Antibody‐dependent Cellular Cytotoxicity (ADCC)

Jean‐Luc Teillaud, Université Paris‐Descartes et Université Pierre et Marie Curie, Paris, France

Published online: July 2012

DOI: 10.1002/9780470015902.a0000498.pub2

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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 References
    Abes R, Dutertre CA, Agnelli L and Teillaud JL (2009) Activating and inhibitory Fcgamma receptors in immunotherapy: being the actor or being the target. Expert Review of Clinical Immunology 5: 735–747.
    Alsmadi O and Tilley SA (1998) Antibody‐dependent cellular cytotoxicity directed against cells expressing human immunodeficiency virus type 1 enveloppe of primary or laboratory‐adapted strains by human and chimpanzee monoclonal antibodies of different epitope specificities. Journal of Virology 72: 286–293.
    Béliard R, Waegemans T, Notelet D et al. (2008) A human anti‐D monoclonal antibody selected for enhanced FcgammaRIII engagement clears RhD+ autologous red cells in human volunteers as efficiently as polyclonal anti‐D antibodies. British Journal of Haematology 141: 109–119.
    Billadeau DD and Leibson PJ (2002) ITAMs versus ITIMs: striking a balance during cell regulation. Journal of Clinical Investigation 109: 161–168.
    Bruhns P, Iannascoli B, England P et al. (2009) Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood 113: 3716–3725.
    Cartron G, Dacheux L, Salles G et al. (2002) Therapeutic activity of humanized ant‐CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99: 754–758.
    Clynes RA, Towers TL, Presta LG and Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nature Medicine 6: 443–446.
    Dechant M, Beyer T, Schneider‐Merck T et al. (2007) Effector mechanisms of recombinant IgA antibodies against epidermal growth factor receptor. Journal of Immunology 179: 2936–2943.
    Dombrowicz D, Quatannens B, Papin JP, Capron A and Capron M (2000) Expression of a functional Fc epsilon RI on rat eosinophils and macrophages. Journal of Immunology 165: 1266–1271.
    Dutertre CA, Bonnin‐Gélizé E, Pulford K et al. (2008) A novel subset of NK cells expressing high levels of inhibitory FcgammaRIIB modulating antibody‐dependent functions. Journal of Leukocyte Biology 84: 1511–1520.
    van Egmond M, Damen CA, van Spriel AB et al. (2001a) IgA and the IgA Fc receptor. Trends in Immunology 22: 205–211.
    van Egmond M, van Spriel AB, Vermeulen H et al. (2001b) Enhancement of polymorphonuclear cell‐mediated tumor cell killing on simultaneous engagement of FcγRI (CD64) and FcαRI (CD89). Cancer Research 61: 4055–4060.
    Fanger MW, Shen L, Graziano RF and Guyre PM (1989) Cytotoxicity mediated by human Fc receptors for IgG. Immunology Today 10: 92–99.
    Forthal DN, Landucci G, Haubrich R et al. (1999) Antibody‐dependent cellular cytotoxicity independently predicts survival in severely immunocompromised human immunodeficiency virus‐infected patients. Journal of Infectious Diseases 180: 1338–1341.
    Golay J, Manganini M, Facchinetti V et al. (2003) Rituximab‐mediated antibody‐dependent cellular cytotoxicity against neoplastic B cells is stimulated strongly by interleukin‐2. Haematologica 88: 1002–1012.
    Graziano RF, Erbe DV and Fanger MW (1989) The mechanisms of antibody‐dependent killing mediated by lymphoid and myeloid cells are distinct based on different divalent cation requirements. Journal of Immunology 143: 3894–3900.
    Herlyn D and Koprowski H (1982) IgG2a monoclonal antibodies inhibit human tumor growth through interaction with effector cells. Proceedings of the National Academy of Sciences of the USA 79: 4761–4765.
    Hessell AJ, Hangartner L, Hunter M et al. (2007) Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449: 101–104.
    Hubert P, Heitzmann A, Veil S et al. (2011) Antibody‐dependent cell cytotoxicity synapses form in mice during tumor‐specific antibody immunotherapy. Cancer Research 71: 5134–5143.
    Karagiannis SN, Bracher MG, Hunt J et al. (2007) IgE‐antibody‐dependent immunotherapy of solid tumors: cytotoxic and phagocytic mechanisms of eradication of ovarian cancer cells. Journal of Immunology 179: 2832–2843.
    Kinet JP and Launay P (2000) Fc alpha/microR: single member or first born in the family? Nature Immunology 1: 371–372.
    Ménager MM, Ménasché G, Romao M et al. (2007) Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13‐4. Nature Immunology 8: 257–267.
    Metes D, Galatiuc C, Moldovan I et al. (1994) Expression and function of Fc gamma RII on human natural killer cells. Nature Immunology 13: 289–300.
    Michon J, Moutel S, Barbet J et al. (1995) In vitro killing of neuroblastoma cells by neutrophils derived from granulocyte colony‐stimulating factor‐treated cancer patients using an anti‐disialoganglioside/anti‐Fc gamma RI bispecific antibody. Blood 86: 1124–1130.
    Moldt B, Schultz N, Dunlop DC et al. (2011) A panel of IgG1 b12 variants with selectively diminished or enhanced affinity for Fc(gamma) receptors to define the role of effector functions in protection against HIV. Journal of Virology 85: 10572–10581.
    Moller E (1967) Cytotoxicity by nonimmune allogeneic lymphoid cells. Specific suppression by antibody treatment of the lymphoid cells. Journal of Experimental Medicine 126: 395–405.
    Musolino A, Naldi N, Bortesi B et al. (2008) Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab‐based therapy in patients with HER‐2/neu‐positive metastatic breast cancer. Journal of Clinical Oncology 26: 1789–1796.
    Nimmerjahn F and Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nature Reviews Immunology 8: 34–47.
    Nimmerjahn F, Lux A, Albert H et al. (2010) FcgammaRIV deletion reveals its central role for IgG2a and IgG2b activity in vivo. Proceedings of the National Academy of Sciences of the USA 9: 19396–19401.
    Niwa R, Shoji‐Hosaka E, Sakurada M et al. (2004) Defucosylated chimeric anti‐C‐C chemokine receptor 4 IgG1 with enhanced antibody‐dependent cellular cytotoxicity shows potent therapeutic activity to T‐cell leukemia and lymphoma. Cancer Research 64: 2127–2133.
    Orange JS (2007) The lytic NK cell immunological synapse and sequential steps in its formation. Advances in Experimental Medicine and Biology 601: 225–233.
    Perussia B (2000) Signaling for cytotoxicity. Nature Immunology 1: 372–374.
    van der Poel CE, Spaapen RM, van de Winkel JG and Leusen JH (2011) Functional characteristics of the high affinity IgG receptor, FcγRI. Journal of Immunology 186: 2699–2704.
    Ravetch JV and Bolland S (2001) IgG Fc receptors. Annual Review of Immunology 19: 275–290.
    Ravetch JV and Lanier LL (2000) Immune inhibitory receptors. Science 290: 84–89.
    Repp R, Valerius T, Wieland G et al. (1995) G‐CSF‐stimulated PMN in immunotherapy of breast cancer with a bispecific antibody to Fc gamma RI and to HER‐2/neu (MDX‐210). Journal of Hematotherapy 4: 415–421.
    Robak T (2009) GA‐101, a third‐generation, humanized and glyco‐engineered anti‐CD20 mAb for the treatment of B‐cell lymphoid malignancies. Current Opinion in Investigational Drugs 10: 588–596.
    Roberti MP, Barrio MM, Bravo AI et al. (2011) IL‐15 and IL‐2 increase cetuximab‐mediated cellular cytotoxicity against triple negative breast cancer cell lines expressing EGFR. Breast Cancer Research Treatment 130: 465–475.
    Roberts RL, Ank BJ, Fanger MW, Shen L and Stiehm ER (1993) Role of oxygen intermediates in cytotoxicity: studies in chronic granulomatous disease. Inflammation 17: 77–92.
    de Saint Basile G, Ménasché G and Fischer A (2010) Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nature Reviews Immunology 10: 568–579.
    Schmitz M, Zhao S, Schakel K et al. (2002) Native human blood dendritic cells as potent effectors in antibody‐dependent cellular cytotoxicity. Blood 100: 1502–1504.
    Shields RL, Lai J, Keck R et al. (2002) Lack of fucose on human IgG1 N‐linked oligosaccharide improves binding to human Fcgamma RIII and antibody‐dependent cellular toxicity. Journal of Biological Chemistry 277: 26733–26740.
    Shields RL, Namenuk AK, Hong K et al. (2001) High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. Journal of Biological Chemistry 276: 6591–6604.
    Shinkawa T, Nakamura K, Yamane N et al. (2003) The absence of fucose but not the presence of galactose or bisecting N‐acetylglucosamine of human IgG1 complex‐type oligosaccharides shows the critical role of enhancing antibody‐dependent cellular cytotoxicicty. Journal of Biological Chemistry 278: 3466–3473.
    Sibéril S, de Romeuf C, Bihoreau N et al. (2006) Selection of a human anti‐RhD monoclonal antibody for therapeutic use: impact of IgG glycosylation on activating and inhibitory Fc gamma R functions. Clinical Immunology 118: 170–179.
    Stavenhagen JB, Gorlatov S, Tuaillon N et al. (2007) Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low‐affinity activating Fcgamma receptors. Cancer Research 67: 8882–8890.
    Sulica A, Morel P, Metes D and Herberman RB (2001) Ig‐binding receptors on human NK cells as effector and regulatory surface molecules. International Reviews of Immunology 20: 371–414.
    Tudor D and Bomsel M (2011) The broadly neutralizing HIV‐1 IgG 2F5 elicits gp41‐specific antibody‐dependent cell cytotoxicity in a FcgammaRI‐dependent manner. AIDS 25: 751–759.
    Valerius T, Repp R, de Wit TP et al. (1993) Involvement of the high‐affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony‐stimulating factor therapy. Blood 82: 931–939.
    Weng WK and Levy R (2003) Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. Journal of Clinical Oncology 21: 3940–3947.
    Zhang W, Gordon M, Schultheis AM et al. (2007) FCGR2A and FCGR3A polymorphism associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single‐agent cetuximab. Journal of Clinical Oncology 25: 3712–3718.
 Further Reading
    Alderson KL and Sondel PM (2011) Clinical cancer therapy by NK cells via antibody‐dependent cell‐mediated cytotoxicity. Journal of Biomedicine and Biotechnology 2011: 379123.
    Boruchov AM, Heller G, Veri MC et al. (2005) Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions. Journal of Clinical Investigation 115: 2914–2923.
    Colucci F, Di Santo JP and Leibson PJ (2002) Natural killer cell activation in mice and men: different triggers for similar weapons? Nature Immunology 3: 807–813.
    Gutenkunst RN, Coombs D, Starr T, Dustin ML and Goldstein B (2011) A biophysical model of cell adhesion mediated by immunoadhesin drugs and antibodies. PLoS One 6: e19701.
    Lanier LL (2005) NK cell recognition. Annual Review of Immunology 23: 225–274.
    Perussia B (1998) Fc receptors on natural killer cells. Current Topics in Microbiology and Immunology 230: 63–88.
    Pleass RJ and Woof JM (2001) Fc receptors and immunity to parasites. Trends in Parasitology 17: 545–551.
    Takai T (2005) Fc receptors and their role in immune regulation and autoimmunity. Journal of Clinical Immunology 25: 1–18.
    Weiner LM, Surana R and Wang S (2010) Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nature Reviews Immunology 10: 317–327.

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Cells of the Immune System | Antibodies
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Article Title: Antibody‐dependent Cellular Cytotoxicity (ADCC)
 
How to Cite close
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]