Mode of cytotoxic action of T cell-engaging BiTE antibody MT110
| Autor: | Eva Krinner, Patrick Hoffmann, Peter Kufer, Bernd Schlereth, Patrick A. Baeuerle, Klaus Brischwein, Cornelia Haas, Ralf Lutterbüse |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
CD4-Positive T-Lymphocytes
Cytotoxicity Immunologic CD3 Complex T cell Immunology Apoptosis DNA Fragmentation CD8-Positive T-Lymphocytes Collagen Type XI Lymphocyte Activation Granzymes Amino Acid Chloromethyl Ketones Interleukin 21 Antigens Neoplasm Cell Line Tumor Neoplasms medicine Humans Immunology and Allergy Cytotoxic T cell IL-2 receptor Antigen-presenting cell CD40 biology ZAP70 Antibodies Monoclonal Hematology Epithelial Cell Adhesion Molecule Caspase Inhibitors Molecular biology medicine.anatomical_structure biology.protein Interleukin 12 Cell Adhesion Molecules Adenylyl Cyclases Single-Chain Antibodies |
| Zdroj: | Immunobiology. 214:441-453 |
| ISSN: | 0171-2985 |
| DOI: | 10.1016/j.imbio.2008.11.014 |
| Popis: | MT110 is an EpCAM/CD3-bispecific antibody construct in clinical development for the treatment of patients with adenocarcinoma expressing EpCAM (CD326). Like other members of this antibody class, MT110 can engage resting, polyclonal CD8(+) and CD4(+) T cells for highly potent redirected lysis of target cells. Here we further explored the mechanism of this action. Complete lysis of EpCAM(+) Kato III gastric cancer cells by previously unstimulated T cells was achieved within 48 h. During this period, a high percentage of CD4(+) and CD8(+) T cells became activated and increased expression of granzyme B. This apparently boosted the capacity for serial target cell lysis as studied at very low effector-to-target ratios. Elimination of cancer cells by MT110-redirected T cells involved membrane damage as was evident from nuclear uptake of propidium iodide and release of the cytosolic enzyme adenylate kinase. Redirected T cells also potently triggered programmed cell death in cancer cells as was evident by membrane blebbing, activation of procaspases 3 and 7, fragmentation of nuclear DNA and cleavage of the caspase substrate poly (ADP ribose) polymerase. Chelation of extracellular calcium fully protected cancer cells from lysis by MT110-redirected T cells, while the pan-caspase inhibitor Z-VAD-FMK blocked activation of procaspases, cleavage of poly (ADP ribose) polymerase and fragmentation of nuclear DNA in cancer cells, but could not prevent nuclear uptake of propidium iodide. Soluble factors did not significantly contribute to cancer cell death. Our study shows that MT110 can efficiently gear up the potential of CD8(+) and CD4(+) T cells for serial lysis, and mediate kill of cancer cells predominantly through poreforming and pro-apoptotic components of cytotoxic T cell granules. |
| Databáze: | OpenAIRE |
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