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In this study, we describe the ability of hybrid mouse monoclonal antibody (mAb) to induce monocyte-mediated cytotoxicity towards human IgA1-coated E (HuIgAl-E), and the effect of mAb binding valency on FcγRI-mediated ADCC. All hybrid monospecific (ms) anti-HulgAl and bispecific (bs) anti-HuIgA1/HRP mAb were capable of inducing monocyte-mediated lysis of HuIgAl-E, in spite of differences in mAb densities essential for optimal lysis. The cytotoxicity induced by hybrid mAb which consist of one or more mlgG2a H chains was predominantly mediated via FcγRI, as shown by inhibition studies on monocytes with FcγRI-blocking mAb TB-3 (≈80% inhibition). However, partial inhibition of mtgGl-2a and mlgG2a-2b-induced cytotoxicity (20-50%) was observed by using FcγRll-blocking mAb IV.3 or CIKM5. For hybrid mIgGl-l mAb the opposite was true; the cytotoxicity was predominantly mediated via FcαRlI (70-80%) and less via FcγRl (20-30%). Comparing the hybrid ms anti-HulgA 1 mAb-induced cytotoxicity with the cytotoxicity induced by hybrid bs anti-HuIgAl/HRP mAb of the same isotype, we observed a decrease in cytotoxicity towards HuIgAl-E sensitized with univalently bound bs anti-HuIgAl/HRP mAb. This decrease was only found for FcγRI-mediated ADCC (mlgG2ae2a, mlgGl -2a and mIgG2a-2b). This diminished recognition of univalently bound IgG relative to bivalently bound IgC by FcγRI was also observed with U937 effector cells. In conclusion, this work shows that hybrid mAb are able to induce monocyte-mediated cytotoxicity towards E-HuIgA1 and that there appears to be an effect of Ag-IgG binding valency on FcγRI-mediated cytotoxicity. [ABSTRACT FROM AUTHOR]