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

Summary, in English

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.

• Författare: Helena Ågerstam; Christine Karlsson; Nils Hansen; Carl Sandén; Maria Askmyr; Sofia von Palffy; Carl Högberg; Marianne Rissler; Mark Wunderlich; Gunnar Juliusson; Johan Richter; Kjell Sjöström; Ravi Bhatia; James C Mulloy; Marcus Järås; Thoas Fioretos
• Avdelning/ar: Translationella genomiska och funktionella studier av leukemi; Avdelningen för klinisk genetik; Avdelningen för molekylärmedicin och genterapi; BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation; Stamcellscentrum (SCC); Målinriktade behandlingar för leukemi; StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
• Publiceringsår: 2015
• Språk: Engelska
• Sidor: 10786-10791
• Publikation/Tidskrift/Serie: Proceedings of the National Academy of Sciences
• Volym: 112
• Issue: 34
• Fulltext: - 954 kB; Download statistics
• Länkar: http://www.ncbi.nlm.nih.gov/pubmed/26261316?dopt=Abstract; http://dx.doi.org/10.1073/pnas.1422749112
• Dokumenttyp: Artikel i tidskrift
• Förlag: National Academy of Sciences
• Ämne: Hematology
• Status: Published
• Forskningsgrupp: Translational Genomic and Functional Studies of Leukemia; Targeted therapies in leukemia
• ISBN/ISSN/Övrigt: ISSN: 1091-6490