Cancer and Metastasis Reviews

, Volume 24, Issue 4, pp 487–499 | Cite as

Role of antibody-dependent cell-mediated cytotoxicity in the efficacy of therapeutic anti-cancer monoclonal antibodies

  • Alexandre Iannello
  • Ali Ahmad


In recent years, interest in anti-cancer therapeutic monoclonal antibodies (mAb) has been renewed. Several of these reagents have been approved for therapy in a variety of cancer patients and many others are in different stages of development. It is believed that multiple mechanisms are involved in the anti-cancer effects of these reagents. However, several in vitro and in vivo studies have demonstrated that antibody-dependent cell-mediated cytotoxicity (ADCC) is their predominant mode of action against cancer cells. The requirement for a direct interaction between mAb and receptors for the Fc region of the antibodies (FcR) has been demonstrated for anti-tumor effects of these antibodies. Consequently, FcR-bearing immune effector cells play an important role in mediating their effects. It is not surprising that cancer cells have developed different strategies to evade these antibodies. Several strategies are proposed to potentiate the mAb-mediated ADCC in cancer patients. They may enhance anti-cancer therapeutic effects of these regents.


ADCC cancer CD16 CD32 CD64 CD89 macrophages monoclonal antibodies neutrophils NK cells Fc receptors 



Antibody-dependent cell-mediated cytotoxicity


B cell receptor complex


Complement-dependent cytotoxicity


Complementarity determining region


Type 1 complement receptor


Dendritic cells


Fragment crystallisable


Receptor for Fc


Federal Drug Agency (USA)


Granulocyte-colony stimulating factor


Granulocyte macrophage-colony stimulating factor


Immune complex




Immunoglobuin like transcript-2


Immunoreceptor tyrosinebased activating motif


Immunoreceptor tyrosine-based inhibitory motif


Human Immunodeficiency virus


Monoclonal antibody




Killer-cell immunoglobulin-like receptor



NK cell

Natural killer cell


Red blood cells


Systemic Lupus Erythrematosis


T cell receptor complex


Vascular endothelial growth factor


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kohler G, Milstein C: Continuous cultures of fused cells secretingantibody of predefined specificity. Nature 256: 495–497, 1975PubMedGoogle Scholar
  2. 2.
    2. Houghton AN, Scheinberg DA: Monoclonal antibody therapies-a‘constant’ threat to cancer. Nat Med 6: 373–374, 2000CrossRefPubMedGoogle Scholar
  3. 3.
    Glennie MJ, van de Winkel JG: Renaissance of cancer therapeuticantibodies. Drug Discov Today 8: 503–510, 2003CrossRefPubMedGoogle Scholar
  4. 4.
    Glennie MJ, Johnson PW: Clinical trials of antibody therapy.Immunol Today 21: 403–410, 2000CrossRefPubMedGoogle Scholar
  5. 5.
    Murillo O, Arina A, Tirapu I, Alfaro C, Mazzolini G, Palencia B, Lopez-Diaz DC, Prieto J, Bendandi M, Melero I: Potentiation oftherapeutic immune responses against malignancies with monoclonalantibodies. Clin Cancer Res 9: 5454–5464, 2003PubMedGoogle Scholar
  6. 6.
    Mellstedt H: Monoclonal antibodies in human cancer. Drugs Today(Barc) 39 (Suppl C): 1–16, 2003Google Scholar
  7. 7.
    Trikha M, Yan L, Nakada MT: Monoclonal antibodies as therapeuticsin oncology. Curr Opin Biotechnol 13: 609–614, 2002CrossRefPubMedGoogle Scholar
  8. 8.
    Gelderman KA, Tomlinson S, Ross GD, Gorter A: Complement function in m AB-mediatedcancer immunotherapy. Trends Immunol 25: 158–164.Google Scholar
  9. 9.
    Ahmad A, Menezes J: Antibody-dependent cellular cytotoxicity in HIV infections. FASEB J 10: 258–266, 1996PubMedGoogle Scholar
  10. 10.
    Morel PA, Ernst LK, Metes D: Functional CD32 molecules on human NK cells. Leuk Lymphoma 35: 47–56, 1999PubMedCrossRefGoogle Scholar
  11. 11.
    Ernst LK, Metes D, Herberman RB, Morel PA: Allelic polymorphismsin the Fcgamma RIIC gene can influence its function on normal humannatural killer cells. J Mol Med 80: 248–257, 2002CrossRefPubMedGoogle Scholar
  12. 12.
    Metes D, Gambotto AA, Nellis J, Ruscin A, Stewart-Akers AM, Morel PA, Rao AS: Identification of the CD32/Fcgamma RIIc-Q13/STP13polymorphism using an allele-specific restriction enzyme digestionassay. J Immunol Methods 258: 85–95, 2001CrossRefPubMedGoogle Scholar
  13. 13.
    Boyle JJ: Human macrophages kill human mesangial cells by Fas-L-induced apoptosis when triggered by antibody via CD16. Clin Exp Immunol 137: 529–537, 2004CrossRefPubMedGoogle Scholar
  14. 14.
    Stockmeyer B, Beyer T, Neuhuber W, Repp R, Kalden JR, Valerius T, Herrmann M: Polymorphonuclear granulocytes induceantibody-dependent apoptosis in human breast cancer cells. JImmunol 171: 5124–5129, 2003Google Scholar
  15. 15.
    Otten MA, Rudolph E, Dechant M, Tuk CW, Reijmers RM, Beelen RH, van de Winkel JG, van Egmond M: Immature neutrophils mediate tumorcell killing via Ig A but not Ig G Fc receptors. J Immunol 174:5472–5480, 2005PubMedGoogle Scholar
  16. 16.
    Ljunggren K, Bottiger B, Biberfeld G, Karlson A, Fenyo EM, Jondal M: Antibody-dependentcellular cytotoxicity-inducing antibodies against human immunodeficiencyvirus. Presence at different clinical stages. J Immunol 139: 2263–2267, 1987PubMedGoogle Scholar
  17. 17.
    Ahmad R, Sindhu STAK, Toma E, Morisset R, Vincelette J, Menezes J, Ahmad A: Evidence for a correlation between antibody-dependentcellular cytotoxicity-mediating anti-HIV-1 antibodies andprognostic predictors of HIV infection. J Clin Immunology 21:227–233, 2001Google Scholar
  18. 18.
    Takai T: Fc receptors and their role in immune regulation andautoimmunity. J Clin Immunol 25: 1–18, 2005CrossRefPubMedGoogle Scholar
  19. 19.
    Clynes RA, Towers TL, Presta LG, Ravetch JV: Inhibitory Fcreceptors modulate in vivo cytoxicity against tumor targets. Nat Med 6: 443–446, 2000PubMedGoogle Scholar
  20. 20.
    Clynes R, Takechi Y, Moroi Y, Houghton A, Ravetch JV: Fc receptorsare required in passive and active immunity to melanoma. Proc Natl Acad Sci USA 95: 652–656, 1998CrossRefPubMedGoogle Scholar
  21. 21.
    Nakamura A, Akiyama K, Takai T: Fc receptor targeting in the treatment of allergy, autoimmune diseases and cancer. Expert Opin Ther Targets 9: 169–190, 2005CrossRefPubMedGoogle Scholar
  22. 22.
    Ravetch JV, Bolland S: Ig G Fc receptors. Annu Rev Immunol 19:275–290, 2001CrossRefPubMedGoogle Scholar
  23. 23.
    Sarmay G, Koncz G, Gergely J: Integration of activatory and inhibitory signals inhuman B Cells. Immunol Lett 54: 93–100, 1996CrossRefPubMedGoogle Scholar
  24. 24.
    Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV: Augmented humoraland anaphylactic responses in Fc gamma RII-deficient mice. Nature379: 346–349, 1996CrossRefPubMedGoogle Scholar
  25. 25.
    Takai T, Nakamura A, Akiyama K: Fc receptors as potential targets for the treatmentof allergy, autoimmune disease and cancer. Curr Drug Targets Endocr Metabol Disord 3:187–197, 2003Google Scholar
  26. 26.
    Stefanesco RN, Olferiev M, Liu Y, Pricop L: Inhibitory Fc gamma receptors: fromgene to disease. J Clin Immunol 24: 315-326, 2004Google Scholar
  27. 27.
    Schmidt RE, Gessner JE: Fc receptors and their interaction with complement inautoimmunity. Immunol Lett 100: 56-67, 2005PubMedGoogle Scholar
  28. 28.
    Jiang XM, Arepally G, Poncz M, McKenzie SE: Rapid detection of the Fc gamma RIIA-H/R 131 ligand-binding polymorphism using anallele-specific restriction enzyme digestion (ASRED). J Immunol Methods 199: 55–59, 1996CrossRefPubMedGoogle Scholar
  29. 29.
    Metes D, Ernst LK, Chambers WH, Sulica A, Herberman RB, Morel PA: Expressionof functional CD32 molecules on human NK cells is determined by an allelicpolymorphism of the Fcgamma RIIC gene. Blood 91: 2369–2380, 1998PubMedGoogle Scholar
  30. 30.
    Ernst LK, Metes D, Herbermam RB, Morel PA: Allelic polymorphisms in the Fcgamma RIIC gene can influence its function on normal human natural killer cells. JMol Med 80: 248–257Google Scholar
  31. 31.
    Dhanji S, Tse K, Teh HS: The low affinity Fc receptor for Ig Gfunctions as an effective cytolytic receptor for self-specific CD8T cells. J Immunol 174: 1253–1258, 2005PubMedGoogle Scholar
  32. 32.
    Matsumoto G, Omi Y, Lee U, Nishimura T, Shindo J, Penninger JM: Adhesionmediated by LFA-1 is required foe efficient IL-12-induced NK and NKT cellcytotoxicity. Eur J Immunol 30: 3723–3731, 2000CrossRefPubMedGoogle Scholar
  33. 33.
    Edberg JC, Kimberly RP: Cell type-specific glycoforms of Fc gamma RIIIa (CD16): Differential ligand binding. J Immunol 159:3849–3857, 1997PubMedGoogle Scholar
  34. 34.
    van Egmond M, van Spriel AB, Vermeulen H, Huls G, van Gaederen E, van de Winkel JG: Enhancement of polymorphonuclear cell-mediated tumor killing onsimultaneous engagement of Fcgamma R1 (CD64) and Fcalpha R1 (CD89). Cancer Res61: 4055–4060, 2001PubMedGoogle Scholar
  35. 35.
    Lancer WI, Blumberg RS: A passionate kiss: exocytosis and recycling of Ig G by FcRn. Trends Cell Biol 15: 5–9, 2005Google Scholar
  36. 36.
    Davis RS, Ehrhardt GR, Leu CM, Hirano M, Cooper MD: An extendedfamily of Fc receptor relatives. Eur J Immunol 35: 674–680, 2005CrossRefPubMedGoogle Scholar
  37. 37.
    Li H, Sanchez-Torres J, Del Carpio A, Salas V, Villalobo A: The Erb B2/Neu/HER2 receptor is a new calmodulin-binding protein.Biochem J 381: 257–266, 2004CrossRefPubMedGoogle Scholar
  38. 38.
    Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME, Shepard HM: Humanization of ananti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89: 4285–4289, 1992PubMedGoogle Scholar
  39. 39.
    Carter P: Improving the efficacy of antibody-based cancertherapies. Nat Rev Cancer 1: 118–129, 2001CrossRefPubMedGoogle Scholar
  40. 40.
    Carson WE, Parihar R, Lindemann MJ, Personeni N, Dierksheide J, Meropol NJ, Baselga J, Caligiuri MA: Interleukin-2 enhances thenatural killer cell response to Herceptin-coated Her2/neu-positivebreast cancer cells. Eur J Immunol 31: 3016–3025, 2001CrossRefPubMedGoogle Scholar
  41. 41.
    Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA: Nonclinical studies addressing the mechanism of action oftrastuzumab (Herceptin). Semin Oncol 26: 60–70, 1999PubMedGoogle Scholar
  42. 42.
    Funakoshi S, Longo DL, Murphy WJ: Differential in vitro and in vivo anti-tumoreffects mediated by anti-CD40 and anti-CD20 monoclonal antibodies against human Bcell lymphomas. J Immunother Emphasis Tumor Immunol 19: 93–101, 1996PubMedGoogle Scholar
  43. 43.
    Dyall R, Vasovie LV, Clynes RA, Nikolic-Zugic: Cellular requirements for themonoclonal antibody-mediated eradication of an established solid tumor. Eur J Immunol29: 30–37, 1999CrossRefPubMedGoogle Scholar
  44. 44.
    Hampton T: Monoclonal antibody therapies shine in breast cancer clinical trials.JAMA 293: 2985–2989Google Scholar
  45. 45.
    Stockmeyer B, Valerius T, Repp R, Heijnen IA, Buhring HJ, Deo YM, Kalden JR, Gramatzki M, van de Winkel JG: Preclinical studies with Fc(gamma)R bispecificantibodies and granulocyte colony-stimulating factor-primed neutrophils as effector cellsagainst HER-2/neu overexpressing breast cancer. Cancer Res 57: 696–701, 1997PubMedGoogle Scholar
  46. 46.
    Shahied LS, Tang Y, Alpaugh RK, Somer R, Greenspon D, Weiner LM:Bispecific minibodies targeting HER2/neu and CD16 exhibit improvedtumor lysis when placed in a divalent tumor antigen bindingformat. J Biol Chem 279: 53907–53914, 2004CrossRefPubMedGoogle Scholar
  47. 47.
    Keefe DL: Trastuzumab-associated cardiotoxicity. Cancer 95:1592–1600, 2002CrossRefPubMedGoogle Scholar
  48. 48.
    Golay J, Manganini M, Facchinetti Y, Gramigna R, Broady R, Borleri G, Rambaldi A, Introna M: Rituximab-mediated antibody-dependent cellular cytotoxicity againstneoplastic B cells is stimulated strongly by interleukin-2. Haematologica 88: 1002–1112, 2003PubMedGoogle Scholar
  49. 49.
    Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H: Therapeutic activity of humanized anti-CD20monoclonal antibody and polymorphism in Ig G Fc receptor Fcgamma RIIIa gene. Blood 99: 754–758, 2002CrossRefPubMedGoogle Scholar
  50. 50.
    Liljefors M, Nilsson B, Hjelm Skog AL, Ragnhammar P, Mellstedt H, Frodin JE: Natural killer (NK) cell function is a strongprognostic factor in colorectal carcinoma patients treated withthe monoclonal antibody 17-1A. Int J Cancer 105: 717–723, 2003CrossRefPubMedGoogle Scholar
  51. 51.
    Sondel PM, Hank JA: Antibody-directed, effector cell-mediatedtumor destruction. Hematol Oncol Clin North Am 15: 703–721, 2001CrossRefPubMedGoogle Scholar
  52. 52.
    Weiner LM, Adams GP: New approaches to antibody therapy. Oncogene 19: 6144–6151, 2000CrossRefPubMedGoogle Scholar
  53. 53.
    van Spriel AB, van Ojik HH, Bakker A, Jansen MJ, van de Winkel JG: Mac-1(CD11b/CD18) is crucial for effective Fc receptor-mediated immunity to melanoma.Blood 101: 253–258, 2003PubMedGoogle Scholar
  54. 54.
    Zhang Z, Zhang M, Goldman CK, Ravetch JV, Waldmann TA: Effectivetherapy for a murine model of adult T-cell leukemia with thehumanized anti-CD52 monoclonal antibody, Campath-1H. Cancer Res63: 6453–6457, 2003PubMedGoogle Scholar
  55. 55.
    Fan Z, Masui H, Altas I, Mendelsohn J: Blockade of epidermalgrowth factor receptor function by bivalent and monovalentfragments of 225 anti-epidermal growth factor receptor monoclonalantibodies. Cancer Res 53: 4322–4328, 1993PubMedGoogle Scholar
  56. 56.
    Demanet C, Mulder A, Deneys V, Worsham MJ, Maes P, Claas FH, Ferrone S: Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTLand NK attack? Blood 103: 3122–3130, 2004CrossRefPubMedGoogle Scholar
  57. 57.
    Ahmad A, Ahmad R: HIV's evasion of NK cell response, and novelways of its countering and boosting anti-HIV immunity. Curren HIVResearch 1: 295–307, 2003Google Scholar
  58. 58.
    Farag SS, Fehniger TA, Ruggeri L, Velardi A, Caligiuri MA: Naturalkiller cell receptors: New biology and insights into the graft-versus-leukemia effect. Blood 100: 1935–1947, 2002CrossRefPubMedGoogle Scholar
  59. 59.
    Koh CY, Blazar BR, George T, Welniak LA, Capitini CM, Raziuddin A, Murphy WJ, Bennett M: Augmentation of antitumor effects by NK cellinhibitory receptor blockade in vitro and in vivo. Blood 97:3132–3137, 2001CrossRefPubMedGoogle Scholar
  60. 60.
    Lefebvre S, Antoine M, Uzan S, McMaster M, Dausset J, Carosella ED, Paul P: Specific activation of the non-classical class Ihistocompatibility HLA-G antigen and expression of the ILT2inhibitory receptor in human breast cancer. J Pathol 196:266–274, 2002CrossRefPubMedGoogle Scholar
  61. 61.
    Papamichail M, Perez SA, Gritzapis AD, Baxevanis CN: Natural killer lymphocyte:biology, development, and function. Cancer Immunol Immunother 53: 176–186, 2003PubMedGoogle Scholar
  62. 62.
    Biassoni R, Cantoni C, Pende D, Sivori S, Parolini S, Vitale M, Bottino C, Moretta A: Human natural killer cell receptors andco-receptors. Immunol Rev 181: 203–214, 2001CrossRefPubMedGoogle Scholar
  63. 63.
    Dorling A, Monk NJ, Lechler RI: HLA-G inhibits thetransendothelial migration of human NK cells. Eur J Immunol 30:586–593, 2000CrossRefPubMedGoogle Scholar
  64. 64.
    Kono K, Takahashi A, Ichihara F, Sugai H, Fujii H, Matsumoto Y:Impaired antibody-dependent cellular cytotoxicity mediated byherceptin in patients with gastric cancer. Cancer Res 62:5813–5817, 2002PubMedGoogle Scholar
  65. 65.
    Weng WK, Levy R: Two immunoglobulin G fragment C receptorpolymorphisms independently predict response to rituximab inpatients with follicular lymphoma. J Clin Oncol 21: 3940–3947, 2003CrossRefPubMedGoogle Scholar
  66. 66.
    Wu J, Edberg JC, Redecha PB, Bansal V, Guyre PM, Coleman K, Salmon JE, Kimberly RP: A novel polymorphism of Fcgamma RIIIa (CD16)alters receptor function and predisposes to autoimmune disease. JClin Invest 100: 1059–1070, 1997Google Scholar
  67. 67.
    Hogarth PM: Fc receptors are major mediators of antibody based inflammation inautoimmunity. Curr Opin Immunol 14: 798–802, 2002CrossRefPubMedGoogle Scholar
  68. 68.
    Cohen-Solal JF, Cassard L, Fridman WH, Sautes-Fridman C: Fc gamma receptors.Immunol Lett 92: 199-205, 2004CrossRefPubMedGoogle Scholar
  69. 69.
    Coggeshall KM: Regulation of signal transduction by the Fc gamma receptor familymembers and their involvement in autoimmunity. Curr Dir Autoimmunity 5: 1–29Google Scholar
  70. 70.
    Su K, Li X, Edberg JC, Wu J, Ferguson P, Kimberly RP: A promoterhaplotype of the immunoreceptor tyrosine-based inhibitorymotif-bearing Fcgamma RIIb alters receptor expression andassociates with autoimmunity. II. Differential binding of GATA4and Yin-Yang1 transcription factors and correlated receptorexpression and function. J Immunol 172: 7192–7199, 2004PubMedGoogle Scholar
  71. 71.
    Xia MQ, Hale G, Lifely MR, Ferguson MA, Campbell D, Packman L, Waldmann H:Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol-anchoredglycoprotein, which is an exceptionally good target for complement lysis. Biochem J 293: 633–640, 1993PubMedGoogle Scholar
  72. 72.
    Spiridon CI, Ghetie MA, Uhr J, Marches R, Li JL, Shen GL, Vitetta ES: Targeting multiple Her-2 epitopes with monoclonal antibodiesresults in improved antigrowth activity of a human breast cancercell line in vitro and in vivo. Clin Cancer Res 8: 1720–1730, 2002PubMedGoogle Scholar
  73. 73.
    Jacobs SA, Foon KA: Monoclonal antibody therapy of leukemias and lymphomas.Expert Opin Biol Ther 5: 1225–1243, 2005CrossRefPubMedGoogle Scholar
  74. 74.
    Palmisano GL, Pistillo MP, Fardin P, Capanni P, Nicolo G, Salvi S, Spina B, Pasciucco G, Ferrara GB: Analysis of HLA-G expression in breast cancer tissues. Hum Immunol 63: 969–976, 2002CrossRefPubMedGoogle Scholar
  75. 75.
    Sondel PM, Hank JA: Combination therapy with interleukin-2 and anti-tumormonoclonal antibodies. Cancer J Sci Am 3: S121–127Google Scholar
  76. 76.
    Stockmeyer B, Elsasser D, Dechant M, Repp R, Gramatzki M, Glennie MJ, van de Winkel JG, Valerius T: Mechanisms of G-CSF and GM-CSF-stimulated tumor cellkilling by Fc receptor-directed bispecific antibodies. J Immuno Methods 248: 103–111, 2001Google Scholar
  77. 77.
    Lustgarten J: Anti-Her-2/neu-IL-2 or heregulin-IL-2 fusionsproteins redirect non-tumor specific CTL to the tumor site fortumor eradication. Cancer Immunol Immunother 52: 751–760, 2003CrossRefPubMedGoogle Scholar
  78. 78.
    Van Ojik HH, Bevaart L, Dahle CE, Bakker A, Jansen MJ, Van Vugt MJ, van de Winkel JG, Weiner GJ: Cp G-A and B oligodeoxynucleotidesenhance the efficacy of antibody therapy by activating differenteffector cell populations. Cancer Res 63: 5595–5600, 2003PubMedGoogle Scholar
  79. 79.
    Green SK, Karlsson MC, Ravetch JV, Kerbel RS: Disruption ofcell-cell adhesion enhances antibody-dependent cellularcytotoxicity: Implications for antibody-based therapeutics ofcancer. Cancer Res 62: 6891–6900, 2002PubMedGoogle Scholar
  80. 80.
    Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J, Xie D, Lai J, Stadlen A, Li B, Fox JA, Presta LG: High resolution mappingof the binding site on human Ig G1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of Ig G1 variants with improvedbinding to the Fc gamma R. J Biol Chem 276: 6591–6604, 2001CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Department of Microbiology & ImmunologySte-Justine Hospital Research Center, University of MontrealCanada

Personalised recommendations