In vivo Cytotoxicity of Type I CD20 Antibodies Critically Depends on Fc Receptor ITAM Signaling

Abstract

Antibody-Fc receptor (FcR) interactions play an important role in the mechanism of action of most therapeutic antibodies against cancer. Effector cell activation through FcR triggering may induce tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC). Reciprocally, FcR cross-linking of antibody may lead to the induction of apoptotic signaling in tumor cells. The relative importance of these bisecting pathways to in vivo antibody activity is unknown. To unravel these roles, we developed a novel mouse model with normal FcR expression but in which FcR signaling was inactivated by mutation of the associated γ-chain. Transgenic mice showed similar immune complex binding compared with wild-type mice. In contrast, ADCC of cells expressing frequently used cancer targets, such as CD20, epidermal growth factor receptor, Her2, and gp75, was abrogated. Using the therapeutic CD20 antibodies ofatumumab and rituximab, we show that FcR cross-linking of antibody-antigen immune complexes in the absence of γ-chain signaling is insufficient for their therapeutic activity in vivo. ADCC therefore represents an essential mechanism of action for immunotherapy of lymphoid tumors. Cancer Res; 70(8); 3209-17. ©2010 AACR.

Cutting Edge: FcγRIII (CD16) and FcγRI (CD64) Are Responsible for Anti-Glycoprotein 75 Monoclonal Antibody TA99 Therapy for Experimental Metastatic B16 Melanoma

“…1E), reduced the tumor load in wt mice, but not in FcRg 2/2 mice (Fig. 1B), an effect reliant on the FcRg ITAMs, as described previously (13). Notably, the quantification of B16-luc2 + metastases using bioluminescence therefore reproduces data from previous studies using metastasis counts by eye (1, 6, 7), and may thus be applied to analyze the contribution of specific FcgRs to the mAb therapy of metastatic melanoma.…”

Characterization and Immunotherapeutic Implications for a Novel Antibody Targeting Interleukin (IL)-13 Receptor α2

“…Several antibodies have been shown to mediate a cytotoxic effect in tumors through Fc-mediated activation of complement (39). Antibody-dependent cell-mediated cytotoxicity-induced activation of effector cells can also contribute to the cytotoxic effect of antibodies against targeted cells (40,41). Anti-IL13R␣2 derived from the sera of animals challenged with D5 melanoma cells expressing human IL13R␣2 demonstrates the ability to inhibit cellular growth in vitro (4).…”

Recombinant Dimeric IgA Antibodies against the Epidermal Growth Factor Receptor Mediate Effective Tumor Cell Killing

“…In addition to direct effector mechanisms such as blockade of growth factor-induced signaling and induction of growth inhibition or apoptosis (37), ADCC is increasingly recognized as an important mechanism of action for therapeutic cancer Abs (38). For example, tumor-directed Abs lost their therapeutic efficacy in animals with disrupted FcgR signaling (39). Because human IgG1 has been demonstrated to optimally recruit NK cells as effector cells for ADCC (17), this isotype has been chosen for most cancer Abs.…”