Wolfgang Strittmatter

Induction of cellular immunity by anti-idiotypic antibodies mimicking GD2 ganglioside

Abstract. Gangliosides are potentially useful targets for tumor destruction by antibodies. However, the role of gangliosides in T cell-mediated immunity to tumors is unclear. We produced three murine monoclonal anti-idiotypic antibodies (Ab2) against a monoclonal antibody (Ab1) that binds strongly to melanoma-associated GD2 ganglioside and weakly to GD3 ganglioside. All three Ab2 induced anti-anti-idiotypic antibodies (Ab3) with Ab1-like binding specificity to tumor cells and antigen in rabbits. The Ab3 specifically bound to GD2+ tumor cells and isolated GD2, and shared idiotopes with the Ab1. Two of the three Ab2 induced GD2-specific delayed-type hypersensitivity responses in BALB/c and C57BL/6 mice, but not in C57BL/6/CD4–/– mice. Peripheral blood mononuclear cells (PBMC) from a melanoma patient proliferated specifically in response to in vitro stimulation with Ab2. Proliferation was accompanied by Th1-type cytokine production. Our studies demonstrate the induction of ganglioside-specific T cell-dependent immunity by Ab2 in mice. These T cells showed specific reactivity to ganglioside expressed by tumor cells.

Induction of tumour cell lysis by a bispecific antibody recognising epidermal growth factor receptor (EGFR) and CD3

A bispecific antibody construct (bAb) recognising CD3 and epidermal growth factor receptor (EGFR) was studied in vitro. Human peripheral blood lymphocytes (PBL), pre-activated with monoclonal antibody OKT-3 or with irradiated tumour cells, were armed with the bAb construct and targeted to autologous and allogeneic tumour target cells in culture. bAb EGFR x CD3 promoted significant cytolysis even at a concentration of 1 ng/ml. The specificity of target cell lysis was provided by the EGFR specificity of the bAb, as tumour cells negative for EGFR were not lysed. However, not only EGFR-positive tumour cells but also EGFR-positive normal cells were killed. Human renal cancer cell lines and the normal autologous kidney cell cultures expressing the same level of EGFR molecules were lysed to a similar extent. These results may contribute toward the planning of future clinical trials with such bAb.