scholarly journals Antibody fucosylation differentially impacts cytotoxicity mediated by NK and PMN effector cells

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2390-2399 ◽  
Author(s):  
Matthias Peipp ◽  
Jeroen J. Lammerts van Bueren ◽  
Tanja Schneider-Merck ◽  
Wim W. K. Bleeker ◽  
Michael Dechant ◽  
...  
Keyword(s):  
Nk Cell ◽  
Growth Factor Receptor ◽  
Polymorphonuclear Cells ◽  
Effector Cells ◽  
Fc Fragment ◽  
Igg1 Monoclonal Antibody ◽  
Epidermal Growth ◽  
Human Igg1 ◽  
The Impact ◽  
First Time

AbstractGlycosylation of the antibody Fc fragment is essential for Fc receptor–mediated activity. Carbohydrate heterogeneity is known to modulate the activity of effector cells in the blood, in which fucosylation particularly affects NK cell–mediated killing. Here, we investigated how the glycosylation profile of 2F8, a human IgG1 monoclonal antibody against epidermal growth factor receptor in clinical development, impacted effector function. Various 2F8 batches differing in fucosylation, galactosylation, and sialylation of the complex-type oligosaccharides in the Fc fragment were investigated. Our results confirmed that low fucose levels enhance mononuclear cell–mediated antibody-mediated cellular cytotoxicity (ADCC). In contrast, polymorphonuclear cells were found to preferentially kill via high-fucosylated antibody. Whole blood ADCC assays, containing both types of effector cells, revealed little differences in tumor cell killing between both batches. Significantly, however, high-fucose antibody induced superior ADCC in blood from granulocyte colony-stimulating factor–primed donors containing higher numbers of activated polymorphonuclear cells. In conclusion, our data demonstrated for the first time that lack of fucose does not generally increase the ADCC activity of therapeutic antibodies and that the impact of Fc glycosylation on ADCC is critically dependent on the recruited effector cell type.

scholarly journals A potential therapy for chordoma via antibody-dependent cell-mediated cytotoxicity employing NK or high-affinity NK cells in combination with cetuximab

2018 ◽  
Vol 128 (5) ◽  
pp. 1419-1427 ◽  
Author(s):  
Rika Fujii ◽  
Jeffrey Schlom ◽  
James W. Hodge
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Growth Factor Receptor ◽  
High Affinity ◽  
Dependent Cell ◽  
Epidermal Growth ◽  
First Time ◽  
Igg1 Isotype ◽  
Egfr Antibody

OBJECTIVEChordoma is a rare bone tumor derived from the notochord and is resistant to conventional therapies such as chemotherapy, radiotherapy, and targeting therapeutics. Expression of epidermal growth factor receptor (EGFR) in a large proportion of chordoma specimens indicates a potential target for therapeutic intervention. In this study the authors investigated the potential role of the anti-EGFR antibody cetuximab in immunotherapy for chordoma.METHODSSince cetuximab is a monoclonal antibody of the IgG1 isotype, it has the potential to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) employing natural killer (NK) cells as effectors. Polymorphisms in the CD16 allele expressed on NK cells have been shown to influence the degree of ADCC of tumor cells, with the high-affinity valine (V)/V allele being responsible for more lysis than the V/phenylalanine (F) or FF allele. Unfortunately, however, only approximately 10% of the population expresses the VV allele on NK cells. An NK cell line, NK-92, has now been engineered to endogenously express IL-2 and the high-affinity CD16 allele. These irradiated high-affinity (ha)NK cells were analyzed for lysis of chordoma cells with and without cetuximab, and the levels of lysis observed in ADCC were compared with those of NK cells from donors expressing the VV, VF, and FF alleles.RESULTSHere the authors demonstrate for the first time 1) that cetuximab in combination with NK cells can mediate ADCC of chordoma cells; 2) the influence of the NK CD16 polymorphism in cetuximab-mediated ADCC for chordoma cell lysis; 3) that engineered haNK cells—that is, cells transduced to express the CD16 V158 FcγRIIIa receptor—bind cetuximab with similar affinity to normal NK cells expressing the high-affinity VV allele; and 4) that irradiated haNK cells induce ADCC with cetuximab in chordoma cells.CONCLUSIONSThese studies provide rationale for the use of cetuximab in combination with irradiated haNK cells for therapy for chordoma.

Interrupted crosstalk between natural killer cells and anti-epidermal growth factor receptor: a possible role in hepatocellular carcinoma treatment failure

2021 ◽  
Vol 21 ◽  
Author(s):  
Hadeer Abosalema ◽  
Shahenda Mahgoub ◽  
Mohamed Emara ◽  
Nahla Kotb ◽  
Sameh Soror
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Major Health Problem ◽  
Advanced Stages ◽  
Epidermal Growth ◽  
First Time ◽  
Late Stages

: Hepatocellular carcinoma (HCC) is a major health problem worldwide. Most patients are diagnosed for the first time at late stages; this leads to a very poor prognosis. It is challenging to discover strategies for treatment at these advanced stages. Recently, monoclonal antibodies (mAbs) targeting specific cellular signaling pathways in HCC have been developed. Unfortunately, they still have a low survival rate, and some of them failed clinically to produce effective responses even if they showed very good results against HCC in preclinical studies. This review focuses on and discusses the possible causes for the failure of mAbs, precisely anti-Epidermal Growth Factor Receptor (EGFR) mAb and the crosstalk between this mAb and patients' NK cells.

Impact of antibody Fc carbohydrate fucosylation on antibody-dependent cellular cytotoxicity by HuMax-EGFr —A fully human epidermal growth factor receptor antibody

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2543-2543 ◽  
Author(s):  
M. Dechant ◽  
J. Lammerts van Bueren ◽  
M. Peipp ◽  
W. Bleeker ◽  
T. Beyer ◽  
...  
Keyword(s):  
Whole Blood ◽  
Cell Mass ◽  
Growth Factor Receptor ◽  
Antibody Binding ◽  
Target Cells ◽  
Inhibition Of Proliferation ◽  
Effector Cells ◽  
Chromium Release ◽  
Highly Active ◽  
Human Igg1

2543 Background: HuMax-EGFr - a human IgG1 EGF-R antibody in phase II clinical trials - was demonstrated to block EGF binding, to interfere with cellular signaling and to efficiently recruit effector cells for ADCC. Triggering of ADCC requires antibody binding to cellular Fc receptors which can be modulated by antibody glycosylation. Here, we investigated whether the glycosylation profile of HuMax-EGFr altered effector functions, and compared the contribution of mononuclear (MNC) and polymorphonuclear (PMN) cells for ADCC in human blood. Methods: Varying concentrations of two HuMax-EGFr batches, differing in the level of fucosylation of the complex-type oligosaccharides present in the Fc fragment, were compared in their capacity to kill EGF-R expressing tumor cells. Antibody binding and inhibition of proliferation was analyzed by flow cytometry and measuring vital cell mass, respectively. ADCC by isolated PMN, MNC and human whole blood was analyzed by chromium release assays. Results: Both batches of HuMax-EGFr bound similarly to target cells, and inhibited their proliferation to a similar extent. Low-fucosylated HuMax-EGFr demonstrated higher affinity for recombinant FcγRIIIa than fully fucosylated antibody. As expected, low-fucosylated antibody was significantly better in mediating ADCC by MNC (EC50 obtained at 10-fold lower antibody concentrations, p<0.05). In contrast, PMN-mediated ADCC was unaffected by the antibody fucosylation level. Importantly, whole blood ADCC assays also revealed little differences between both batches. ADCC was significantly enhanced by blood from G-CSF-primed patients, but again both high- and low-fucosylated antibody performed similarly. Conclusions: Both HuMax-EGFr batches were equally potent in inhibiting cell proliferation, and were highly active in triggering ADCC by MNC and PMN. Differences in fucosylation of Fc carbohydrate affected MNC-mediated lysis, whereas PMN- and whole blood-mediated cell killing were only minimally affected. Thus, fucosylation of antibody Fc may only prove critical for therapeutic antibodies which predominantly recruit NK cells for ADCC, while it may be less relevant for PMN-recruiting antibodies. [Table: see text]

Randomized phase II trial of two dose schedules of carboplatin/paclitaxel/cetuximab in stage IIIB/IV non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7586-7586 ◽  
Author(s):  
M. N. Saleh ◽  
M. A. Socinski ◽  
D. Trent ◽  
T. Dobbs ◽  
L. M. Zehngebot ◽  
...  
Keyword(s):  
Phase Ii ◽  
Survival Data ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Stage Iiib ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Igg1 Monoclonal Antibody ◽  
Epidermal Growth

7586 Background: Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) on both normal and tumor cells, has been investigated in advanced NSCLC as a single agent and in combination with chemotherapy. This ongoing randomized phase II open-label trial evaluates cetuximab in combination with carboplatin (Cb) and paclitaxel (Pac) when given in two dose schedules to patients (pts) with previously untreated stage IIIB/IV NSCLC. Methods: Eligible pts were randomized to 1 of 2 treatment arms. Cetuximab treatment was identical in both arms: 400 mg/m2 IV on day 1 and 250 mg/m2 weekly thereafter. Beginning on day 8, a schedule of Cb AUC=6 IV and Pac 225 mg/m2 IV given on a 3-week cycle was compared with a schedule of Cb AUC=6 IV q4 weeks and Pac 100 mg/m2 IV given weekly for 3 weeks of each 4-week cycle. Pts who achieve CR, PR, or SD after 4 cycles may continue weekly cetuximab monotherapy until disease progression or unacceptable toxicity. The primary objectives were to estimate median progression-free survival (PFS) and the PFS rate at 6 months. Secondary objectives included response rate. Results: The study has completed accrual, with 168 pts randomized and 165 treated. Data are available for 164 pts and confirmed responses for 155 pts. Conclusions: Cetuximab combined with Cb and Pac in both dose schedules demonstrated activity and an acceptable toxicity profile in pts with NSCLC. Final PFS and overall survival data are pending. No significant financial relationships to disclose. [Table: see text]

Activity of insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic refractory adrenocortical carcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4639-4639
Author(s):  
Aung Naing ◽  
Patricia LoRusso ◽  
Siqing Fu ◽  
David S. Hong ◽  
Helen Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Adrenocortical Carcinoma ◽  
Mtor Inhibitor ◽  
Growth Factor Receptor ◽  
Median Number ◽  
Insulin Growth Factor ◽  
Igg1 Monoclonal Antibody ◽  
Human Igg1 ◽  
Insulin Growth Factor Receptor ◽  
Human Igg1 Monoclonal Antibody

4639 Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancywithout an available effective systemic chemotherapy. IGF-R2 overexpression leading to the activation of the IGF1R/mTOR pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at insulin growth factor-1 receptor (IGF-1R), was combined with temsirolimus on the basis of preclinical data. Methods: Patientsreceived cixutumumab, 3-6 mg/kg IV weekly, and temsirolimus, 25 mg-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. Results: Twenty-six patients were enrolled (13 [50%] men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug-related, were grade 1-2 thrombocytopenia (38%), mucositis (58%), hypercholesterolemia (31%), hypertriglyceridemia (35%), and hyperglycemia (31%). Eleven of 26 patients (42%) achieved stable disease (SD) > 6 months (duration range = 6 to 21 months) with 3 of the 11 having received a prior IGF-1R inhibitor. Conclusions: Cixutumumab combined with temsirolimus was well tolerated and more than 40% of patients achieved prolonged SD. This study was supported by R21CA13763301A1 (AN), U01CA62461 (RK), and U01CA62487 (PL).

scholarly journals EGFRAmplification and Glioblastoma Stem-Like Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Katrin Liffers ◽  
Katrin Lamszus ◽  
Alexander Schulte
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Current Knowledge ◽  
Growth Factor Receptor ◽  
Model Systems ◽  
Preclinical Research ◽  
Epidermal Growth ◽  
Methodological Approaches ◽  
The Impact

Glioblastoma (GBM), the most common malignant brain tumor in adults, contains a subpopulation of cells with a stem-like phenotype (GS-cells). GS-cells can be maintainedin vitrousing serum-free medium supplemented with epidermal growth factor, basic fibroblast growth factor-2, and heparin. However, this method does not conserve amplification of the Epidermal Growth Factor Receptor (EGFR) gene, which is present in over 50% of all newly diagnosed GBM cases. GS-cells with retainedEGFRamplification could overcome the limitations of currentin vitromodel systems and contribute significantly to preclinical research on EGFR-targeted therapy. This review recapitulates recent methodological approaches to expand stem-like cells from GBM with differentEGFRstatus in order to maintain EGFR-dependent intratumoral heterogeneityin vitro. Further, it will summarize the current knowledge about the impact ofEGFRamplification and overexpression on the stem-like phenotype of GBM-derived GS-cells and different approaches to target the EGFR-dependent GS-cell compartment of GBM.

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