Human K/natural killer cells targeted with hetero-cross-linked antibodies specifically lyse tumor cells in vitro and prevent tumor growth in vivo.
We have induced fresh peripheral blood K/natural killer cells to lyse a variety of target cells by coating them with anti-Fc gamma receptor (anti-Fc gamma R) (CD16) antibody hetero-cross-linked with anti-target cell antibody. The cytotoxic cell mediating this activity is different, as judged by depletion studies, from the CD3+, CD8+ T cell which is targeted by anti-CD3 cross-linked to anti-target cell antibody. Targeted K cell activity from some donors is enhanced by exposure to interleukin 2 but not interferon-gamma; other donors exhibit high amounts of this activity without stimulation. Specificity of lysis mediated by targeted K cells is dictated by the specificity of the anti-target cell antibody within the heteroconjugate, and bystander cells are not lysed by targeted K cells. Hetero-cross-linked antibodies containing anti-histocompatibility leukocyte antigen class I instead of anti-Fc gamma R (CD16) do not promote lysis, suggesting that the bridging of the target cell to Fc gamma R on the K cell is required to activate the lytic process. Lysis mediated by targeted K cells is much less inhibitable by polymerized IgG than is classical antibody-dependent cellular cytotoxicity. Fresh human melanoma cells are lysed specifically by K cells coated with anti-Fc gamma R (CD16) cross-linked to the 96.5 anti-melanoma antibody. In vivo, targeted K cells prevent tumor growth at low effector to target ratios in Winn-type tumor neutralization assays. Targeted K cells may therefore provide a new immunotherapeutic approach for the destruction of detrimental cells, such as tumor and virally infected cells.
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology*; D011961:Receptors, Fc / Q000276:immunology*; D017452:Receptors, IgG; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000906:Antibodies; D000945:Antigens, Differentiation, T-Lymphocyte; D007376:Interleukin-2; D011961:Receptors, Fc; D017452:Receptors, IgG; D007371:Interferon-gamma