ROLE OF T-CELL SUBSETS IN THE BISPECIFIC ANTIBODY (ANTIIDIOTYPE X ANTI-CD3) TREATMENT OF THE BCL(1) LYMPHOMA

We reported previously on the successful use of bispecific antibodies in two well characterized B-cell lymphoma models. These bispecific ant ibodies were hybrid-hybridoma antibodies with dual specificity for the TcR/CD3 complex and for the tumor-specific idiotype of the surface Ig M expressed by the lymphoma cells. Class-matched control antibodies, e ither monovalent for CD3, monovalent for idiotype, or bivalent for the se surface markers, were always used in parallel with the bispecific a ntibodies. We extended our studies to determine the relative contribut ion of antibody-dependent cellular cytotoxicity and a T-cell-mediated therapeutic effect in the BCL(1) lymphoma model. In tumor-bearing mice depleted of CD4+, CD8+ or both T-cell subsets and treated with bispec ific antibodies, we could show that both T-cell populations contribute to the therapeutic outcome and have an additive role. In vitro studie s demonstrate that bridging BCL(1) tumor cells to T-cells by bispecifi c antibodies induces T-cell activation and secretion of tumor growth i nhibiting lymphokines by both CD4+ and CD8+ T-cell populations. Partic ularly gamma-interferon seems to be the major tumor-inhibiting substan ce for BCL(1) tumor cells. However, in vivo experiments using anti-cyt okine antibodies showed that both gamma-interferon and tumor necrosis factor alpha have an effect on the tumor growth. The former acts direc tly by inhibiting tumor growth, the latter via an indirect mechanism, possibly by activating macrophages. In conclusion, our results show th at induction of targeted cytolytic activity by the direct CD3/TcR cros s-linking and development of targeted cytotoxic activity, mediated by gamma-interferon, by both T-cell subsets, contribute to the therapeuti c success of bispecific antibody therapy.