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Acute Leukemias

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


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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  1. Ravandi F, Burnett AK, Agura ED, Kantarjian HM . Progress in the treatment of acute myeloid leukemia. Cancer 2007; 110: 1900–1910.

    Article  CAS  Google Scholar 

  2. Doepfner KT, Boller D, Arcaro A . Targeting receptor tyrosine kinase signaling in acute myeloid leukemia. Crit Rev Oncol Hematol 2007; 63: 215–230.

    Article  Google Scholar 

  3. Pratz K, Levis M . Incorporating FLT3 inhibitors into acute myeloid leukemia treatment regimens. Leuk Lymphoma 2008; 49: 852–863.

    Article  CAS  Google Scholar 

  4. Giles F, Estey E, O′Brien S . Gemtuzumab ozogamicin in the treatment of acute myeloid leukemia. Cancer 2003; 98: 2095–2104.

    Article  CAS  Google Scholar 

  5. Tsimberidou AM, Giles FJ, Estey E, O′Brien S, Keating MJ, Kantarjian HM . The role of gemtuzumab ozogamicin in acute leukaemia therapy. Br J Haematol 2006; 132: 398–409.

    CAS  PubMed  Google Scholar 

  6. Alvarez-Errico D, Aguilar H, Kitzig F, Brckalo T, Sayos J, Lopez-Botet M . IREM-1 is a novel inhibitory receptor expressed by myeloid cells. Eur J Immunol 2004; 34: 3690–3701.

    Article  CAS  Google Scholar 

  7. Sui L, Li N, Liu Q, Zhang W, Wan T, Wang B et al. IgSF13, a novel human inhibitory receptor of the immunoglobulin superfamily, is preferentially expressed in dendritic cells and monocytes. Biochem Biophys Res Commun 2004; 319: 920–928.

    Article  CAS  Google Scholar 

  8. Marquez JA, Galfre E, Dupeux F, Flot D, Moran O, Dimasi N . The crystal structure of the extracellular domain of the inhibitor receptor expressed on myeloid cells IREM-1. J Mol Biol 2007; 367: 310–318.

    Article  CAS  Google Scholar 

  9. Alvarez-Errico D, Sayos J, Lopez-Botet M . The IREM-1 (CD300f) inhibitory receptor associates with the p85alpha subunit of phosphoinositide 3-kinase. J Immunol 2007; 178: 808–816.

    Article  CAS  Google Scholar 

  10. Vitale C, Romagnani C, Puccetti A, Olive D, Costello R, Chiossone L et al. Surface expression and function of p75/AIRM-1 or CD33 in acute myeloid leukemias: engagement of CD33 induces apoptosis of leukemic cells. Proc Natl Acad Sci USA 2001; 98: 5764–5769.

    Article  CAS  Google Scholar 

  11. Jordan CT . The leukemic stem cell. Best Pract Res Clin Haematol 2007; 20: 13–18.

    Article  CAS  Google Scholar 

  12. Caron PC, Co MS, Bull MK, Avdalovic NM, Queen C, Scheinberg DA . Biological and immunological features of humanized M195 (anti-CD33) monoclonal antibodies. Cancer Res 1992; 52: 6761–6767.

    CAS  PubMed  Google Scholar 

  13. Jilani I, Estey E, Huh Y, Joe Y, Manshouri T, Yared M et al. Differences in CD33 intensity between various myeloid neoplasms. Am J Clin Pathol 2002; 118: 560–566.

    Article  Google Scholar 

  14. Bakker AB, van den Oudenrijn S, Bakker AQ, Feller N, van Meijer M, Bia JA et al. C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. Cancer Res 2004; 64: 8443–8450.

    Article  CAS  Google Scholar 

  15. Legrand O, Perrot JY, Baudard M, Cordier A, Lautier R, Simonin G et al. The immunophenotype of 177 adults with acute myeloid leukemia: proposal of a prognostic score. Blood 2000; 96: 870–877.

    CAS  PubMed  Google Scholar 

  16. Kossman SE, Scheinberg DA, Jurcic JG, Jimenez J, Caron PC . A phase I trial of humanized monoclonal antibody HuM195 (anti-CD33) with low-dose interleukin 2 in acute myelogenous leukemia. Clin Cancer Res 1999; 5: 2748–2755.

    CAS  PubMed  Google Scholar 

  17. Jurcic J . Ab therapy of AML: native anti-CD33 Ab and drug conjugates. Cytotherapy 2007; 10: 7–12.

    Article  Google Scholar 

  18. Voisin T, El Firar A, Rouyer-Fessard C, Gratio V, Laburthe M . A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism. Faseb J 2008; 22: 1993–2002.

    Article  CAS  Google Scholar 

  19. Can I, Tahara-Hanaoka S, Hitomi K, Nakano T, Nakahashi-Oda C, Kurita N et al. Caspase-independent cell death by CD300LF (MAIR-V), an inhibitory immunoglobulin-like receptor on myeloid cells. J Immunol 2008; 180: 207–213.

    Article  CAS  Google Scholar 

  20. Walter RB, Raden BW, Kamikura DM, Cooper JA, Bernstein ID . Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity. Blood 2005; 105: 1295–1302.

    Article  CAS  Google Scholar 

  21. Wu H, Windmiller DA, Wang L, Backer JM . YXXM motifs in the PDGF-beta receptor serve dual roles as phosphoinositide 3-kinase binding motifs and tyrosine-based endocytic sorting signals. J Biol Chem 2003; 278: 40425–40428.

    Article  CAS  Google Scholar 

  22. Kohler G, Milstein C . Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495–497.

    Article  CAS  Google Scholar 

  23. Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA et al. Current Protocols in Molecular Biology. John Wiley & Sons, 2005.

    Google Scholar 

  24. Robinson JP, Darzynkiewicz Z, Dobrucki J, Hyun W, Nolan J, Orfao A et al. Current Protocols in Cytometry. John Wiley & Sons, 2006.

    Google Scholar 

  25. Canziani GA, Klakamp S, Myszka DG . Kinetic screening of antibodies from crude hybridoma samples using Biacore. Anal Biochem 2004; 325: 301–307.

    Article  CAS  Google Scholar 

  26. Bonifacino JS, Dasso M, Harford JB, Lippincott-Schwartz J, Yamada KM . Current Protocols in Cell Biology. John Wiley & Sons, 2003.

    Google Scholar 

  27. Korver W, Singh S, Liu S, Zhao X, Yonkovich S, Sweeney A et al. The lymphoid cell surface receptor NTB-A: a novel monoclonal antibody target for leukaemia and lymphoma therapeutics. Br J Haematol 2007; 137: 307–318.

    Article  CAS  Google Scholar 

  28. Coleman EJ, Brooks KJ, Smallshaw JE, Vitetta ES . The Fc portion of UV3, an anti-CD54 monoclonal antibody, is critical for its antitumor activity in SCID mice with human multiple myeloma or lymphoma cell lines. J Immunother 2006; 29: 489–498.

    Article  CAS  Google Scholar 

  29. Naumovski L, Ramos J, Sirisawad M, Chen J, Thiemann P, Lecane P et al. Sapphyrins induce apoptosis in hematopoietic tumor-derived cell lines and show in vivo antitumor activity. Mol Cancer Ther 2005; 4: 968–976.

    Article  CAS  Google Scholar 

  30. Walter RB, Boyle KM, Appelbaum FR, Bernstein ID, Pagel JM . Simultaneously targeting CD45 significantly increases cytotoxicity of the anti-CD33 immunoconjugate, gemtuzumab ozogamicin, against acute myeloid leukemia (AML) cells and improves survival of mice bearing human AML xenografts. Blood 2008; 111: 4813–4816.

    Article  CAS  Google Scholar 

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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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Correspondence to W Korver.

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Supplementary Information accompanies the paper on the Leukemia website (

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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).

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  • acute myeloid leukemia
  • antibody therapy
  • minimal residual disease

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