Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct

✍ Scribed by Patrick Hoffmann; Robert Hofmeister; Klaus Brischwein; Christian Brandl; Sandrine Crommer; Ralf Bargou; Christian Itin; Nadja Prang; Patrick A. Baeuerle

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: French
• Weight: 359 KB
• Volume: 115
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.20908

✦ Synopsis

Abstract

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. © 2005 Wiley‐Liss, Inc.