Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct
| Autor: | Christian Brandl, Klaus Brischwein, Sandrine Crommer, Patrick Hoffmann, Robert Hofmeister, Nadja Prang, Patrick A. Baeuerle, Christian Itin, Ralf C. Bargou |
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| Rok vydání: | 2005 |
| Předmět: |
Cytotoxicity
Immunologic Cancer Research Time Factors CD3 Complex T-Lymphocytes Antigens CD19 Biology Lymphocyte Activation CD19 Interleukin 21 Antigen Cell Line Tumor Neoplasms Antibodies Bispecific Humans Cytotoxic T cell Antigen-presenting cell Immunoglobulin Fragments Cell Nucleus B-Lymphocytes Microscopy Video Lymphokine-activated killer cell CD40 Dose-Response Relationship Drug Cell Membrane Flow Cytometry Virology Molecular biology Kinetics Cell killing Oncology biology.protein Interleukin-2 Immunotherapy T-Lymphocytes Cytotoxic |
| Zdroj: | International Journal of Cancer. 115:98-104 |
| ISSN: | 1097-0215 0020-7136 |
| Popis: | Certain bispecific antibodies exhibit an extraordinary potency and efficacy for target cell lysis by eliciting a polyclonal T-cell response. One example is a CD19-/CD3-bispecific single-chain antibody construct (bscCD19xCD3), which at femtomolar concentrations can redirect cytotoxic T cells to eliminate human B lymphocytes, B lymphoma cell lines and patient-derived malignant B cells. Here we have further explored the basis for this high potency. Using video-assisted microscopy, bscCD19xCD3 was found to alter the motility and activity of T cells from a scanning to a killing mode. Individual T cells could eliminate multiple target cells within a 9 hr time period, resulting in nuclear fragmentation and membrane blebbing of target cells. Complete target cell elimination was observed within 24 hr at effector-to-target cell ratios as low as 1:5. Under optimal conditions, cell killing started within minutes after addition of bscCD19xCD3, suggesting that the rate of serial killing was mostly determined by T-cell movement and target cell scanning and lysis. At all times, T cells remained highly motile, and no clusters of T and target cells were induced by the bispecific antibody. Bystanding target-negative cells were not detectably affected. Repeated target cell lysis by bscCD19xCD3-activated T cells increased the proportion of CD19/CD3 double-positive T cells, which was most likely a consequence of transfer of CD19 from B to T cells during cytolytic synapse formation. To our knowledge, this is the first study showing that a bispecific antibody can sustain multiple rounds of target cell lysis by T cells. |
| Databáze: | OpenAIRE |
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