Lymphokine-activated killer cells targeted by monoclonal antibodies to the disialogangliosides GD2 and GD3 specifically lyse human tumor cells of neuroectodermal origin.
Monoclonal antibodies 14.18 (IgG3) and 11C64 (IgG3) directed against disialogangliosides GD2 and GD3, respectively, when used in conjunction with human peripheral blood mononuclear cells (PBMCs) stimulated with human recombinant interleukin (rIL-2) lyse both human melanoma and neuroblastoma cells by antibody-dependent cellular cytotoxicity. Such monoclonal antibody-"armed" effector cells are specifically directed to targets expressing the given disialoganglioside without detectable cross-reactivity. In addition, antibody-dependent cellular cytotoxicity as well as the natural killing ability of human PBMCs is augmented by a brief coincubation with rIL-2. PBMCs augmented by rIL-2 and armed with monoclonal antibodies significantly suppressed tumor growth in the xenotransplant nude mouse model. Our results suggest that once a threshold level of activation of PBMCs is achieved, additional rIL-2 (over three orders of magnitude of concentration) does not significantly enhance cytolytic augmentation. Furthermore, anti-GD3 monoclonal antibody 11C64 together with rIL-2-stimulated PBMCs from melanoma patients with widely differing tumor burdens effectively lyse melanoma tumor targets in antibody-dependent cellular cytotoxicity. Our results also suggest that GD2 and GD3 represent distinct and relevant immunotherapeutic target structures on melanoma whereas GD2 does the same for neuroblastoma tumors. Our data suggest that targeting of activated human effector cells may provide a new and effective cancer immunotherapy protocol.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D002460:Cell Line; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2; D007694:Killer Cells, Natural / Q000276:immunology*; D008222:Lymphokines / Q000494:pharmacology*; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009447:Neuroblastoma / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D005732:Gangliosides; D007376:Interleukin-2; D008222:Lymphokines; D011994:Recombinant Proteins