We reported previously on the successful use of
bispecific antibodies in two well characterized
B-cell lymphoma models. These
bispecific antibodies were hybrid-hybridoma
antibodies with dual specificity for the
TcR/CD3 complex and for the
tumor-specific idiotype of the surface
IgM expressed by the
lymphoma cells. Class-matched control
antibodies, either monovalent for CD3, monovalent for idiotype, or bivalent for these surface markers, were always used in parallel with the
bispecific antibodies. We extended our studies to determine the relative contribution of antibody-dependent cellular cytotoxicity and a T-cell-mediated
therapeutic effect in the BCL1
lymphoma model. In
tumor-bearing mice depleted of CD4+, CD8+ or both T-cell subsets and treated with
bispecific antibodies, we could show that both T-cell populations contribute to the therapeutic outcome and have an additive role. In vitro studies demonstrate that bridging BCL1
tumor cells to T-cells by
bispecific antibodies induces T-cell activation and secretion of
tumor growth inhibiting
lymphokines by both CD4+ and CD8+ T-cell populations. Particularly
gamma-interferon seems to be the major
tumor-inhibiting substance for BCL1
tumor cells. However, in vivo experiments using anti-
cytokine antibodies showed that both
gamma-interferon and
tumor necrosis factor alpha have an effect on the
tumor growth. The former acts directly by inhibiting
tumor growth, the latter via an indirect mechanism, possibly by activating macrophages. In conclusion, our results show that induction of targeted cytolytic activity by the direct CD3/TcR cross-linking and development of targeted cytotoxic activity, mediated by
gamma-interferon, by both T-cell subsets, contribute to the therapeutic success of bispecific antibody
therapy.