Low affinity immunoglobulin gamma Fc receptor IIIa (FcγRIIIa) (158F variant) (FcγRIIIa (158F))

Low affinity immunoglobulin gamma Fc receptor IIIa (FcγRIIIa), also known as CD16a, is a crucial activating receptor expressed on natural killer (NK) cells and macrophages that mediates antibody-dependent cellular cytotoxicity (ADCC) [6, 19]. The 158F variant is a common genetic polymorphism (rs396991) where phenylalanine replaces valine at position 158, resulting in a receptor with significantly lower binding affinity for the Fc region of IgG1 antibodies [1, 9]. This reduced affinity is a major clinical challenge, as approximately 80-85% of the population carries at least one 158F allele, which is associated with diminished responses to standard monoclonal antibodies like trastuzumab and rituximab [4, 12, 15]. To overcome this limitation, Fc-engineered antibodies such as margetuximab have been developed to specifically enhance binding to the 158F variant, thereby restoring or boosting ADCC activity [2, 3]. In addition to its role in cancer immunotherapy, the 158F variant has been implicated in the pathogenesis of autoimmune diseases and the clearance of immune complexes [10, 13]. Understanding a patient's FCGR3A genotype is increasingly important in oncology and rheumatology for predicting drug efficacy and selecting the most appropriate therapeutic agent [10, 17]. This polymorphism serves as a critical biomarker for patient stratification in clinical trials involving Fc-optimized therapeutic antibodies [3, 4].

Other names

CD16aFCGR3ALow affinity immunoglobulin gamma Fc receptor III-AIgG Fc receptor III-ACD16A-158FFc gamma receptor IIIA

Binding of the Fc portion of IgG antibodies to the receptor on immune effector cells (NK cells, macrophages) to trigger antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) [6, 8, 14].