Specific targeting of cytokine-secreting cells: a bispecific diabody recognizing human interleukin-6 and CD3 induces T cell-mediated killing.
Cytokines have been implicated in the pathophysiology of many diseases. Although there have been many attempts to neutralize the activity of cytokines in vivo and in vitro, no strategies have been developed to specifically eliminate cells that overexpress cytokines. Considering the fact that cytokines in part remain cell associated on secretion, we have constructed a bispecific diabody consisting of a nonneutralizing scFv antibody recognizing human interleukin-6 (IL-6) and an scFv corresponding to the monoclonal antibody (mAb) OKT3, which recognizes and activates the human T cell receptor. Here we show that the diabody recognized both human IL-6 and human CD3. In the presence of human T cells, the diabody induced killing of human hepatoma cells that had been transfected with a human IL-6 cDNA. The extent of killing was dependent on the ratio of effector/target cells and increased with increasing concentrations of the diabody. Untransfected control cells or human hepatoma cells that secrete the IL-6-related cytokine leukemia inhibitory factor (LIF) remained unaffected. We conclude that diabodies recognizing cytokines can be used to specifically target cytokine-secreting cells.
Department of Medicine, Johannes Gutenberg-University of Mainz, Germany.
B
B
Krebs
B
B
Ackermann
S
S
Rose-John
D018033:Antibodies, Bispecific / Q000276:immunology*; D000911:Antibodies, Monoclonal; D000937:Antigen-Antibody Reactions; D017252:CD3 Complex / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell