Combinations of the cytokines IL-12, IL-2 and IFN-alpha significantly augment whereas the cytokine IL-4 suppresses the cytokine-induced antibody-dependent cellular cytotoxicity of monoclonal antibodies 17-1A and BR55-2

Since some cytokines effectively enhance the cytotoxicity of monoclonal ant ibodies, we investigated whether a combination of cytokines can augment the antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies 1 7-1A and BR55-2 against the colorectal carcinoma cell line HT29, Since mono cytes/macrophages are important effector cells for ADCC, we used a new flow cytometric cytotoxicity assay, which allows the analysis of long-term-ADCC exerted by these cells. In our previous studies with peripheral blood mono nuclear cells from normal donors, we found that IL-2, IL-12 and IFN-alpha i ncrease ADCC, Therefore, we examined whether combination of these three cyt okines with IL-2, IL-4, IL-6, IL-10, IL12, IFN-alpha, IFN-gamma, GM-CSF, M- CSF and TNF-alpha may yield higher ADCC than obtained by the application of single cytokines. Indeed, we found that the combinations IL-2/IFN-alpha, I L-2/IL-12 and IL-12/IFN-alpha potentiated ADCC. Interestingly, the ineffect ive single cytokines TNF-alpha and CM-CSF in the combinations IL-2/TNF-alph a, IFN-alpha/TNF-alpha and IFN-alpha/GM-CSF also proved to enhance ADCC. In contrast, IL-4 significantly suppressed the IL-2, IL-12 and IFN-alpha-indu ced ADCC, In addition, the immunosuppressive cytokine IL-10 in higher conce ntrations significantly suppressed the IL-12-induced-ADCC. Our results may be useful to find combinations of cytokines and mAb for the treatment of ca ncer. (C) 2000 Academic Press.