THERAPEUTIC POTENTIAL OF CHIMERIC AND MURINE ANTI-(EPIDERMAL GROWTH-FACTOR RECEPTOR) ANTIBODIES IN A METASTASIS MODEL FOR HUMAN-MELANOMA

On many tumors, high numbers of epidermal growth factor (EGF) receptor s provide a target for anti-body-mediated tumor therapy. We evaluate h ere the therapeutic potential of a mouse/human chimeric anti-(EGF rece ptor) antibody and compare it to the parental murine antibody in a xen ograft model for metastatic melanoma. Our model is based on the human cell line M24met, which overexpresses the EGF receptor and metastasize s spontaneously in SCID mice. Both the chimeric anti-(EGF receptor) an tibody (ch225) and the mouse monoclonal antibody (m225) exhibited satu rable, high-affinity binding to M24met cells and were equivalent in th eir ability to target M24met tumors in mice. Neither anti-(EGF recepto r) antibodies nor EGF modulated the growth of M24met cells in vitro. F urther analysis revealed that the EGF receptor on these cells is not p hosphorylated upon EGF binding, indicating an anomalous receptor on th ese cells. In antibody-dependent cellular cytotoxicity experiments, ch 225 and m225 were potent mediators of M24met cytolysis by effector cel ls. Antibody-mediated cytotoxicity revealed a marked species preferenc e, with ch225 activating human peripheral blood mononuclear cells and m225 activating mouse splenocytes and to a lesser degree mouse macroph ages. Neither antibody mediated cytolysis in the presence of human com plement. In SCID mice, m225 suppressed spontaneous metastasis consider ably while ch225 had only a modest effect. Our data indicate that in t he M24met melanoma tumor model, anti-(EGF receptor) antibodies suppres s spontaneous metastasis solely by activating immune effector cells.