TUMOR-GROWTH INHIBITION WITH BISPECIFIC ANTIBODY FRAGMENTS IN A SYNGENEIC MOUSE MELANOMA MODEL - THE ROLE OF TARGETED T-CELL CO-STIMULATIONVIACD28

The ability of bispecific antibodies with anti-tumor x anti-CD3 specif icity to mediate the killing of tumor cells by activated T cells has b een demonstrated in many in vitro experiments, Moreover, long-term sur vival of lymphoma-bearing mice has been observed after treatment with such reagents. The therapeutic effect of bispecific antibodies in soli d-tumor models has been less impressive, in particular if fragmented a ntibodies were used to avoid systemic T-cell activation by bispecific constructs binding to Fc-receptor-positive cells, Here we report that bispecific anti tumor x anti-CD3-fragments markedly inhibit intraperit oneal as well as pulmonary tumor growth in mice inoculated with B16 me lanoma cells, resulting in the long-term survival of animals. Therapeu tic success critically depends on the number of recruitable effector c ells at the site of tumor growth. A second bispecific construct trigge ring 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 s howed improved survival after i.v. rechallenge with tumor cells, indic ating that bispecific antibodies are capable of inducing long-lasting protective immunity. (C) 1999 Wiley-Liss, Inc.