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

Ågerstam, Helena LU ; Karlsson, Christine LU ; Hansen, Nils LU ; Sandén, Carl LU ; Askmyr, Maria LU ; von Palffy, Sofia LU ; Högberg, Carl LU ; Rissler, Marianne LU ; Wunderlich, Mark and Juliusson, Gunnar LU , et al. (2015) In Proceedings of the National Academy of Sciences 112(34). p.10786-10791
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... (More)
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. (Less)
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publication status
published
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Proceedings of the National Academy of Sciences
volume
112
issue
34
pages
10786 - 10791
publisher
National Acad Sciences
external identifiers
  • wos:000360005600068
  • pmid:26261316
  • scopus:84940544514
ISSN
1091-6490
DOI
10.1073/pnas.1422749112
language
English
LU publication?
yes
id
0c5154c0-8f8a-4061-9e5d-2f05e0072441 (old id 7844248)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26261316?dopt=Abstract
date added to LUP
2015-09-05 16:24:09
date last changed
2017-10-31 07:58:25
@article{0c5154c0-8f8a-4061-9e5d-2f05e0072441,
  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.},
  author       = {Ågerstam, Helena and Karlsson, Christine and Hansen, Nils and Sandén, Carl and Askmyr, Maria and von Palffy, Sofia and Högberg, Carl and Rissler, Marianne and Wunderlich, Mark and Juliusson, Gunnar and Richter, Johan and Sjöström, Kjell and Bhatia, Ravi and Mulloy, James C and Järås, Marcus and Fioretos, Thoas},
  issn         = {1091-6490},
  language     = {eng},
  number       = {34},
  pages        = {10786--10791},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia.},
  url          = {http://dx.doi.org/10.1073/pnas.1422749112},
  volume       = {112},
  year         = {2015},
}