TY - JOUR
T1 - Selective killing of candidate AML stem cells by antibody targeting of IL1RAP
AU - Askmyr, Maria
AU - Ågerstam, Helena
AU - Hansen, Nils
AU - Gordon, Sandra
AU - Arvanitakis, Alexandros
AU - Rissler, Marianne
AU - Juliusson, Gunnar
AU - Richter, Johan
AU - Järås, Marcus
AU - Fioretos, Thoas
PY - 2013/5/2
Y1 - 2013/5/2
N2 - 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 = 6), IL1RAP intermediate (n = 11), and IL1RAP high (n = 12). Within the CD34+CD38- 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, CD34+CD38+, and CD34+CD38- cells. Our findings demonstrate that IL1RAP is a promising new therapeutic target in AML.
AB - 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 = 6), IL1RAP intermediate (n = 11), and IL1RAP high (n = 12). Within the CD34+CD38- 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, CD34+CD38+, and CD34+CD38- cells. Our findings demonstrate that IL1RAP is a promising new therapeutic target in AML.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antibodies/pharmacology
KW - Antibody Specificity
KW - Cells, Cultured
KW - Cytotoxicity, Immunologic/drug effects
KW - Female
KW - Humans
KW - Immunotherapy/methods
KW - Interleukin-1 Receptor Accessory Protein/antagonists & inhibitors
KW - Leukemia, Myeloid, Acute/pathology
KW - Male
KW - Middle Aged
KW - Molecular Targeted Therapy
KW - Neoplastic Stem Cells/drug effects
U2 - 10.1182/blood-2012-09-458935
DO - 10.1182/blood-2012-09-458935
M3 - Journal article
C2 - 23479569
SN - 0006-4971
VL - 121
SP - 3709
EP - 3713
JO - Blood
JF - Blood
IS - 18
ER -