Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Myeloma

Thymoglobulin targets multiple plasma cell antigens and has in vitro and in vivo activity in multiple myeloma

Leukemia volume 20, pages 1863–1869 (2006)Cite this article

Abstract

Multiple myeloma is characterized by the proliferation of clonal plasma cells that have a heterogeneous expression of various cell surface markers, precluding successful use of monoclonal antibodies for therapeutic targeting of the tumor cell. Thymoglobulin (rabbit-derived polyclonal anti-thymocyte globulin), by virtue of its method of preparation, contains antibodies against several B-cell and plasma cell antigens and offers an attractive option for immunotherapy of myeloma. Here, we demonstrate potent anti-myeloma activity of the rabbit anti-thymocyte globulin preparation Thymoglobulin in vitro and in vivo in an animal model of myeloma. Thymoglobulin was able to induce dose- and time-dependent apoptosis of several myeloma cell lines, including those resistant to conventional anti-myeloma agents. Importantly, the anti-myeloma activity was preserved even when myeloma cells were grown with different cytokines demonstrating the ability to overcome microenvironment-mediated resistance. Thymoglobulin induced apoptosis of freshly isolated primary myeloma cells from patients. Using a competitive flow cytometric analysis, we were able to identify the potential antigen targets for Thymoglobulin preparation. Finally, in a plasmacytoma mouse model of myeloma, Thymoglobulin delayed the tumor growth in a dose-dependent manner providing convincing evidence for continued evaluation of this agent in the clinic in patients with myeloma, either alone or in combination with other agents.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, O'Sullivan EJ, Johnson MR, Heroux AL et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990; 323: 1723–1728.

    Article  CAS  PubMed  Google Scholar 

  2. Bonnefoy-Berard N, Flacher M, Revillard JP . Antiproliferative effect of antilymphocyte globulins on B cells and B-cell lines. Blood 1992; 79: 2164–2170.

    CAS  PubMed  Google Scholar 

  3. Shah A, Nadasdy T, Arend L, Brennan J, Leong N, Coppage M et al. Treatment of C4d-positive acute humoral rejection with plasmapheresis and rabbit polyclonal antithymocyte globulin. Transplantation 2004; 77: 1399–1405.

    Article  CAS  PubMed  Google Scholar 

  4. Zand MS, Vo T, Huggins J, Felgar R, Liesveld J, Pellegrin T et al. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation 2005; 79: 1507–1515.

    Article  CAS  PubMed  Google Scholar 

  5. Ayuk FA, Fang L, Fehse B, Zander AR, Kroger N . Antithymocyte globulin induces complement-dependent cell lysis and caspase-dependent apoptosis in myeloma cells. Exp Hematol 2005; 33: 1531–1536.

    Article  CAS  PubMed  Google Scholar 

  6. Zand MS, Vo T, Pellegrin T, Felgar R, Liesveld JL, Ifthikharuddin JJ et al. Apoptosis and complement-mediated lysis of myeloma cells by polyclonal rabbit antithymocyte globulin. Blood 2006; 107: 2895–2903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tassone P, Goldmacher VS, Neri P, Gozzini A, Shammas MA, Whiteman KR et al. Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells. Blood 2004; 104: 3688–3696.

    Article  CAS  PubMed  Google Scholar 

  8. Stevenson FK, Bell AJ, Cusack R, Hamblin TJ, Slade CJ, Spellerberg MB et al. Preliminary studies for an immunotherapeutic approach to the treatment of human myeloma using chimeric anti-CD38 antibody. Blood 1991; 77: 1071–1079.

    CAS  PubMed  Google Scholar 

  9. Goldmacher VS, Bourret LA, Levine BA, Rasmussen RA, Pourshadi M, Lambert JM et al. Anti-CD38-blocked ricin: an immunotoxin for the treatment of multiple myeloma. Blood 1994; 84: 3017–3025.

    CAS  PubMed  Google Scholar 

  10. Peng KW, Donovan KA, Schneider U, Cattaneo R, Lust JA, Russell SJ . Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker. Blood 2003; 101: 2557–2562.

    Article  CAS  PubMed  Google Scholar 

  11. Perez-Andres M, Almeida J, Martin-Ayuso M, Moro MJ, Martin-Nunez G, Galende J et al. Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leukemia show different expression profiles of molecules involved in the interaction with the immunological bone marrow microenvironment. Leukemia 2005; 19: 449–455.

    Article  CAS  PubMed  Google Scholar 

  12. Szczepek AJ, Belch AR, Pilarski LM . Expression of IL-6 and IL-6 receptors by circulating clonotypic B cells in multiple myeloma: potential for autocrine and paracrine networks. Exp Hematol 2001; 29: 1076–1081.

    Article  CAS  PubMed  Google Scholar 

  13. Uchiyama H, Barut BA, Chauhan D, Cannistra SA, Anderson KC . Characterization of adhesion molecules on human myeloma cell lines. Blood 1992; 80: 2306–2314.

    CAS  PubMed  Google Scholar 

  14. Okada T, Hawley RG, Kodaka M, Okuno H . Significance of VLA-4-VCAM-1 interaction and CD44 for transendothelial invasion in a bone marrow metastatic myeloma model. Clin Exp Metastasis 1999; 17: 623–629.

    Article  CAS  PubMed  Google Scholar 

  15. Sanz-Rodriguez F, Ruiz-Velasco N, Pascual-Salcedo D, Teixido J . Characterization of VLA-4-dependent myeloma cell adhesion to fibronectin and VCAM-1. Br J Haematol 1999; 107: 825–834.

    Article  CAS  PubMed  Google Scholar 

  16. Vacca A, Di Loreto M, Ribatti D, Di Stefano R, Gadaleta-Caldarola G, Iodice G et al. Bone marrow of patients with active multiple myeloma: angiogenesis and plasma cell adhesion molecules LFA-1, VLA-4, LAM-1, and CD44. Am J Hematol 1995; 50: 9–14.

    Article  CAS  PubMed  Google Scholar 

  17. Sanz-Rodriguez F, Teixido J . VLA-4-dependent myeloma cell adhesion. Leukemia Lymphoma 2001; 41: 239–245.

    Article  CAS  PubMed  Google Scholar 

  18. Sanz-Rodriguez F, Hidalgo A, Teixido J . Chemokine stromal cell-derived factor-1alpha modulates VLA-4 integrin-mediated multiple myeloma cell adhesion to CS-1/fibronectin and VCAM-1. Blood 2001; 97: 346–351.

    Article  CAS  PubMed  Google Scholar 

  19. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS . Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999; 93: 1658–1667.

    CAS  PubMed  Google Scholar 

  20. Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y et al. Characterization of clonogenic multiple myeloma cells. Blood 2004; 103: 2332–2336.

    Article  CAS  PubMed  Google Scholar 

  21. Lin P, Owens R, Tricot G, Wilson CS . Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol 2004; 121: 482–488.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported in part by Mayo Clinic Hematological Malignancies program (SK), and a grant from Genzyme Corp., Cambridge, MA (SK).

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA

    M M Timm, T K Kimlinger, J L Haug, M P Kline, P R Greipp, S V Rajkumar & S K Kumar

Authors
  1. M M Timm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T K Kimlinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J L Haug
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M P Kline
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P R Greipp
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S V Rajkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S K Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S K Kumar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Timm, M., Kimlinger, T., Haug, J. et al. Thymoglobulin targets multiple plasma cell antigens and has in vitro and in vivo activity in multiple myeloma. Leukemia 20, 1863–1869 (2006). https://doi.org/10.1038/sj.leu.2404359

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404359

Keywords

This article is cited by

Search

Advanced search

Quick links