Selective killing of candidate AML stem cells by antibody targeting of IL1RAP

Abstract

Key Points• IL1RAP is overexpressed on candidate AML stem cells and is a promising target for antibody-based therapy.IL1RAP, a co-receptor for interleukin (IL)-1 and IL-33 receptors, was previously found to be highly upregulated on candidate chronic myeloid leukemia stem cells, allowing for leukemia-selective killing using IL1RAP-targeting antibodies. We analyzed IL1RAP expression in a consecutive series of 29 patients with acute myeloid leukemia (AML) and, based on the level of expression in mononuclear cells (MNCs), we divided the samples into 3 groups: IL1RAP low (n 5 6), IL1RAP intermediate (n 5 11), and IL1RAP high (n 5 12). Within the CD341CD382 population, the intermediate and high groups expressed higher levels of IL1RAP than did corresponding normal cells. With the aim to target AML stem cells, an anti-IL1RAP monoclonal antibody was generated followed by isotype switching for improved antibody-dependent, cell-mediated cytotoxicity activity. Using this antibody, we achieved selective killing of AML MNC, CD341CD381, and CD341CD382 cells. Our findings demonstrate that IL1RAP is a promising new therapeutic target in AML. (Blood. 2013;121(18):3709-3713)

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

“…Given that ADCC also could have an effect on normal tissues expressing IL1RAP, we next investigated the tissue expression of IL1RAP on an array of 30 different normal human tissues using mAb3F8. We have previously shown that, among normal blood cells, IL1RAP is expressed mainly on monocytes, and that primary AML cells are more sensitive to mAb81.2-mediated ADCC than corresponding normal BM cells (8,9). We now show that IL1RAP staining was observed in only five tissues: BM, esophagus, lymph node, placenta, and spleen ( Fig.…”

“…However, apart from CD123, which showed limited efficacy in early clinical trials (28), to our knowledge, none has progressed to clinical evaluation in AML. IL1RAP is expressed on candidate AML stem cells, but not on corresponding normal cells (9). By using MA9Ras cells engrafted into immunodeficient mice, a strong antileukemic effect of the two independent IL1RAP-targeting antibodies mAb81.2 and mAb3F8 was observed in all hematopoietic compartments, including PB, BM, and spleen.…”

“…Nonspecific binding of a therapeutic antibody may lead to serious adverse effects. IL1RAP is expressed on candidate AML stem cells, but not on corresponding normal hematopoietic stem cells (9,10). Among normal blood cells, IL1RAP is expressed mainly on monocytes, and AML cells are more sensitive than corresponding normal BM cells to ADCC induced by IL1RAP-targeting antibodies (8,9).…”

“…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).…”

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…Recently, there have been increasing efforts to identify molecular aberrations that could serve as pharmacologic targets within AML and MDS stem cell compartments. [10][11][12][13][14][15][16] Resulting therapies have shown promising effects in preclinical studies, 17,18 but further work will be necessary to identify therapeutic targets against preleukemic stem cells that would lead to long-term remission and prevention of relapse in AML and MDS.…”