Inhibition of whole blood antibody dependent cellular cytotoxicity by heat aggregated human IgG

Macdonald, Ileene M.; Dumble, Lynette J.; Jack, Ian; Clunie, G. J. A.

doi:10.1016/0022-1759(81)90334-3

Cited by 4 publications

(3 citation statements)

References 3 publications

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“…This method is analogous, in principle, to that described by Macdonald et al [12]. Human breast cancer cell line SKBR-3, which over-expresses human epidermal growth factor receptor (HER)2, and epidermal cancer cell line A431, which over-expresses epidermal growth factor receptor (EGFR)/HER1, were obtained from ATCC (Manassas, VA, USA).…”

Section: Cell Cytotoxicity By Adcc and Adcc Inhibitionmentioning

confidence: 99%

“…Interactions between monomeric IgG and low-affinity FcgRs are unstable and require multivalent interactions for their persistence [11]. To make the interaction between the low-affinity FcgRIIIa and IgG1 more stable, the affinity-purified IgG1 was heat aggregated, following the protocol of others who have used ADCC inhibition assays [12] or have investigated IgG-FcgR interactions [13].…”

Section: Allotyping Affinity Purification and Heat Aggregation Of Igmentioning

confidence: 99%

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Differential inhibition of trastuzumab- and cetuximab-induced cytotoxicity of cancer cells by immunoglobulin G1 expressing different GM allotypes

Namboodiri

Pandey

2011

Clinical and Experimental Immunology

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SummaryAntibody-dependent cell-mediated cytotoxicity (ADCC), which links the innate and the adaptive arms of immunity, is a major host immunosurveillance mechanism against tumours, as well as the leading mechanism underlying the clinical efficacy of therapeutic antibodies such as cetuximab and trastuzumab, which target tumour antigens, human epidermal growth factor receptor (HER)1 and HER2, respectively. Immunoglobulin (Ig)G antibodymediated ADCC is triggered upon ligation of Fcg receptor (FcgR) to the Fc region of IgG molecules. It follows that genetic variation in FcgR and Fc could contribute to the differences in the magnitude of ADCC. Genetic variation in FcgR is known to contribute to the differences in the magnitude of ADCC, but the contribution of natural genetic variation in Fc, GM allotypes, in this interaction has hitherto not been investigated. Using an ADCC inhibition assay, we show that IgG1 expressing the GM 3+, 1-, 2-allotypes was equally effective in inhibiting cetuximab-and trastuzumab-mediated ADCC of respective target cells, in the presence of natural killer (NK) cells expressing either valine or phenylalanine allele of FcgRIIIa. In contrast, IgG1 expressing the allelic GM 17+, 1+, 2+ allotypes was significantly more effective in inhibiting the ADCC -mediated by both monoclonal antibodies -when NK cells expressed the valine, rather than the phenylalanine, allele of FcgRIIIa. These findings have important implications for engineering antibodies (with human g1 constant region) against malignancies characterized by the over-expression of tumour antigens HER1 and HER2 -especially for patients who, because of their FcgRIIIa genotype, are unlikely to benefit from the currently available therapeutics.

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Section: Cell Cytotoxicity By Adcc and Adcc Inhibitionmentioning

confidence: 99%

Section: Allotyping Affinity Purification and Heat Aggregation Of Igmentioning

confidence: 99%

Differential inhibition of trastuzumab- and cetuximab-induced cytotoxicity of cancer cells by immunoglobulin G1 expressing different GM allotypes

Namboodiri

Pandey

2011

Clinical and Experimental Immunology

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“…FCGR3A genotyping was performed by real-time PCR (RT-PCR), using a pre-designed TaqMan® genotyping assay from Applied Biosystems Inc. NK cells were isolated from peripheral blood mononuclear cells (PBMCs) by affinity depletion of non-NK cells, using a kit from Milteneyi Biotec, according to the manufacturer’s protocol. ADCC assays were performed by a technique modified from Macdonald et al, 14 using the Cytotox-96 kit from Promega Corporation, which quantify lactate dehydrogenase (LDH) activity. The spontaneous release of LDH from target cells incubated with NK cells—possibly due to killer-cell immunoglobulin-like receptor (KIR)-dependent cytotoxicity—was used as blank (negative control).…”

mentioning

confidence: 99%

Genetic variants of IgG1 antibodies and FcγRIIIa receptors influence the magnitude of antibody-dependent cell-mediated cytotoxicity against prostate cancer cells

Pandey¹,

Namboodiri

2014

OncoImmunology

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Antibody-dependent, cell-mediated cytotoxicity (ADCC) is one of the major mechanisms underlying the clinical efficacy of anticancer monoclonal antibodies (mAbs), such as the mucin 1 (MUC1)-targeting molecule HuHMFG1. IgG antibodies trigger ADCC upon interaction with Fcγ receptors (FcγRs) expressed on the surface of immune effector cells. Polymorphisms affecting FcγRs are known to influence the magnitude of ADCC, but the impact of natural genetic variations in the Fc-coding sequence, γ marker (GM) allotypes, has not been adequately investigated. Using an ADCC inhibition assay, we demonstrate that IgG1 antibodies of the 3+, 1−, 2− GM allotype block almost all valine-containing FcγRIIIa receptors expressed by natural killer (NK) cells, inhibiting by 93% their ability to mediate HuHMFG1-dependent ADCC against DU145 prostate cancer cells. Of note, the ADCC-inhibitory effect of the same IgG1 molecules was significantly reduced when NK cells expressed phenylalanine-containing FcγRIIIa (93% vs. 50%; P = 0.0000005). These and other findings presented here have important therapeutic implications for the use of anti-MUC1 mAbs in patients with prostate cancer and other MUC1-overexpressing adenocarcinomas.

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Fc receptor—More answers, more questions

Fornůsek

Větvička

1984

Folia Microbiol

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Fc receptors, belonging to the most important surface structures of a number of cells participating in the immune processes, have been intensely studied during the past decade. The present review summarizes the contemporary knowledge of the specificity and heterogeneity of Fc receptors and of factors influencing their expression, and includes some views on their function. In addition, it mentions their relationship to other cell surface structures, expression of Fc receptors during ontogeny of the organism and in certain diseases. Finally, data concerning the isolation and biochemical characterization of the Fc receptor molecule are presented.

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Inhibition of whole blood antibody dependent cellular cytotoxicity by heat aggregated human IgG

Cited by 4 publications

References 3 publications

Differential inhibition of trastuzumab- and cetuximab-induced cytotoxicity of cancer cells by immunoglobulin G1 expressing different GM allotypes

Differential inhibition of trastuzumab- and cetuximab-induced cytotoxicity of cancer cells by immunoglobulin G1 expressing different GM allotypes

Genetic variants of IgG1 antibodies and FcγRIIIa receptors influence the magnitude of antibody-dependent cell-mediated cytotoxicity against prostate cancer cells

Fc receptor—More answers, more questions

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