Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia.
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.
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden; helena.agerstam@med.lu.se thoas.fioretos@med.lu.se.
Helena
H
Ågerstam
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden;
Christine
C
Karlsson
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden;
Nils
N
Hansen
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden;
Carl
C
Sandén
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden;
Maria
M
Askmyr
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden;
Sofia
S
von Palffy
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden;
Carl
C
Högberg
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden;
Marianne
M
Rissler
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229;
Mark
M
Wunderlich
Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden;
Gunnar
G
Juliusson
Department of Hematology and Vascular Disorders, Skåne University Hospital, 22185 Lund, Sweden;
Johan
J
Richter
Innovagen AB, 22370 Lund, Sweden;
Kjell
K
Sjöström
Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
Ravi
R
Bhatia
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229;
James C
JC
Mulloy
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden;
Marcus
M
Järås
Department of Clinical Genetics, Lund University, 22184 Lund, Sweden; helena.agerstam@med.lu.se thoas.fioretos@med.lu.se.
Thoas
T
Fioretos
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D002455:Cell Division; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D053577:Interleukin-1 Receptor Accessory Protein / Q000037:antagonists & inhibitors* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C507765:IL1RAP protein, human; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D009363:Neoplasm Proteins
AML; IL1RAP; antibody; immunotherapy; leukemia