Low-affinity immunoglobulin gamma Fc region receptor III-A (CD16a) (FCGR3A)

Fc gamma receptor IIIa (CD16a) is a cluster of differentiation molecule and a transmembrane glycoprotein primarily expressed on natural killer (NK) cells and macrophages (UniProt: P08637). It functions as a low-affinity activating receptor for the Fc region of immunoglobulin G (IgG), serving as the essential link for antibody-dependent cellular cytotoxicity (ADCC). In oncology, CD16a is the primary receptor through which therapeutic monoclonal antibodies, such as Rituximab and Trastuzumab, engage the innate immune system to eliminate opsonized tumor cells. The clinical efficacy of these treatments is significantly influenced by the FCGR3A V158F genetic polymorphism; the 158V (valine) variant possesses a higher affinity for IgG1 than the 158F (phenylalanine) variant, often leading to superior clinical outcomes (PMID: 10713390). Recent therapeutic strategies involve using donor NK cells or engineering NK cells to express high-affinity CD16a variants to enhance the ADCC response against refractory tumors. Additionally, next-generation antibodies like Margetuximab have been Fc-engineered specifically to increase binding affinity to CD16a, thereby boosting immune effector function (PMID: 31611614).

Other names

CD16aFc gamma receptor IIIaFCGR3FcRIIIaIgG Fc receptor III-2Fc-gamma RIII-alpha

The receptor binds the Fc portion of IgG1 or IgG3 antibodies that have opsonized (coated) tumor cells. This binding clusters the receptors and triggers the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) by Src family kinases. This signaling cascade recruits Syk or ZAP-70 kinases, leading to the release of cytotoxic granules containing perforin and granzymes, which induce apoptosis in the target tumor cell (PMID: 25614319).