Distribution, cellular localization, and therapeutic potential of the tumor-associated antigen Ku70/80 in glioblastoma multiforme.
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.
Persson
Oscar
O
Department of Neurosurgery and The Rausing Laboratory, Lund University, Universitetssjukhuset EA14, 221 85, Lund, Sweden. oscar.persson@med.lu.se
Salford
Leif G
LG
Fransson
Johan
J
Widegren
Bengt
B
Borrebaeck
Carl A K
CA
Holmqvist
Bo
B
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D034961:Antigens, Nuclear / Q000276:immunology / Q000378:metabolism*; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D000072200:Ku Autoantigen; D018613:Microscopy, Confocal
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen