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) receptors provide a target for antibody-mediated tumor therapy. We evaluate here the therapeutic potential of a mouse/human chimeric anti-(EGF receptor) antibody and compare it to the parental murine antibody in a xenograft model for metastatic melanoma. Our model is based on the human cell line M24met, which overexpresses the EGF receptor and metastasizes spontaneously in SCID mice. Both the chimeric anti-(EGF receptor) antibody (ch225) and the mouse monoclonal antibody (m225) exhibited saturable, high-affinity binding to M24met cells and were equivalent in their ability to target M24met tumors in mice. Neither anti-(EGF receptor) antibodies nor EGF modulated the growth of M24met cells in vitro. Further analysis revealed that the EGF receptor on these cells is not phosphorylated upon EGF binding, indicating an anomalous receptor on these cells. In antibody-dependent cellular cytotoxicity experiments, ch225 and m225 were potent mediators of M24met cytolysis by effector cells. Antibody-mediated cytotoxicity revealed a marked species preference, with ch225 activating human peripheral blood mononuclear cells and m225 activating mouse splenocytes and to a lesser degree mouse macrophages. Neither antibody mediated cytolysis in the presence of human complement. In SCID mice, m225 suppressed spontaneous metastasis considerably while ch225 had only a modest effect. Our data indicate that in the M24met melanoma tumor model, anti-(EGF receptor) antibodies suppress spontaneous metastasis solely by activating immune effector cells.
Naramura
M
M
Scripps Research Institute, La Jolla, CA 92037.
Gillies
S D
SD
Mendelsohn
J
J
Reisfeld
R A
RA
Mueller
B M
BM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000378:metabolism / Q000627:therapeutic use*; D003601:Cytotoxicity Tests, Immunologic; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008545:Melanoma / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D011233:Precipitin Tests; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D007457:Iodine Radioisotopes; D066246:ErbB Receptors