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Recent advances in adult T-cell leukemia therapy: focus on a new anti-transferrin receptor monoclonal antibody

Leukemia volume 22, pages 42–48 (2008)Cite this article

Abstract

HTLV-I is an endemic retrovirus responsible for the adult T-cell leukemia/lymphoma (ATLL). This aggressive lymphoid proliferation is associated with a bad prognosis due to the resistance of HTLV-I-infected cells to most classical chemotherapeutic agents. Here we review recent advances in ATLL immunotherapy. We particularly focus on promising data from our group, characterizing a new mouse monoclonal antibody (mAb A24) against the human transferrin receptor (TfR-1). Monoclonal antibodies to target cell differentiation markers on ATLL cells have already been proposed as therapeutic agents. However, in clinical trials acute forms of ATLL were resistant to these immunotherapies. A24 binds TfR-1 (Kd 2.7 nM) and competes with transferrin for receptor binding. It blocks the proliferation of malignant cells (TfR-1high), such as HTLV-I-infected T cells but not of resting cells. A24 induces TfR-1 endocytosis in lysosomal compartments where the receptor is degraded leading to intracellular iron deprivation. In HTLV-I-infected cells, A24 targets and induces apoptosis of both chronic and acute ATLL forms, independent of antibody aggregation, antibody-dependent cellular cytotoxicity and/or complement addition. The antibody efficacy was confirmed in animal models. We are currently developing strategies to use A24 in clinical trials.

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References

  1. Hinuma Y, Komoda H, Chosa T, Kondo T, Kohakura M, Takenaka T et al. Antibodies to adult T-cell leukemia-virus-associated antigen (ATLA) in sera from patients with ATL and controls in Japan: a nation-wide sero-epidemiologic study. Int J Cancer 1982; 29: 631–635.

    Article  CAS  Google Scholar 

  2. Gessain A, Barin F, Vernant JC, Gout O, Maurs L, Calender A et al. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet 1985; 2: 407–410.

    Article  CAS  Google Scholar 

  3. Proietti FA, Carneiro-Proietti AB, Catalan-Soares BC, Murphy EL . Global epidemiology of HTLV-I infection and associated diseases. Oncogene 2005; 24: 6058–6068.

    Article  CAS  Google Scholar 

  4. Ando Y, Ekuni Y, Matsumoto Y, Nakano S, Saito K, Kakimoto K et al. Long-term serological outcome of infants who received frozen-thawed milk from human T-lymphotropic virus type-I positive mothers. J Obstet Gynaecol Res 2004; 30: 436–438.

    Article  Google Scholar 

  5. Shimoyama M . Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–87). Br J Haematol 1991; 79: 428–437.

    Article  CAS  Google Scholar 

  6. Takatsuki K . Adult T-cell leukemia/lymphoma. In: Gallo RC, Wong-Staal F (eds). Retrovirus Biology and Human Disease. Marcel Dekker: New York, 1990, pp 147–159.

    Google Scholar 

  7. Okayama A, Stuver S, Matsuoka M, Ishizaki J, Tanaka G, Kubuki Y et al. Role of HTLV-1 proviral DNA load and clonality in the development of adult T-cell leukemia/lymphoma in asymptomatic carriers. Int J Cancer 2004; 110: 621–625.

    Article  CAS  Google Scholar 

  8. Franchini G . Molecular mechanisms of human T-cell leukemia/lymphotropic virus type I infection. Blood 1995; 86: 3619–3639.

    CAS  Google Scholar 

  9. Yoshida M . Multiple viral strategies of HTLV-1 for dysregulation of cell growth control. Annu Rev Immunol 2001; 19: 475–496.

    Article  CAS  Google Scholar 

  10. Maruyama K, Fukushima T, Kawamura K, Mochizuki S . Chromosome and gene rearrangements in immortalized human lymphocytes infected with human T-lymphotropic virus type I. Cancer Res 1990; 50 (17 Suppl): 5697S–5702S.

    CAS  Google Scholar 

  11. Tsukasaki K, Tsushima H, Yamamura M, Hata T, Murata K, Maeda T et al. Integration patterns of HTLV-I provirus in relation to the clinical course of ATL: frequent clonal change at crisis from indolent disease. Blood 1997; 89: 948–956.

    CAS  Google Scholar 

  12. Bazarbachi A, Ghez D, Lepelletier Y, Nasr R, de The H, El-Sabban ME et al. New therapeutic approaches for adult T-cell leukaemia. Lancet Oncol 2004; 5: 664–672.

    Article  CAS  Google Scholar 

  13. Waldmann TA, Goldman CK, Bongiovanni KF, Sharrow SO, Davey MP, Cease KB et al. Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2. Blood 1988; 72: 1805–1816.

    CAS  Google Scholar 

  14. Waldmann TA, White JD, Carrasquillo JA, Reynolds JC, Paik CH, Gansow OA et al. Radioimmunotherapy of interleukin-2R alpha-expressing adult T-cell leukemia with Yttrium-90-labeled anti-Tac. Blood 1995; 86: 4063–4075.

    CAS  Google Scholar 

  15. Azimi N, Jacobson S, Leist T, Waldmann TA . Involvement of IL-15 in the pathogenesis of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: implications for therapy with a monoclonal antibody directed to the IL-2/15R beta receptor. J Immunol 1999; 163: 4064–4072.

    CAS  Google Scholar 

  16. Zhang Z, Zhang M, Ravetch JV, Goldman C, Waldmann TA . Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD2 monoclonal antibody, MEDI-507. Blood 2003; 102: 284–288.

    Article  CAS  Google Scholar 

  17. Zhang Z, Zhang M, Goldman CK, Ravetch JV, Waldmann TA . Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD52 monoclonal antibody, Campath-1H. Cancer Res 2003; 63: 6453–6457.

    CAS  Google Scholar 

  18. Taylor GP, Matsuoka M . Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. Oncogene 2005; 24: 6047–6057.

    Article  CAS  Google Scholar 

  19. Moura IC, Lepelletier Y, Arnulf B, England P, Baude C, Beaumont C et al. A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients. Blood 2004; 103: 1838–1845.

    Article  CAS  Google Scholar 

  20. Richardson DR, Ponka P . The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim Biophys Acta 1997; 1331: 1–40.

    Article  CAS  Google Scholar 

  21. Ponka P, Lok CN . The transferrin receptor: role in health and disease. Int J Biochem Cell Biol 1999; 31: 1111–1137.

    Article  CAS  Google Scholar 

  22. Neckers LM, Trepel JB . Transferrin receptor expression and the control of cell growth. Cancer Invest 1986; 4: 461–470.

    Article  CAS  Google Scholar 

  23. Klausner RD, Ashwell G, van Renswoude J, Harford JB, Bridges KR . Binding of apotransferrin to K562 cells: explanation of the transferrin cycle. Proc Natl Acad Sci USA 1983; 80: 2263–2266.

    Article  CAS  Google Scholar 

  24. van Renswoude J, Bridges KR, Harford JB, Klausner RD . Receptor-mediated endocytosis of transferrin and the uptake of Fe in K562 cells: identification of a nonlysosomal acidic compartment. Proc Natl Acad Sci USA 1982; 79: 6186–6190.

    Article  CAS  Google Scholar 

  25. Pantopoulos K . Iron metabolism and the IRE/IRP regulatory system: an update. Ann NY Acad Sci 2004; 1012: 1–13.

    Article  CAS  Google Scholar 

  26. Gatter KC, Brown G, Trowbridge IS, Woolston RE, Mason DY . Transferrin receptors in human tissues: their distribution and possible clinical relevance. J Clin Pathol 1983; 36: 539–545.

    Article  CAS  Google Scholar 

  27. Faulk WP, Hsi BL, Stevens PJ . Transferrin and transferrin receptors in carcinoma of the breast. Lancet 1980; 2: 390–392.

    Article  CAS  Google Scholar 

  28. Habeshaw JA, Lister TA, Stansfeld AG, Greaves MF . Correlation of transferrin receptor expression with histological class and outcome in non-Hodgkin lymphoma. Lancet 1983; 1: 498–501.

    Article  CAS  Google Scholar 

  29. Sieff C, Bicknell D, Caine G, Robinson J, Lam G, Greaves MF . Changes in cell surface antigen expression during hemopoietic differentiation. Blood 1982; 60: 703–713.

    CAS  Google Scholar 

  30. Taetle R . The role of transferrin receptors in hemopoietic cell growth. Exp Hematol 1990; 18: 360–365.

    CAS  Google Scholar 

  31. Yeh CJ, Taylor CG, Faulk WP . Transferrin binding by peripheral blood mononuclear cells in human lymphomas, myelomas and leukemias. Vox Sang 1984; 46: 217–223.

    Article  CAS  Google Scholar 

  32. Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP . Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem 2000; 275: 16618–16625.

    Article  CAS  Google Scholar 

  33. Trinder D, Baker E . Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol 2003; 35: 292–296.

    Article  CAS  Google Scholar 

  34. Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP . Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood 2001; 98: 2714–2719.

    Article  CAS  Google Scholar 

  35. Robb A, Wessling-Resnick M . Regulation of transferrin receptor 2 protein levels by transferrin. Blood 2004; 104: 4294–4299.

    Article  CAS  Google Scholar 

  36. Deaglio S, Capobianco A, Cali A, Bellora F, Alberti F, Righi L et al. Structural, functional, and tissue distribution analysis of human transferrin receptor-2 by murine monoclonal antibodies and a polyclonal antiserum. Blood 2002; 100: 3782–3789.

    Article  CAS  Google Scholar 

  37. Calzolari A, Deaglio S, Sposi NM, Petrucci E, Morsilli O, Gabbianelli M et al. Transferrin receptor 2 protein is not expressed in normal erythroid cells. Biochem J 2004; 381 (Part 3): 629–634.

    Article  CAS  Google Scholar 

  38. Calzolari A, Oliviero I, Deaglio S, Mariani G, Biffoni M, Sposi NM et al. Transferrin receptor 2 is frequently expressed in human cancer cell lines. Blood Cells Mol Dis 2007; 39: 82–91.

    Article  CAS  Google Scholar 

  39. Trowbridge IS, Lesley J, Schulte R . Murine cell surface transferrin receptor: studies with an anti-receptor monoclonal antibody. J Cell Physiol 1982; 112: 403–410.

    Article  CAS  Google Scholar 

  40. Trowbridge IS, Collawn J, Jing S, White S, Esekogwu V, Stangel M . Structure-function analysis of the human transferrin receptor: effects of anti-receptor monoclonal antibodies on tumor growth. Curr Stud Hematol Blood Transfus 1991; 58: 139–147.

    Article  CAS  Google Scholar 

  41. Lesley JF, Schulte RJ . Inhibition of cell growth by monoclonal anti-transferrin receptor antibodies. Mol Cell Biol 1985; 5: 1814–1821.

    Article  CAS  Google Scholar 

  42. Kemp JD, Cardillo T, Stewart BC, Kehrberg E, Weiner G, Hedlund B et al. Inhibition of lymphoma growth in vivo by combined treatment with hydroxyethyl starch deferoxamine conjugate and IgG monoclonal antibodies against the transferrin receptor. Cancer Res 1995; 55: 3817–3824.

    CAS  Google Scholar 

  43. Taetle R, Honeysett JM, Trowbridge I . Effects of anti-transferrin receptor antibodies on growth of normal and malignant myeloid cells. Int J Cancer 1983; 32: 343–349.

    Article  CAS  Google Scholar 

  44. Petrini M, Pelosi-Testa E, Sposi NM, Mastroberardino G, Camagna A, Bottero L et al. Constitutive expression and abnormal glycosylation of transferrin receptor in acute T-cell leukemia. Cancer Res 1989; 49 (24 Part 1): 6989–6996.

    CAS  Google Scholar 

  45. Trowbridge IS, Omary MB . Human cell surface glycoprotein related to cell proliferation is the receptor for transferrin. Proc Natl Acad Sci USA 1981; 78: 3039–3043.

    Article  CAS  Google Scholar 

  46. Taetle R, Castagnola J, Mendelsohn J . Mechanisms of growth inhibition by anti-transferrin receptor monoclonal antibodies. Cancer Res 1986; 46 (4 Part 1): 1759–1763.

    CAS  Google Scholar 

  47. Brooks D, Taylor C, Dos Santos B, Linden H, Houghton A, Hecht TT et al. Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6. Clin Cancer Res 1995; 1: 1259–1265.

    CAS  Google Scholar 

  48. Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC . Monoclonal antibody successes in the clinic. Nat Biotechnol 2005; 23: 1073–1078.

    Article  CAS  Google Scholar 

  49. Qing Y, Shuo W, Zhihua W, Huifen Z, Ping L, Lijiang L et al. The in vitro antitumor effect and in vivo tumor-specificity distribution of human-mouse chimeric antibody against transferrin receptor. Cancer Immunol Immunother 2006; 55: 1111–1121.

    Article  Google Scholar 

  50. Ng PP, Dela Cruz JS, Sorour DN, Stinebaugh JM, Shin SU, Shin DS et al. An anti-transferrin receptor-avidin fusion protein exhibits both strong proapoptotic activity and the ability to deliver various molecules into cancer cells. Proc Natl Acad Sci USA 2002; 99: 10706–10711.

    Article  CAS  Google Scholar 

  51. Ng PP, Helguera G, Daniels TR, Lomas SZ, Rodriguez JA, Schiller G et al. Molecular events contributing to cell death in malignant human hematopoietic cells elicited by an IgG3-avidin fusion protein targeting the transferrin receptor. Blood 2006; 108: 2745–2754.

    Article  CAS  Google Scholar 

  52. Moura IC, Centelles MN, Arcos-Fajardo M, Malheiros DM, Collawn JF, Cooper MD et al. Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J Exp Med 2001; 194: 417–425.

    Article  CAS  Google Scholar 

  53. Lepelletier Y, Camara-Clayette V, Jin H, Hermant A, Coulon S, Dussiot M et al. Prevention of mantle lymphoma tumor establishment by routing transferrin receptor toward lysosomal compartments. Cancer Res 2007; 67: 1145–1154.

    Article  CAS  Google Scholar 

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Acknowledgements

This study is supported by ARC grant ML/MLD/CM-A03/1, Arreca, Canceropole Ile de France, FRM, INCA, Association Laurette Fugain, La Ligue Contre le Cancer and Fondation de France.

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Author notes

  1. C Callens: C Callens is a recipient of an INSERM fellowship (poste d'accueil, interne en biologie).

Authors and Affiliations

  1. CNRS UMR 8147, Université Paris 5, Faculté de Médecine Necker, Paris, France

    C Callens, Y Lepelletier, S Coulon, A Renand, M Dussiot & O Hermine

  2. INSERM U699, Paris, France

    I C Moura, M Benhamou & R C Monteiro

  3. Université Paris 7, Faculté de Médecine Denis Diderot, Paris, France

    I C Moura, M Benhamou & R C Monteiro

  4. Service d’Hématologie, Assistance Publique des Hôpitaux de Paris, Hôpital Necker, Paris, France

    D Ghez & O Hermine

  5. Department of Internal Medicine, American University of Beirut, Beirut, Lebanon

    A Bazarbachi

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  1. C Callens
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Correspondence to O Hermine.

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Callens, C., Moura, I., Lepelletier, Y. et al. Recent advances in adult T-cell leukemia therapy: focus on a new anti-transferrin receptor monoclonal antibody. Leukemia 22, 42–48 (2008). https://doi.org/10.1038/sj.leu.2404958

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