The many faces of FcγRI: implications for therapeutic antibody function

Abstract

Fcγ receptor I (FcγRI or CD64) is the sole human Fc receptor with high affinity for monovalent IgG. While it contains an immunoreceptor tyrosine-based activation motif in its cytoplasmic domain, binding of FcγRI can result in a complex array of activating and inhibitory outcomes. For instance, binding of monomeric IgG provides a low-intensity tonic signal through FcγRI that is necessary for full interferon γ receptor signaling in the same cell. Interaction of FcγRI with larger high-avidity complexes can result in phagocytosis, the generation of reactive oxygen species, as well as the synthesis and release of inflammatory cytokines. However, numerous reports also document potent anti-inflammatory effects brought about by FcγRI engagement with immune complexes such as the inhibition of IFNγ and TLR4 signaling, and secretion of interleukin-10. This has led to conflicting hypotheses regarding the function of FcγRI, especially with regard to its role in the efficacy of several therapeutic monoclonal antibodies. While many of these issues are still unclear, continued characterization of the regulation and context dependence of FcγRI function, as well as the molecular mechanisms responsible for these various outcomes, will improve our understanding of FcγRI biology as well as the therapeutic strategies designed to harness or constrain its actions.

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

“…It is likely that both mechanisms were, at least to some extent, involved in mediating toxicity in these patients. Evidence supporting the latter assertion comes from recent work describing contributions of stimulation-induced FcγR signaling to the induction of pro-inflammatory cytokines 168, 169 , in addition to the suggested role of pro-inflammatory M1 macrophages in mediating immunotherapy-associated toxicity 170 .…”

“…1F), represents another source of FcR-mediated inputs 184 . ITAMi signaling after FcγRI (an activating receptor) binding by immune complexes has been shown, for example, to attenuate IFN-γ signaling and induce the secretion of immunosuppressive IL-10 169 . The size of immune complexes seems to be an important factor in determining whether FcR signaling generates a pro- or anti-inflammatory response 168 , with larger complexes generally triggering pro-inflammatory cytokine activity (Fig.…”

Gene-modified NK-92MI cells expressing a chimeric CD16-BB-ζ or CD64-BB-ζ receptor exhibit enhanced cancer-killing ability in combination with therapeutic antibody

“…Some effector cells, such as neutrophils and macrophages, can express FcγRI (CD64), which is a high-affinity receptor [16, 20]. Additionally, these effectors may also cause the destruction of tumor cells by ADCP in combination with monoclonal antibodies [39, 40]. CD16 positive immune effector cells, especially for NK cells, constitute the backbone of anti-tumor mechanisms of antibody therapy in vivo [18, 19].…”

The high‐affinity receptor for IgG, FcγRI, of humans and non‐human primates

“…FcRs for IgG, the most abundant antibody class in humans, are known as Fcγ receptors (FcγR). All innate immune cells express at least one type of FcγR and the functional consequences of this expression have been extensively (reviewed in ).…”