Role of T-cell subsets in the bispecific antibody (anti-idiotype x anti-CD3) treatment of the BCL1 lymphoma.
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.
Demanet
C
C
Laboratory of Physiology, Medical School of the Vrije Universiteit Brussel (VUB), Belgium.
Brissinck
J
J
Leo
O
O
Moser
M
M
Thielemans
K
K
D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D008212:Lymphocyte Depletion; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma