Monoclonal antibodies against IREM-1: Potential for targeted therapy of AML

W. Korver, X. Zhao, S. Singh, C. Pardoux, J. Zhao, M. L. Guzman, S. Sen, S. Yonkovich, S. Liu, X. Zhan, N. Tomasevic, C. Zhou, D. Gros, C. T. Jordan, J. Gotlib, E. D. Hsi, A. Abo

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

IREM-1 is an inhibitory cell surface receptor with an unknown function and is expressed on myeloid cell lineages, including cell lines derived from acute myeloid leukemia (AML) patients. We have generated a series of monoclonal antibodies (mAbs) against the extracellular domain of IREM-1 and further assessed its expression in normal and AML cells. IREM-1 was restricted to cells from myeloid origin and extensive expression analysis in primary cells obtained from AML patients showed IREM-1 expression in leukemic blasts of 72% (39/54) of samples. We therefore searched for specific IREM-1 mAbs with activity in functional complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Lead mAbs against IREM-1 showed specific cytotoxic activity against a variety of AML-derived cell lines and freshly isolated blasts from AML patients. Internalization of mAbs upon IREM-1 binding was also shown. In vivo anticancer activity of lead mAbs was observed in an established HL-60 xenograft model with a tumor growth delay of up to 40% and in a model using primary human AML cells, where treatment with anti-IREM-1 mAb resulted in a significant reduction of engrafted human cells. These results demonstrate IREM-1 as a potential novel target for immunotherapy of AML.

Original languageEnglish (US)
Pages (from-to)1587-1597
Number of pages11
JournalLeukemia
Volume23
Issue number9
DOIs
StatePublished - Sep 2009

Keywords

  • Acute myeloid leukemia
  • Antibody therapy
  • Minimal residual disease

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Korver, W., Zhao, X., Singh, S., Pardoux, C., Zhao, J., Guzman, M. L., Sen, S., Yonkovich, S., Liu, S., Zhan, X., Tomasevic, N., Zhou, C., Gros, D., Jordan, C. T., Gotlib, J., Hsi, E. D., & Abo, A. (2009). Monoclonal antibodies against IREM-1: Potential for targeted therapy of AML. Leukemia, 23(9), 1587-1597. https://doi.org/10.1038/leu.2009.99