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.

Keywords: ADCC; cytotoxic granules; effector cells; Fc receptors (FcR); granzyme; ITAM; ITIM; perforin

Figure 1.

Schematic view of human‐activating FcγR. In most cases, human‐activating Fcγ receptors comprise an IgG binding α chain associated with a transducing subunit, a γ chain (γγ) homodimer. In NK cells, the presence of a γ/ζ heterodimer or of a ζ/ζ homodimer has also been reported (the ζ chain is also part of the T cell receptor (TcR) complex). The associated γ or ζ chain contains an ITAM (immuno‐receptor tyrosine‐based activating motif) (black square) that is phosphorylated upon crosslinking of FcγR. Human FcγRIIa is the only activating receptor where the IgG‐binding α chain intracellular domain contains an ITAM, although its association with a transducing γ chain homodimer has been debated. Myeloid cells can express both activating and inhibitory FcγRIIb (not shown in the diagram) and it is considered that cellular activation will result from the fine tuning of the balance between activating and inhibitory signals. NK cells express activating FcγRIIIa, although the expression of activating FcγRIIc and of inhibitory FcγRIIb by small NK cell subsets has also been reported. FcγRIIIa is also expressed by some T cells. FcγRIIIb, a GPI‐linked surface receptor expressed by neutrophils is not presented. In mouse, there is no FcγRIIa and inhibitory FcγRIIb is referred only as FcγRII. In contrast, there is another activating FcγR, termed FcγRIV, also associated with a γ chain homodimer.

Figure 2.

Schematic view of ADCC. The binding of an IgG antitumour mAb to the target cell (here a tumour cell) allows the recruitment and crosslinking of activating FcγR expressed by effector cells (NK cells, neutrophils, etc.). In humans, activating receptors include FcγRI (CD64), FcγRIIa (CD32) and FcγRIIIa (CD16). In mouse, they include FcγRI, FcγRIII and FcγRIV. Effector cells are then activated and release molecules that will lead to the death of tumour cells. The diagram represents a NK cell containing granules that polarised towards the contact zone with tumour cell once FcγRIIIa (CD16) has been engaged and crosslinked. The granule content (perforin and granzyme B) is then released in the close vicinity of the tumour cell (NK cell ‘synapse’), initiating an apoptotic process that will lead to cell death.

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Teillaud, Jean‐Luc(Jul 2012) Antibody‐dependent Cellular Cytotoxicity (ADCC). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000498.pub2]