BISPECIFIC MOLECULES DIRECTED TO THE FC RECEPTOR FOR IGA (FC-ALPHA-RI, CD89) AND TUMOR-ANTIGENS EFFICIENTLY PROMOTE CELL-MEDIATED CYTOTOXICITY OF TUMOR TARGETS IN WHOLE-BLOOD

The FcR for IgA (F alpha RI, CD89) is primarily expressed on cytotoxic immune effector cells, By chemically cross-linking F(ab') fragments o f the FcR for IgA (Fc alpha RI)-specific mAb (A77) with tumor Ag-speci fic mAb (anti-HER2/neu and anti-epidermal growth factor receptor), we have developed bispecific molecules (BSM) that simultaneously bind to respective tumor Ags and Fc alpha RI-expressing effector cells in whol e blood. These BSM mediated up to 55 % of specific lysis of appropriat e tumor Ag-expressing target cells (from a variety of tumors) with pur ified polymorphonuclear leukocytes, monocytes, or whole blood effector cells without preactivation with exogenous cytokines, To our knowledg e, this is the first demonstration of Ab-dependent cell-mediated cytot oxic activity via Fc alpha RI in whole blood. Also, monocyte-derived m acrophages mediated phagocytosis of HER2/neu-expressing tumor cells (> 95% tumor cell loss). These BSM-mediated cytotoxic activities were com pletely inhibited by F(ab')(2) of A77, demonstrating the specific role of Fc alpha RI as a trigger molecule. Furthermore, the binding of the se BSM;I to monocytes or polymorphonuclear leukocytes in whole blood d id not induce modulation of Fc alpha RI in the absence of the target A g, Therefore, immune effector cells may be ''armed'' with Fc alpha RI- directed BSM in whale blood. These Fc alpha RI-directed BSM may offer new treatment options for various malignancies and other disease condi tions.