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Acute Leukemias

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

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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.

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Acknowledgements

WK, XZ, SS, CP, JZ, MLG, SS, SY, SL, XZ, NT, CZ and DG performed experiments; WK, XZ, MLG, CTJ, JG, EDH and AA designed the studies, wrote and critically revised the manuscript.

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Authors and Affiliations

  1. Discovery Research, Nuvelo Inc., CA, San Carlos, USA

    W Korver, S Singh, C Pardoux, J Zhao, S Yonkovich, S Liu, X Zhan, N Tomasevic, C Zhou, D Gros & A Abo

  2. Department of Clinical Pathology, Cleveland Clinic, OH, Cleveland, USA

    X Zhao & E D Hsi

  3. James P. Wilmot Cancer Center, University of Rochester School of Medicine, NY, Rochester, USA

    M L Guzman, S Sen & C T Jordan

  4. Stanford Cancer Center, CA, Stanford, USA

    J Gotlib

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  1. W Korver
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  2. X Zhao
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  3. S Singh
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  4. C Pardoux
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  5. J Zhao
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  6. M L Guzman
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  7. S Sen
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  8. S Yonkovich
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  9. S Liu
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  10. X Zhan
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  11. N Tomasevic
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  12. C Zhou
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  13. D Gros
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  14. C T Jordan
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  15. J Gotlib
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  16. E D Hsi
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  17. A Abo
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Corresponding author

Correspondence to W Korver.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Korver, W., Zhao, X., Singh, S. et al. Monoclonal antibodies against IREM-1: potential for targeted therapy of AML. Leukemia 23, 1587–1597 (2009). https://doi.org/10.1038/leu.2009.99

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  • DOI: https://doi.org/10.1038/leu.2009.99

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