Low affinity immunoglobulin gamma Fc region receptor III-A (CD16A) (FCGR3A)

Low affinity immunoglobulin gamma Fc region receptor III-A (CD16A) is a critical activating receptor expressed on the surface of natural killer (NK) cells and certain macrophage populations [1, 2, 4]. As a member of the immunoglobulin superfamily, it specializes in recognizing and binding the fragment crystallizable (Fc) region of IgG antibodies, particularly the IgG1 and IgG3 subclasses [10, 12]. This binding event is the fundamental trigger for antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are vital processes for the elimination of tumor cells and virally infected host cells [4, 7, 17]. The therapeutic efficacy of numerous blockbuster monoclonal antibodies, including rituximab, trastuzumab, and cetuximab, is largely dependent on their ability to engage CD16A and recruit these effector cells [11, 12]. Genetic polymorphisms in the FCGR3A gene, most notably the V158F (rs396991) variant, significantly alter the receptor's binding affinity and serve as important biomarkers for predicting clinical response to antibody-based immunotherapies [6, 13, 20]. Recent pharmacological strategies include the development of Fc-optimized antibodies like margetuximab and bispecific innate cell engagers (ICEs) such as acimtamig, which are designed to enhance CD16A-mediated immune responses [9, 23]. However, the receptor's activity is regulated by proteolytic shedding via ADAM17, a process that can limit therapeutic efficacy but may also be necessary for the efficient detachment and serial killing capabilities of NK cells [17, 23].

Other names

CD16ACD16Fc-gamma RIIIaFcGRIIIAFCG3FCGR3IGFR3CD16-II

CD16A mediates antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) by binding to the Fc region of IgG antibodies, which activates intracellular signaling cascades leading to the release of cytotoxic granules and inflammatory cytokines [1, 2, 4, 11, 17].