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

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Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia. / Ågerstam, Helena; Karlsson, Christine; Hansen, Nils; Sandén, Carl; Askmyr, Maria; von Palffy, Sofia; Högberg, Carl; Rissler, Marianne; Wunderlich, Mark; Juliusson, Gunnar; Richter, Johan; Sjöström, Kjell; Bhatia, Ravi; Mulloy, James C; Järås, Marcus; Fioretos, Thoas.

I: Proceedings of the National Academy of Sciences, Vol. 112, Nr. 34, 2015, s. 10786-10791.

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T1 - Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia.

AU - Ågerstam, Helena

AU - Karlsson, Christine

AU - Hansen, Nils

AU - Sandén, Carl

AU - Askmyr, Maria

AU - von Palffy, Sofia

AU - Högberg, Carl

AU - Rissler, Marianne

AU - Wunderlich, Mark

AU - Juliusson, Gunnar

AU - Richter, Johan

AU - Sjöström, Kjell

AU - Bhatia, Ravi

AU - Mulloy, James C

AU - Järås, Marcus

AU - Fioretos, Thoas

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1422749112

DO - 10.1073/pnas.1422749112

M3 - Article

VL - 112

SP - 10786

EP - 10791

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 34

ER -