Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets

Inhibitory receptors have been proposed to modulate the in vivo cytotoxic r esponse against tumor targets for both spontaneous and antibody-dependent p athways'. Using a variety of syngenic and xenograft models, we demonstrate here that the inhibitory Fc gamma RIIB molecule is a potent regulator of an tibody-dependent cell-mediated cytotoxicity in vivo, modulating the activit y of Fc gamma RIII on effector cells. Although many mechanisms have been pr oposed to account for the anti-tumor activities of therapeutic antibodies, including extended half-life, blockade of signaling pathways, activation of apoptosis and effector-cell-mediated cytotoxicity, we show here that engag ement of Fc gamma receptors on effector cells is a dominant component of th e in vivo activity of antibodies against tumors. Mouse monoclonal antibodie s, as well as the humanized, clinically effective therapeutic agents trastu zumab (Herceptin(R)) and rituximab (Rituxan(R)), engaged both activation (F c gamma RIII) and inhibitory (Fc gamma RIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential. Mice deficient in Fc gamm a RIIB showed much more antibody-dependent cell-mediated cytotoxicity; in c ontrast, mice deficient in activating Fc receptors as well as antibodies en gineered to disrupt Fc binding to those receptors were unable to arrest tum or growth in vivo. These results demonstrate that Fc-receptor-dependent mec hanisms contribute substantially to the action of cytotoxic antibodies agai nst tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory p artner Fc gamma RIIB.