Tumor‐growth inhibition with bispecific antibody fragments in a syngeneic mouse melanoma model: The role of targeted T‐cell co‐stimulation via CD28

The ability of bispecific antibodies with anti‐tumor × anti‐CD3 specificity to mediate the killing of tumor cells by activated T cells has been demonstrated in many in vitro experiments. Moreover, long‐term survival of lymphoma‐bearing mice has been observed after treatment with such reagents. The therapeutic effect of bispecific antibodies in solid‐tumor models has been less impressive, in particular if fragmented antibodies were used to avoid systemic T‐cell activation by bispecific constructs binding to Fc‐receptor‐positive cells. Here we report that bispecific anti‐tumor × anti‐CD3‐fragments markedly inhibit intraperitoneal as well as pulmonary tumor growth in mice inoculated with B16 melanoma cells, resulting in the long‐term survival of animals. Therapeutic success critically depends on the number of recruitable effector cells at the site of tumor growth. A second bispecific construct triggering the co‐stimulatory CD28‐molecule on the T‐cell surface increased tumor‐cell killing in vitro and in vivo, despite rather low avidity of this reagent to mouse T cells. Finally, long‐term‐surviving animals showed improved survival after i.v. rechallenge with tumor cells, indicating that bispecific antibodies are capable of inducing long‐lasting protective immunity. Int. J. Cancer 80:138–144, 1999. © 1999 Wiley‐Liss, Inc.