Both activating and inhibitory Fc gamma receptors mediate rituximab-induced trogocytosis of CD20 in mice

Antigenic modulation by trogocytosis during anti-CD20 mAb treatment with rituximab (RTX) leads to loss of CD20 and therefore can compromise therapy. During trogocytosis, effector cells, such as macrophages, remove CD20 from the surface of antibody-coated cells in an Fc receptor-dependent manner. Importantly, Fc gamma receptors (Fc gamma Rs) are also crucial in the anti-tumor effects of RTX by inducing antibody dependent cell-mediated cytotoxicity (ADCC). Here we studied the role of Fc gamma R during RTX-induced trogocytosis of CD20 in an intraperitoneal tumor model with EL4-CD20 cells. We found marked RTX-induced trogocytosis of CD20 in Fc gamma RI- or Fc gamma RIII-deficient mice, similar to wild type mice, demonstrating a redundancy for activating Fc gamma R in trogocytosis. Interestingly, in FcR gamma-chain-deficient mice, trogocytosis was still apparent, indicating that the inhibitory receptor Fc gamma RIIB alone can also mediate trogocytosis. These data were confirmed by in vitro analysis with blocking antibodies. Decreasing the amount of RTX in vivo resulted in less trogocytosis of CD20, supporting clinical studies with lower RTX dose. Importantly, we show that cells which undergo in vivo trogocytosis can still be killed ex vivo by ADCC but not by complement-mediated cytotoxicity (CDC), underscoring the clinical relevance of trogocytosis. Taken together, our study provides more insights into the mechanism and consequences of RTX-induced trogocytosis of CD20. (C) 2012 Elsevier B.V. All rights reserved.