Antibody‐dependent Cellular Cytotoxicity (ADCC)

Abstract Antibody‐dependent cell‐mediated cytotoxicity (ADCC) is the killing of an antibody‐coated target cell by a cytotoxic effector cell through a nonphagocytic process, characterised by the release of the content of cytotoxic granules or by the expression of cell death‐inducing molecules. ADCC is triggered through interaction of target‐bound antibodies (belonging to IgG or IgA or IgE classes) with certain Fc receptors (FcRs), glycoproteins present on the effector cell surface that bind the Fc region of immunoglobulins (Ig). Effector cells that mediate ADCC include natural killer (NK) cells, monocytes, macrophages, neutrophils, eosinophils and dendritic cells. ADCC is a rapid effector mechanism whose efficacy is dependent on a number of parameters (density and stability of the antigen on the surface of the target cell; antibody affinity and FcR‐binding affinity). ADCC involving human IgG1, the most used IgG subclass for therapeutic antibodies, is highly dependent on the glycosylation profile of its Fc portion and on the polymorphism of Fcγ receptors. Key Concepts: Antibodies bound to target cells (virus‐infected or tumour cells) and Fc receptors expressed by cytotoxic cells are the major actors of ADCC. IgG and IgA can trigger ADCC by binding specifically to FcγR and FcαR, respectively. ADCC mechanisms that lead to target cell death vary depending on effector cells that are recruited by antibodies. FcγRIIa and FcγRIIIa polymorphism impact ADCC efficacy by IgG1 antibodies. Engineering FcIgG either by introducing point mutations or by modifying the glycosylation profile allows to optimise IgG1 antibodies for enhanced ADCC. Bispecific antibodies that bind activating molecules expressed by cytotoxic cells and tumour cells can mimic classical ADCC.