Skip to main content

Advertisement

SpringerLink
Log in

Antitumor effects of polyclonal antithymocyte globulins: focus on B-cell malignancies and multiple myeloma

  • Review Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Polyclonal antithymocyte globulins (ATGs) are used in organ and allogeneic stem cell transplantation mainly due to their immunomodulatory potential. Since ATGs contain antibodies against antigens expressed on various hematopoetic cells, it is not surprising that they induce cell death not only in healthy T-, B-, NK, and dendritic cells but also in malignant cells of lymphatic and to a lesser extent of myeloid lineage. The cytotoxic and antiproliferative effects of ATGs in malignant B-cells have been known for many years, without attracting clinical attention due to the advent of monoclonal antibodies like rituximab. Recent data indicate a potential role of ATGs in the therapy of multiple myeloma, a disease in which monoclonal serotherapy has been rather unsuccessful. This review discusses available data demonstrating the cytotoxic effects of ATGs and envisages a possible new role of these polyclonal antibodies in the therapy of hematological malignancies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Zander AR, Zabelina T, Kröger N et al (1999) Use of a five-agent GvHD prevention regimen in recipients of unrelated donor marrow. Bone Marrow Transplant 23:889–893

    Article  PubMed  CAS  Google Scholar 

  2. Finke J, Bertz H, Schmoor C et al (2000) Allogeneic bone marrow transplantation from unrelated donors using in vivo anti-T cell globulin. Br J Haematol 111:303–313

    Article  PubMed  CAS  Google Scholar 

  3. Remberger M, Svahn B-M, Hentschke P et al (1991) Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies during conditioning for unrelated haematopoietic stem cell transplantation. Bone Marrow Transplant 24:823–830

    Article  Google Scholar 

  4. Bacigalupo A, Lamparelli T, Bruzzi P et al (2001) Antithymocyte globulin for graft-versus-host disease prophylaxes in transplants form unrelated donor: 2 randomized studies from Gruppo Italiono Trapianti Midollo Osseo (GITMO). Blood 98:2942–2947

    Article  PubMed  CAS  Google Scholar 

  5. Meijer E, Cornelissen JJ, Lowenberg B, Verdonck LF (2003) Antithymocyteglobulin as prophylaxis of graft-versus-host disease in recipients of partially depleted grafts from matched unrelated donors: a dose finding study. Exp Hematol 31:1026–1030

    Article  PubMed  CAS  Google Scholar 

  6. Kalwak K, Moson I, Cwian J et al (2003) A prospective analysis of immune recovery in children following allogeneic transplantation of t-cell-depleted or non-T-cell-depleted hematopoietic cells from HLA-disparate family donors. Transplant Proc 35:1551–1555

    Article  PubMed  CAS  Google Scholar 

  7. Meijer E, Bloem AC, Dekker AW, Verdonk LF (2003) Effect of antithymocyte globulin on quantitative immune recovery and graft-versus-host disease after partially T-cell depleted bone marrow transplantation: a comparison of matched related and matched unrelated grafts. Transplantation 75:1910–1913

    Article  PubMed  CAS  Google Scholar 

  8. Fehse N, Fehse B, Kroger N et al (2003) Influence of anti-thymocyte globulin as part of the conditioning regimen on immune reconstitution following matched related bone marrow transplantation. J Hematother Stem Cell Res 12:237–242

    Article  PubMed  CAS  Google Scholar 

  9. Kröger N, Shaw B, Iacobelli S et al (2005) The Clinical Trial Committee of the British Society of Blood and Marrow Transplantation and the German Cooperative Transplant Group Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR–ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. Br J Haematol 129(5):631–643

    Article  PubMed  CAS  Google Scholar 

  10. Ayuk F, Perez-Simon A, Shimoni A et al (2008) Clinical impact of human Jurkat T-cell-line-derived antithymocyte globulin in multiple myeloma patients undergoing allogeneic stem cell transplantation. Haematologica 93(9):1343–1350, Sep

    Article  PubMed  Google Scholar 

  11. Bonnefoy-Berard N, Genestier L, Flacher M et al (1994) Apoptosis induced by polyclonal antilymphocyte globulins in human B-cell lines. Blood 83:1051–1059

    PubMed  CAS  Google Scholar 

  12. Zand MS, Vo T, Huggins J et al (2005) Polyclonal rabbit antithymocyte globulin triggers B-cell apoptosis by multiple pathways. Transplantation 79:1507–1515

    Article  PubMed  CAS  Google Scholar 

  13. Ayuk F, Fang L, Fehse B et al (2005) Antithymocyte globulin induces complement-dependent cell lysis and caspase-dependent apoptosis in myeloma cells. Exp Hematol 33:1531–1536

    Article  PubMed  CAS  Google Scholar 

  14. Bonnefoy-Berard N, Revillard JP (1996) Mechanisms of immunosuppression induced by antithymocyte globulins and OKT3. J Heart Lung Transplant 15(5):435–442

    PubMed  CAS  Google Scholar 

  15. Michallet MC, Preville X, Flacher M, Fournel S, Genestier L, Revillard JP (2003) Functional antibodies to leukocyte adhesion molecules in antithymocyte globulins. Transplantation 75:657–662

    Article  PubMed  CAS  Google Scholar 

  16. Bonnefoy-Berard N, Vincent C, Revillard JP (1991) Antibodies against functional leukocyte surface molecules in polyclonal antilymphocyte and antithymocyte globulins. Transplantation 51:669–673

    Article  PubMed  CAS  Google Scholar 

  17. Raefsky EL, Gascon P, Gratwohl A, Speck B, Young NS (1986) Biological and immunological characterization of ATG and ALG. Blood 68:712–719

    PubMed  CAS  Google Scholar 

  18. Rebellato LM, Gross U, Verbanac KM, Thomas JM (1994) A comprehensive definition of the major antibody specificities in polyclonal rabbit antithymocyte globulins. Transplantation 57:685–694

    Article  PubMed  CAS  Google Scholar 

  19. Preville X, Nicolas L, Flacher M, Revillard J (2000) A quantitative flow cytometry assay for the preclinical testing and pharmacological monitoring of rabbit antilymphocyte globulin (rATG). J Immunol Methods 245:45–54

    Article  PubMed  CAS  Google Scholar 

  20. Pistillo MP, Tazzari PL, Bonifazi F et al (2002) Detection of a novel specificity (CTLA-4) in ATG/TMG Globulins and sera from ATG-treated leukemic patients. Transplantation 73:1295–1302

    Article  PubMed  CAS  Google Scholar 

  21. Bourdage JS, Hamlin DM (1995) Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry. Transplantation 27:1194–1200

    Google Scholar 

  22. Bacigalupo A, Lamparelli T, Bruzzi P et al (2001) Antithymocyte globulin for graft-versus-host disease prophylaxes in transplants form unrelated donor: 2 randomized studies from Gruppo Italiono Trapianti Midollo Osseo (GITMO). Blood 98:2942–2947

    Article  PubMed  CAS  Google Scholar 

  23. Meijer E, Cornelissen JJ, Lowenberg B, Verdonck LF (2003) Antithymocyteglobulin as prophylaxis of graft-versus-host disease in recipients of partially depleted grafts from matched unrelated donors: a dose finding study. Exp Hematol 31:1026–1030

    Article  PubMed  CAS  Google Scholar 

  24. Duggan P, Booth K, Chaudhry A et al (2002) Alberta Blood and Bone Marrow Transplant Program. Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis. Bone Marrow Transplant 30:681–686

    Article  PubMed  CAS  Google Scholar 

  25. Schleuning M, Gunther W, Tischer J et al (2003) Dose-dependent effects of in vivo antithymocyte globulin during conditioning for allogeneic bone marrow transplantation from unrelated donors in patients with chronic phase CML. Bone Marrow Transplant 32:243–250

    Article  PubMed  CAS  Google Scholar 

  26. Zander AR, Zabelina T, Kröger N et al (1999) Use of a five-agent GvHD prevention regimen in recipients of unrelated donor marrow. Bone Marrow Transplant. 23:889–893

    Article  PubMed  CAS  Google Scholar 

  27. Eiermann TH, Lambrecht P, Zander AR (1999) Monitoring anti-thymocyte globulin (ATG) in bone marrow recipients. Bone Marrow Transplant 23:779–781

    Article  PubMed  CAS  Google Scholar 

  28. Yoshimi A, Ito M, Kojima S (2005) Leukemic cell death induced by antithymocyte globulin. Leuk Res 29:821–827

    Article  PubMed  CAS  Google Scholar 

  29. Bonnefoy-Berard N, Flacher M, Revillard JP (1992) Antiproliferative effect of antilymphocyte globulins on B cells and B-cell lines. Blood 79(8):2164–2170, Apr 15

    PubMed  CAS  Google Scholar 

  30. Ayuk F, Atassi N, Schuch G et al (2008) Complement-dependent and complement-independent cytotoxicity of polyclonal antithymocyte globulins in chronic lymphocytic leukemia. Leuk Res. 32(8):1200–1206, Aug

    Article  PubMed  CAS  Google Scholar 

  31. Singal R, Winfield DA, Greaves M (1991) Bone marrow aplasia in B cell chronic lymphocytic leukaemia: successful treatment with antithymocyte globulin. J Clin Pathol 44:954–956

    Article  PubMed  CAS  Google Scholar 

  32. Radosevich CA, Gordon LI, Weil SC, Marder RJ, Rosen ST (1988) Complete resolution of pure red cell aplasia in a patient with chronic lymphocytic leukemia following antithymocyte globulin therapy. JAMA 5:723–725

    Article  Google Scholar 

  33. Lowsky R, Takahashi T, Liu YP et al (2005) Protective conditioning for acute graft-versus-host disease. N Engl J Med 353(13):1321–1331

    Article  PubMed  CAS  Google Scholar 

  34. Zand MS, Vo T, Pellogrin T et al (2006) Apoptosis and complement-mediated lysis of myeloma cells by polyclonal rabbit antithymocyte globulin. Blood 107:2895–2903

    Article  PubMed  CAS  Google Scholar 

  35. Timm MM, Kimlinger TK, Haug JL et al (2006) Thymoglobulin targets multiple plasma cell antigens and has in vitro and in vivo activity in multiple myeloma. Leukemia 20:1863–1869

    Article  PubMed  CAS  Google Scholar 

  36. Kröger N, Perez-Simon JA, Myint H et al (2004) Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose-reduced allogeneic stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant 10:698–708

    Article  PubMed  CAS  Google Scholar 

  37. Perez-Simon JA, Martino R, Alegre A et al (2003) Chronic but not acute graft-versus-host disease improves outcome in multiple myeloma patients after non-myeloablative allogeneic transplantation. Br J Hematol 121:104–108

    Article  Google Scholar 

  38. Treon SP, Pilarski LM, Belch AR et al (2002) CD20-directed serotherapy in patients with multiple myeloma: biological considerations and the therapeutic applications. J Immunother 25:72–81

    Article  PubMed  Google Scholar 

  39. Tai YT, Catley LP, Mitsiades CS et al (2004) Mechanisms by which SGN-40, a humanized anti-CD40 antibody induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res 64:2846–2852

    Article  PubMed  CAS  Google Scholar 

  40. Matsui W, Huff CA, Wang Q et al (2004) Characterization of clonogenic multiple myeloma cells. Blood 103:2332–2336

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Francis Ayuk, Axel Zander & Nicolaus Kröger

Authors
  1. Francis Ayuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Axel Zander
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolaus Kröger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francis Ayuk.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ayuk, F., Zander, A. & Kröger, N. Antitumor effects of polyclonal antithymocyte globulins: focus on B-cell malignancies and multiple myeloma. Ann Hematol 88, 401–404 (2009). https://doi.org/10.1007/s00277-009-0696-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-009-0696-8

Keywords

Search

Navigation