standard therapy is thought to contribute to the high incidence of relapse (3, 4). Although therapeutic antibodies directed at cell-surface molecules have proven effective for the treatment of malignant disorders such as lymphomas and acute lymphoblastic leukemia, as well as solid tumors (5, 6), no antibody-based therapy is currently approved for AML.The interleukin 1 receptor accessory protein (IL1RAP), also called IL1R3, is a coreceptor of type 1 interleukin 1 receptor (IL1R1) and is indispensable for transmission of IL-1 signaling (7). We have previously reported that IL1RAP is a biomarker for putative chronic myeloid leukemia stem cells (8). In a recent study, we showed that IL1RAP is expressed on the cell surface in ∼80% of AML patients and that candidate CD34 + CD38 − AML stem cells can be selectively killed in vitro by antibody-dependent cellular cytotoxicity (ADCC) (9). Furthermore, IL1RAP is upregulated on immature cells in high-risk AML with chromosome 7 aberrations, and increased IL1RAP expression correlates with poor prognosis (10). These findings could suggest IL1RAP as a novel and specific target for an antibody-based therapy in AML; however, in vivo evidences for therapeuti...

GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells

“…IL-1β supports AML cell survival and proliferation (Dubois et al, 1994; Estrov et al, 1999; Turzanski et al, 2004), and antagonizing IL-1β signaling inhibits AML cell proliferation (Ågerstam et al, 2015; Rambaldi et al, 1991). IL-1β-mediated GM-CSF induction contributes to this growth effect (Delwel et al, 1989; Bradbury et al, 1990).…”

The family of the interleukin‐1 receptors

“…One exception is in certain hematopoietic tumors such a myeloma or acute myeloid leukemia, in which IL‐1R3 is upregulated and correlates with poor prognosis . Here inhibition of IL‐1R3 had an effect on tumor progression in xenograft models, a finding that identifies IL‐1R3 as a possible therapeutic target in cancer . As IL‐1R3 is the common accessory chain for several receptor complexes (IL‐1R, IL‐33R, IL‐36R), its therapeutic targeting would affect several inflammatory pathways.…”

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

“…84 Of note, a chronic increase in IL-1b is also anticipated to deplete normal HSCs through cell-intrinsic effects 86 while concomitantly expanding malignant cells through binding to IL1RAP, a newly identified putative LSC marker and therapeutic target in MDS, AML, and CML. [87][88][89][90][91] Although sympathetic nerve degeneration is observed both in MPN and AML, experimental modulation in mice demonstrated that defective b3-adrenergic signals are responsible for the phenotypes observed in MPN, whereas b2-adrenergic signals seem to be the main mediators in AML. Although b3-AR agonist or IL-1b antagonist appear to be promising therapeutic strategies, the use of b2-AR agonists is mitigated by the risk of promoting the growth of the AML LSCs, which also express b2-AR.…”

“…114 Of note, IL-33 is also a ligand for IL1RAP, which has emerged as a putative selective LSC marker and therapeutic target in higher-risk MDS, AML, and CML. [87][88][89] In summary, pharmacological approaches aiming at reverting niche changes are increasingly recognized to be of therapeutic interest. These include, but are not limited to, reverting vascular leakiness (eg, NO synthase inhibitors), sympathetic neuropathy (eg, neuroprotective agents), and stromal remodeling (eg, b3-AR agonists and CCL3 antagonists).…”