Bispecific single-chain antibodies as effective tools for eliminating epithelial cancer cells from human stem cell preparations by redirected cell cytotoxicity.
High-dose chemotherapy (HDC) with autologous bone marrow or peripheral stem cell transplantation is discussed as one option to treat the extensive stage of a variety of tumors. Effective methods to eliminate contaminating tumor cells from human bone marrow or stem cell grafts may improve the outcome of the patients. We investigated 3 recombinant bispecific single-chain antibodies (bscAbs) directed against 17-1A (EpCAM), c-erbB-2 (HER-2/neu) and LeY on the one and CD3 on the other binding site for their ability to induce lysis of epithelial tumor cells by retargeting autochthonous T lymphocytes present in bone marrow mononuclear cells (BMMC) and in peripheral stem cell mononuclear cells (PSMC). The bscAbs showed remarkable specific lysis of different epithelial tumor cell lines with BMMCs as well as with PSMCs as effector cells. Investigation of the alpha 17-1A-alpha CD3 bscAb revealed a significant correlation between the percentage of CD3(+) cells present in the BMMCs and the rate of lysis as well as the absence of detrimental effects on the viability of hematopoietic progenitor cells as determined by colony-forming unit assays (CFUs). Our results indicate that recombinant bispecific single-chain antibodies could be new tools for purging of human bone marrow and peripheral stem cell grafts from contaminating epithelial cancer cells for patients receiving autologous stem cell transplantation after HDC.
Maletz
K
K
Institute for Immunology, Ludwig-Maximilians-Universität Munchen, Munich, Germany.
Kufer
P
P
Mack
M
M
Raum
T
T
Pantel
K
K
Riethmüller
G
G
Gruber
R
R
D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017252:CD3 Complex / Q000276:immunology; D003114:Colony-Forming Units Assay; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000276:immunology / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D013274:Stomach Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D014182:Transplantation, Autologous
D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D018719:Erb-b2 Receptor Tyrosine Kinases; C050928:carcinoma-associated antigen 17-1A