Journal of Neuro-Oncology

, Volume 97, Issue 2, pp 207–215 | Cite as

Distribution, cellular localization, and therapeutic potential of the tumor-associated antigen Ku70/80 in glioblastoma multiforme

  • Oscar Persson
  • Leif G. Salford
  • Johan Fransson
  • Bengt Widegren
  • Carl A. K. Borrebaeck
  • Bo Holmqvist
Laboratory Investigation - Human/Animal Tissue

Abstract

Antibodies specifically targeting tumor-associated antigens have proved to be important tools in the treatment of human cancer. A desirable target antigen should be unique to tumor cells, abundantly expressed, and readily available for antibody binding. The Ku70/80 DNA-repair protein is expressed in the nucleus of most cells; it is, however, also present on the cell surface of tumor cell lines, and antibodies binding Ku70/80 at the cell surface were recently shown to internalize into tumor cells. To evaluate the potential of Ku70/80-antigen as a therapeutic target for immunotoxins in glioblastoma multiforme, we investigated binding and localization of Ku70/80-specific antibodies in tissue samples from glioblastomas and normal human brains, and in glioma cell cultures. Furthermore, the internalization and drug-delivery capacity were evaluated by use of immunotoxicity studies. We demonstrate that Ku70/80 is localized on the cell plasma membrane of glioma cell lines, and is specifically present in human glioblastoma tissue. Antibodies bound to the Ku70/80 antigen on the cell surface of glioma cells were found to internalize via endocytosis, and shown to efficiently deliver toxins into glioblastoma cells. The data further imply that different antibodies directed against Ku70/80 possess different abilities to target the antigen, in relation to its presentation on the cell surface or intracellular localization. We conclude that Ku70/80 antigen is uniquely presented on the plasma membrane in glioblastomas, and that antibodies specific against the antigen have the capacity to selectively bind, internalize, and deliver toxins into tumor cells. These results imply that Ku70/80 is a potential target for immunotherapy of glioblastoma multiforme.

Keywords

Glioma Tumor antigen Immunotherapy Ku70/80 

Abbreviations

CLSM

Confocal laser-scanning microscopy

DIC

Differential interference contrast

EGFR

Epidermal growth-factor receptor

GBM

Glioblastoma multiforme

IF

Immunofluorescence

IL

Interleukin

mAb

Monoclonal antibody

TAA

Tumor-associated antigen

References

  1. 1.
    Lambert JM (2005) Drug-conjugated monoclonal antibodies for the treatment of cancer. Curr Opin Pharmacol 5:543–549CrossRefPubMedGoogle Scholar
  2. 2.
    Sharkey RM, Goldenberg DM (2006) Targeted therapy of cancer: new prospects for antibodies and immunoconjugates. CA Cancer J Clin 56:226–243CrossRefPubMedGoogle Scholar
  3. 3.
    Shimamura T, Husain SR, Puri RK (2006) The IL-4 and IL-13 pseudomonas exotoxins: new hope for brain tumor therapy. Neurosurg Focus 20:E11CrossRefPubMedGoogle Scholar
  4. 4.
    Chari RV (2008) Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 41:98–107CrossRefPubMedGoogle Scholar
  5. 5.
    Bigner DD, Brown MT, Friedman AH, Coleman RE, Akabani G, Friedman HS, Thorstad WL, McLendon RE, Bigner SH, Zhao XG, Pegram CN, Wikstrand CJ et al (1998) Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results. J Clin Oncol 16:2202–2212PubMedGoogle Scholar
  6. 6.
    Sampson JH, Akabani G, Archer GE, Bigner DD, Berger MS, Friedman AH, Friedman HS, Herndon JE II, Kunwar S, Marcus S, McLendon RE, Paolino A et al (2003) Progress report of a phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors. J Neurooncol 65:27–35CrossRefPubMedGoogle Scholar
  7. 7.
    Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD (2008) Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol 20:267–275CrossRefPubMedGoogle Scholar
  8. 8.
    Fransson J, Borrebaeck CA (2006) The nuclear DNA repair protein Ku70/80 is a tumor-associated antigen displaying rapid receptor mediated endocytosis. Int J Cancer 119:2492–2496CrossRefPubMedGoogle Scholar
  9. 9.
    Muller C, Paupert J, Monferran S, Salles B (2005) The double life of the Ku protein: facing the DNA breaks and the extracellular environment. Cell Cycle 4:438–441PubMedGoogle Scholar
  10. 10.
    Mimori T, Hardin JA, Steitz JA (1986) Characterization of the DNA-binding protein antigen Ku recognized by autoantibodies from patients with rheumatic disorders. J Biol Chem 261:2274–2278PubMedGoogle Scholar
  11. 11.
    Monferran S, Paupert J, Dauvillier S, Salles B, Muller C (2004) The membrane form of the DNA repair protein Ku interacts at the cell surface with metalloproteinase 9. EMBO J 23:3758–3768CrossRefPubMedGoogle Scholar
  12. 12.
    Prabhakar BS, Allaway GP, Srinivasappa J, Notkins AL (1990) Cell surface expression of the 70-kD component of Ku, a DNA-binding nuclear autoantigen. J Clin Investig 86:1301–1305CrossRefPubMedGoogle Scholar
  13. 13.
    Ginis I, Faller DV (2000) Hypoxia affects tumor cell invasiveness in vitro: the role of hypoxia-activated ligand HAL1/13 (Ku86 autoantigen). Cancer Lett 154:163–174CrossRefPubMedGoogle Scholar
  14. 14.
    Ginis I, Mentzer SJ, Li X, Faller DV (1995) Characterization of a hypoxia-responsive adhesion molecule for leukocytes on human endothelial cells. J Immunol 155:802–810PubMedGoogle Scholar
  15. 15.
    Lynch EM, Moreland RB, Ginis I, Perrine SP, Faller DV (2001) Hypoxia-activated ligand HAL-1/13 is lupus autoantigen Ku80 and mediates lymphoid cell adhesion in vitro. Am J Physiol Cell Physiol 280:C897–C911PubMedGoogle Scholar
  16. 16.
    Dalziel RG, Mendelson SC, Quinn JP (1992) The nuclear autoimmune antigen Ku is also present on the cell surface. Autoimmunity 13:265–267CrossRefPubMedGoogle Scholar
  17. 17.
    Salford LG, Siesjo P, Skagerberg G, Persson BRR, Larsson E-M, Lindvall M, Visse E, Widegren B (2002) Search for effective therapy against glioblastoma multiforme—clinical immunisation with autologous glioma cells transduced with the human interferon-gamma gene. Int Congr Ser 1247:211–220CrossRefGoogle Scholar
  18. 18.
    Bergamaschi G, Perfetti V, Tonon L, Novella A, Lucotti C, Danova M, Glennie MJ, Merlini G, Cazzola M (1996) Saporin, a ribosome-inactivating protein used to prepare immunotoxins, induces cell death via apoptosis. Br J Haematol 93:789–794CrossRefPubMedGoogle Scholar
  19. 19.
    Kohls MD, Lappi DA (2000) Mab-ZAP: a tool for evaluating antibody efficacy for use in an immunotoxin. Biotechniques 28:162–165PubMedGoogle Scholar
  20. 20.
    Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JN (2007) Molecularly targeted therapy for malignant glioma. Cancer 110:13–24CrossRefPubMedGoogle Scholar
  21. 21.
    Zalutsky MR, Moseley RP, Coakham HB, Coleman RE, Bigner DD (1989) Pharmacokinetics and tumor localization of 131I-labeled anti-tenascin monoclonal antibody 81C6 in patients with gliomas and other intracranial malignancies. Cancer Res 49:2807–2813PubMedGoogle Scholar
  22. 22.
    Rainov NG, Gorbatyuk K, Heidecke V (2008) Clinical trials with intracerebral convection-enhanced delivery of targeted toxins in malignant glioma. Rev Recent Clin Trials 3:2–9CrossRefPubMedGoogle Scholar
  23. 23.
    Sampson JH, Akabani G, Archer GE, Berger MS, Coleman RE, Friedman AH, Friedman HS, Greer K, Herndon JE II, Kunwar S, McLendon RE, Paolino A et al (2008) Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors. Neuro-oncology 10:320–329CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Oscar Persson
    • 1
  • Leif G. Salford
    • 1
  • Johan Fransson
    • 2
  • Bengt Widegren
    • 1
    • 3
  • Carl A. K. Borrebaeck
    • 2
  • Bo Holmqvist
    • 4
  1. 1.Department of Neurosurgery and The Rausing LaboratoryLund UniversityLundSweden
  2. 2.Department of ImmunotechnologyLund UniversityLundSweden
  3. 3.Division of Tumor ImmunologyLund UniversityLundSweden
  4. 4.Department of Oncology and LBIC Optical UnitLund UniversityLundSweden

Personalised recommendations