Genomes and Genes
antibody dependent cell cytotoxicity
Summary: The phenomenon of antibody-mediated target cell destruction by non-sensitized effector cells. The identity of the target cell varies, but it must possess surface IMMUNOGLOBULIN G whose Fc portion is intact. The effector cell is a "killer" cell possessing Fc receptors. It may be a lymphocyte lacking conventional B- or T-cell markers, or a monocyte, macrophage, or polynuclear leukocyte, depending on the identity of the target cell. The reaction is complement-independent.
- Preithner S, Elm S, Lippold S, Locher M, Wolf A, da Silva A, et al. High concentrations of therapeutic IgG1 antibodies are needed to compensate for inhibition of antibody-dependent cellular cytotoxicity by excess endogenous immunoglobulin G. Mol Immunol. 2006;43:1183-93 pubmed..Competition of serum IgG for binding of therapeutic IgG1 to NK cell may be one important reason why high antibody doses are required in the clinic for treatment of cancer by an ADCC-based mechanism. ..
- McEarchern J, Oflazoglu E, Francisco L, McDonagh C, Gordon K, Stone I, et al. Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities. Blood. 2007;109:1185-92 pubmed..These data suggest that an anti-CD70 antibody, when engineered to contain human IgG1 constant domains, possesses effector cell-mediated antitumor activity and has potential utility for anticancer therapy. ..
- Kawaguchi Y, Kono K, Mimura K, Sugai H, Akaike H, Fujii H. Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma. Int J Cancer. 2007;120:781-7 pubmed..Some modalities aiming at enhancing the Cetuximab-mediated ADCC may be necessary for successful Cetuximab treatment of patients with esophageal SCC. ..
- Zhang W, Gordon M, Schultheis A, Yang D, Nagashima F, Azuma M, et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol. 2007;25:3712-8 pubmed..Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab. ..
- Alvarez Rueda N, Leprieur S, Clémenceau B, Supiot S, Sébille Rivain V, Faivre Chauvet A, et al. Binding activities and antitumor properties of a new mouse/human chimeric antibody specific for GD2 ganglioside antigen. Clin Cancer Res. 2007;13:5613s-5620s pubmed..0005). Immune effector functions mediated by this antibody and its potentially reduced immunogenicity make chimeric c.60C3 a promising therapeutic agent against neuroectodermic tumors. ..
- Nechansky A, Schuster M, Jost W, Siegl P, Wiederkum S, Gorr G, et al. Compensation of endogenous IgG mediated inhibition of antibody-dependent cellular cytotoxicity by glyco-engineering of therapeutic antibodies. Mol Immunol. 2007;44:1815-7 pubmed..Noteworthy, moss production of glyco-modified Abs should be applicable to a broad variety of therapeutic Abs currently in use indicative for the potential of this technology platform. ..
- Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol. 2008;26:1789-96 pubmed publisher..Prospective studies are needed to confirm the role of Fc gamma R polymorphisms in predicting clinical outcome of patients with breast cancer treated with trastuzumab-based therapy. ..
- Kurai J, Chikumi H, Hashimoto K, Yamaguchi K, Yamasaki A, Sako T, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res. 2007;13:1552-61 pubmed..These observations suggest the importance of ADCC activity as an immunologic mechanism of cetuximab in biological therapy for lung cancer patients. ..
- Jafarshad A, Dziegiel M, Lundquist R, Nielsen L, Singh S, Druilhe P. A novel antibody-dependent cellular cytotoxicity mechanism involved in defense against malaria requires costimulation of monocytes FcgammaRII and FcgammaRIII. J Immunol. 2007;178:3099-106 pubmed..These findings have both fundamental and practical implications, particularly for vaccine discovery. ..
- Kanda Y, Yamane Ohnuki N, Sakai N, Yamano K, Nakano R, Inoue M, et al. Comparison of cell lines for stable production of fucose-negative antibodies with enhanced ADCC. Biotechnol Bioeng. 2006;94:680-8 pubmed..Our results demonstrate that FUT8 knockout has the essential characteristics of host cells for robust manufacture of fucose-negative therapeutic antibodies with enhanced ADCC. ..
- Arnould L, Gelly M, Penault Llorca F, Benoit L, Bonnetain F, Migeon C, et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?. Br J Cancer. 2006;94:259-67 pubmed..These results suggest that trastuzumab plus taxanes lead to enhanced NK cell activity, which may partially account for the synergistic activity of trastuzumab and docetaxel in breast cancer. ..
- Guyre C, Gomes D, Smith K, Kaplan J, Perricone M. Development of an in vivo antibody-mediated killing (IVAK) model, a flow cytometric method to rapidly evaluate therapeutic antibodies. J Immunol Methods. 2008;333:51-60 pubmed publisher..This report demonstrates the feasibility and utility of a powerful method for the rapid evaluation in vivo of therapeutic antibody candidates for cancer. ..
- Ferrara C, Brünker P, Suter T, Moser S, Püntener U, Umana P. Modulation of therapeutic antibody effector functions by glycosylation engineering: influence of Golgi enzyme localization domain and co-expression of heterologous beta1, 4-N-acetylglucosaminyltransferase III and Golgi alpha-mannosidase II. Biotechnol Bioeng. 2006;93:851-61 pubmed..We show that apart from GnT-III overexpression, engineering of GnT-III localization is a versatile tool to modulate the biological activities of antibodies relevant for their therapeutic application. ..
- Niwa R, Sakurada M, Kobayashi Y, Uehara A, Matsushima K, Ueda R, et al. Enhanced natural killer cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density. Clin Cancer Res. 2005;11:2327-36 pubmed..Our data showed that fucose removal from IgG1 could reduce the antigen amount required for ADCC induction via efficient recruitment and activation of NK cells. ..
- Schuster M, Umana P, Ferrara C, Brünker P, Gerdes C, Waxenecker G, et al. Improved effector functions of a therapeutic monoclonal Lewis Y-specific antibody by glycoform engineering. Cancer Res. 2005;65:7934-41 pubmed
- Galandrini R, Micucci F, Tassi I, Cifone M, Cinque B, Piccoli M, et al. Arf6: a new player in FcgammaRIIIA lymphocyte-mediated cytotoxicity. Blood. 2005;106:577-83 pubmed..Our findings suggest that Arf6 plays a crucial role in the generation of a phosphatidylinositol4,5-bisphosphate (PIP2) plasma membrane pool required for cytolytic granule-mediated target cell killing. ..
- Suzuki E, Niwa R, Saji S, Muta M, Hirose M, Iida S, et al. A nonfucosylated anti-HER2 antibody augments antibody-dependent cellular cytotoxicity in breast cancer patients. Clin Cancer Res. 2007;13:1875-82 pubmed..This preliminary study suggests that the use of fucose-negative antibodies may improve the therapeutic effects of anti-HER2 therapy for patients independent of clinical backgrounds. ..
- Rebuffat S, Nguyen B, Robert B, Castex F, Peraldi Roux S. Antithyroperoxidase antibody-dependent cytotoxicity in autoimmune thyroid disease. J Clin Endocrinol Metab. 2008;93:929-34 pubmed..The monocytes, via their FcgammaRI, are important effector cells in ADCC mediated by anti-TPO aAbs and may contribute with T cells to the destruction of thyroid gland in AITD. ..
- Varchetta S, Gibelli N, Oliviero B, Nardini E, Gennari R, Gatti G, et al. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Res. 2007;67:11991-9 pubmed
- Richards J, Karki S, Lazar G, Chen H, Dang W, Desjarlais J. Optimization of antibody binding to FcgammaRIIa enhances macrophage phagocytosis of tumor cells. Mol Cancer Ther. 2008;7:2517-27 pubmed publisher..The enhancements in phagocytosis described here provide the potential to improve the performance of therapeutic antibodies targeting cancers. ..
- Kanda Y, Yamada T, Mori K, Okazaki A, Inoue M, Kitajima Miyama K, et al. Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. Glycobiology. 2007;17:104-18 pubmed..The present study provides basic information on the effects of core fucose-lacking N-linked Fc oligosaccharides on antibody biological activities. ..
- Masuda K, Kubota T, Kaneko E, Iida S, Wakitani M, Kobayashi Natsume Y, et al. Enhanced binding affinity for FcgammaRIIIa of fucose-negative antibody is sufficient to induce maximal antibody-dependent cellular cytotoxicity. Mol Immunol. 2007;44:3122-31 pubmed..These results indicate that the affinity of binding to FcgammaRIIIa does not predict ADCC beyond a certain threshold and that each method alone is sufficient to induce maximal ADCC of the antibody. ..
- Spiridon C, Ghetie M, Uhr J, Marches R, Li J, Shen G, et al. Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo. Clin Cancer Res. 2002;8:1720-30 pubmed..Taken together, these activities might explain the superior performance of the MAb mixture in vivo. ..
- Weng W, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940-7 pubmed..It will be important to include information on Fc receptor polymorphisms in future trials of rituximab therapy. ..
- Carter P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer. 2001;1:118-29 pubmed..Although antibodies have yet to achieve the ultimate goal of curing cancer, many innovative approaches stand poised to improve the efficacy of antibody-based therapies. ..
- Niwa R, Shoji Hosaka E, Sakurada M, Shinkawa T, Uchida K, Nakamura K, et al. Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res. 2004;64:2127-33 pubmed..These results indicate that defucosylated antibodies with enhanced ADCC as well as potent antitumor activity in vivo are promising candidates for the novel antibody-based therapy. ..
- Schmitz M, Zhao S, Schakel K, Bornhauser M, Ockert D, Rieber E. Native human blood dendritic cells as potent effectors in antibody-dependent cellular cytotoxicity. Blood. 2002;100:1502-4 pubmed..The results provide evidence that, in addition to their pivotal role in primary T-cell activation, a subset of blood DCs displays efficient cytotoxicity in ADCC. ..
- Kono K, Takahashi A, Ichihara F, Sugai H, Fujii H, Matsumoto Y. Impaired antibody-dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer. Cancer Res. 2002;62:5813-7 pubmed..Thus, some modalities such as interleukin 2 treatment aimed at reversing NK dysfunction may be necessary for successful Herceptin treatment of gastric cancer. ..
- Olszewski A, Grossbard M. Empowering targeted therapy: lessons from rituximab. Sci STKE. 2004;2004:pe30 pubmed..Lessons learned from the research on rituximab may be applied to the rational development of antibody-based therapies against other forms of cancer. ..
- Yamane Ohnuki N, Kinoshita S, Inoue Urakubo M, Kusunoki M, Iida S, Nakano R, et al. Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity. Biotechnol Bioeng. 2004;87:614-22 pubmed..Our results demonstrate that FUT8(-/-) cells are ideal host cell lines to stably produce completely defucosylated high-ADCC antibodies with fixed quality and efficacy for therapeutic use. ..
- Di Gaetano N, Cittera E, Nota R, Vecchi A, Grieco V, Scanziani E, et al. Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol. 2003;171:1581-7 pubmed..These data demonstrate that C activation is fundamental for rituximab therapeutic activity in vivo. ..
- Shinkawa T, Nakamura K, Yamane N, Shoji Hosaka E, Kanda Y, Sakurada M, et al. 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 cytotoxicity. J Biol Chem. 2003;278:3466-73 pubmed
- Dall Ozzo S, Tartas S, Paintaud G, Cartron G, Colombat P, Bardos P, et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res. 2004;64:4664-9 pubmed..Rituximab administration could therefore be adjusted according to FCGR3A genotype. ..
- Gennari R, Menard S, Fagnoni F, Ponchio L, Scelsi M, Tagliabue E, et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res. 2004;10:5650-5 pubmed
- Naundorf S, Preithner S, Mayer P, Lippold S, Wolf A, Hanakam F, et al. In vitro and in vivo activity of MT201, a fully human monoclonal antibody for pancarcinoma treatment. Int J Cancer. 2002;100:101-10 pubmed..The fully human nature and the improved ADCC of MT201 with human effector cells will make MT201 a promising candidate for the clinical development of a novel pan-carcinoma antibody that is superior to edrecolomab. ..
- Moreno M, Mol B, von Mensdorff Pouilly S, Verheijen R, von Blomberg B, van den Eertwegh A, et al. Toll-like receptor agonists and invariant natural killer T-cells enhance antibody-dependent cell-mediated cytotoxicity (ADCC). Cancer Lett. 2008;272:70-6 pubmed publisher..These results suggest that transfer of ex vivo expanded iNKT cells or TLR agonist treatment may improve the efficacy of NK cell-mediated antibody-based tumour immunotherapies. ..
- Kawaguchi Y, Kono K, Mizukami Y, Mimura K, Fujii H. Mechanisms of escape from trastuzumab-mediated ADCC in esophageal squamous cell carcinoma: relation to susceptibility to perforin-granzyme. Anticancer Res. 2009;29:2137-46 pubmed..Lower susceptibility to the perforin-granzyme system is one of the important mechanisms explaining escape from trastuzumab-mediated ADCC. ..
- El Sahwi K, Bellone S, Cocco E, Cargnelutti M, Casagrande F, Bellone M, et al. In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma. Br J Cancer. 2010;102:134-43 pubmed publisher..We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu...
- van Meerten T, van Rijn R, Hol S, Hagenbeek A, Ebeling S. Complement-induced cell death by rituximab depends on CD20 expression level and acts complementary to antibody-dependent cellular cytotoxicity. Clin Cancer Res. 2006;12:4027-35 pubmed..These data give new insights into novel strategies to improve the efficacy of CD20-specific antibodies for the treatment of CD20+ tumors. ..
- Strome S, Sausville E, Mann D. A mechanistic perspective of monoclonal antibodies in cancer therapy beyond target-related effects. Oncologist. 2007;12:1084-95 pubmed..Accordingly, all monoclonal antibodies directed against a given target should not be considered equivalent in their ability to stimulate immune-mediated effector functions. ..
- STAVENHAGEN J, Gorlatov S, Tuaillon N, Rankin C, Li H, Burke S, et al. 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 Res. 2007;67:8882-90 pubmed..The design of new generations of improved antibodies for immunotherapy should aim at Fc optimization to increase the engagement of activating FcgammaR present on the surface of tumor-infiltrating effector cell populations. ..
- Presta L. Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev. 2006;58:640-56 pubmed..g., affinity maturation, stability) and altering the effector functions (e.g. antibody-dependent cellular cytotoxicity, complement-dependent cellular cytotoxicity, and clearance rate). ..
- Hodoniczky J, Zheng Y, James D. Control of recombinant monoclonal antibody effector functions by Fc N-glycan remodeling in vitro. Biotechnol Prog. 2005;21:1644-52 pubmed
- Kawai S, Koishihara Y, Iida S, Ozaki S, Matsumoto T, Kosaka M, et al. Construction of a conventional non-radioisotope method to quantify HM1.24 antigens: correlation of HM1.24 levels and ADCC activity of the humanized antibody against HM1.24. Leuk Res. 2006;30:949-56 pubmed..24. Thus, AHM is likely to be more efficacious against MM cells with high levels of HM1.24. This conventional non-RI method to quantify HM1.24 will be useful to select patients most likely to respond to AHM. ..
- Barbin K, Stieglmaier J, Saul D, Stieglmaier K, Stockmeyer B, Pfeiffer M, et al. Influence of variable N-glycosylation on the cytolytic potential of chimeric CD19 antibodies. J Immunother. 2006;29:122-33 pubmed..The data demonstrate the influence of the N-glycosylation pattern on the ADCC activity of chimeric CD19 antibodies and point to the importance of suitable expression systems for the production of highly active therapeutic antibodies. ..
- Hsi E, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14:2775-84 pubmed publisher..These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma. ..
- Stein R, Qu Z, Chen S, Solis D, Hansen H, Goldenberg D. Characterization of a humanized IgG4 anti-HLA-DR monoclonal antibody that lacks effector cell functions but retains direct antilymphoma activity and increases the potency of rituximab. Blood. 2006;108:2736-44 pubmed..In addition, combination of hL243gamma4P with rituximab offers the prospect for improved patient outcome. ..
- Snively A. The cytokines and the B-cell malignancies: a new spin on maximizing therapeutic outcomes. ONS News. 2006;21:13-4 pubmed
- Joshi T, Ganesan L, Cheney C, Ostrowski M, Muthusamy N, Byrd J, et al. The PtdIns 3-kinase/Akt pathway regulates macrophage-mediated ADCC against B cell lymphoma. PLoS ONE. 2009;4:e4208 pubmed publisher..Taken together, these findings illustrate that the PtdIns 3-kinase/Akt pathway plays a critical role in macrophage ADCC through its influence on conjugate formation between macrophages and antibody-coated tumor cells. ..
- Huhn C, Selman M, Ruhaak L, Deelder A, Wuhrer M. IgG glycosylation analysis. Proteomics. 2009;9:882-913 pubmed publisher..Alternatively, intact IgGs or fragments thereof obtained by enzymatic cleavages in the hinge region and by reduction may be analyzed by a large number of analytical techniques, including MS and chromatography or CE. ..
- Dall Acqua W, Kiener P, Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem. 2006;281:23514-24 pubmed..Therefore, the YTE substitutions allow the simultaneous modulation of serum half-life, tissue distribution and activity of a given human IgG1. ..
- Gowda A, Ramanunni A, Cheney C, Rozewski D, Kindsvogel W, Lehman A, et al. Differential effects of IL-2 and IL-21 on expansion of the CD4+ CD25+ Foxp3+ T regulatory cells with redundant roles in natural killer cell mediated antibody dependent cellular cytotoxicity in chronic lymphocytic leukemia. MAbs. 2010;2:35-41 pubmed..Given the infusion related toxicities and pro-survival effect of IL-2 in CLL, these studies provide a rationale to explore IL-21 as an alternate gamma chain cytokine in CLL therapy. ..
- Shiokawa M, Takahashi T, Murakami A, Kita S, Ito M, Sugamura K, et al. In vivo assay of human NK-dependent ADCC using NOD/SCID/gammac(null) (NOG) mice. Biochem Biophys Res Commun. 2010;399:733-7 pubmed publisher..This system, therefore, is useful for evaluating the in vivo function of human NK cells. ..