ADCC responses and blocking of EGFR-mediated signaling and cell growth by combining the anti-EGFR antibodies imgatuzumab and cetuximab in NSCLC cells

Kol, Arjan; Scheltinga, Anton Terwisscha van; Pool, Martin; Gerdes, Christian; Vries, Elisabeth G.E. de; Jong, Steven de

doi:10.18632/oncotarget.17139

Cited by 23 publications

(24 citation statements)

References 32 publications

(42 reference statements)

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“…Glycoengineering antibodies in this manner is currently being applied to various monoclonal antibodies to increase their capability to enhance ADCC and phagocytosis. This modification is well-documented to increase binding to FcγRIIIa, which is expressed by natural killer cells, monocytes and macrophages, (62, 70, 71). Less consideration has been given to the fact that this type of glycoengineering similarly enhances its affinity to FcγRIIIb, which is only present on granulocytes (44).…”

Section: Discussionmentioning

confidence: 99%

FcγRIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by Human Neutrophils

et al. 2019

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The function of the low-affinity IgG-receptor FcγRIIIb (CD16b), which is uniquely and abundantly expressed on human granulocytes, is not clear. Unlike the other Fcγ receptors (FcγR), it is a glycophosphatidyl inositol (GPI) -anchored molecule and does not have intracellular signaling motifs. Nevertheless, FcγRIIIb can cooperate with other FcγR to promote phagocytosis of antibody-opsonized microbes by human neutrophils. Here we have investigated the role of FcγRIIIb during antibody-dependent cellular cytotoxicity (ADCC) by neutrophils toward solid cancer cells coated with either trastuzumab (anti-HER2) or cetuximab (anti-EGFR). Inhibiting FcγRIIIb using CD16-F(ab')2 blocking antibodies resulted in substantially enhanced ADCC. ADCC was completely dependent on FcγRIIa (CD32a) and the enhanced ADCC seen after FcγRIIIb blockade therefore suggested that FcγRIIIb was competing with FcγRIIa for IgG on the opsonized target cells. Interestingly, the function of neutrophil FcγRIIIb as a decoy receptor was further supported by using neutrophils from individuals with different gene copy numbers of FCGR3B causing different levels of surface FcγRIIIb expression. Individuals with one copy of FCGR3B showed higher levels of ADCC compared to those with two or more copies. Finally, we show that therapeutic antibodies intended to improve FcγRIIIa (CD16a)-dependent natural killer (NK) cell ADCC due to the lack of fucosylation on the N-linked glycan at position N297 of the IgG1 heavy chain Fc-region, show decreased ADCC as compared to regularly fucosylated antibodies. Together, these data confirm FcγRIIIb as a negative regulator of neutrophil ADCC toward tumor cells and a potential target for enhancing tumor cell destruction by neutrophils.

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Section: Discussionmentioning

confidence: 99%

FcγRIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by Human Neutrophils

et al. 2019

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“…EGFR is the target for cetuximab, a human anti-EGFR IgG1 MAb with the ability to mediate ADCC. 38,39,40 Lysis of H441 targets exposed to cetuximab was also evaluated with untreated NK cells and N-809treated NK cells ( Figure 6(e)). Cetuximab was used at a concentration of 10 ng/ml, which has been previously shown to elicit ADCC.…”

Section: Effect Of Exposure Of Tumor Cells To N-809 On Nk Cell Lysis mentioning

confidence: 99%

The multi-functionality of N-809, a novel fusion protein encompassing anti-PD-L1 and the IL-15 superagonist fusion complex

et al. 2018

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Here we describe a novel bifunctional fusion protein, designated N-809. This molecule comprises the IL-15/IL15Rα superagonist complex containing the Fc-domain of IgG1 (N-803, formerly designated as ALT-803) fused to two single chain anti-PD-L1 domains. The fully human IgG1 portion of the N-809 molecule was designed to potentially mediate antibody dependent cellular cytotoxicity (ADCC). The studies reported here show that N-809 has the same ability to bind PD-L1 as an anti-PD-L1 monoclonal antibody. RNAseq studies show the ability of N-809 to alter the expression of an array of genes of both CD4+ and CD8+ human T cells, and to enhance their proliferation; CD8+ T cells exposed to N-809 also have enhanced ability to lyse human tumor cells. An array of genes was differentially expressed in human natural killer (NK) cells following N-809 treatment, and there was increased expression of several surface activating receptors; there was, however, no increase in the expression of inhibitory receptors known to be upregulated in exhausted NK cells. N-809 also increased the cytotoxic potential of NK cells, as shown by increased expression of granzyme B and perforin. The lysis of several tumor cell types was increased when either NK cells or tumor cells were exposed to N-809. Similarly, the highest level of ADCC was seen when both NK cells (from donors or cancer patients) and tumor cells were exposed to N-809. These studies thus demonstrate the multi-functionality of this novel agent.

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“…Many types of targeted therapies are based on monoclonal antibody functioning to inhibit the abnormal function of a specific receptor on the plasma membrane (i.e., Anti-Epidermal Growth Factor Receptor (EGFR)). An anti EGFR, for example, cetuximab has been shown to induce internalization of the EGFR, followed by degradation of EGFR through cellular lysosomes [ 101 ]. Thereby, the process results in downregulation of the EGFR and suppression of proliferation.…”

Section: Targeted Therapy Reverses Immunotherapy Tolerancementioning

confidence: 99%

“…Thereby, the process results in downregulation of the EGFR and suppression of proliferation. Apart from that, these monoclonal antibody targeted agents can also induce immune related cell killing through the process of ADCC and complement dependent cytotoxicity (CDC) [ 101 ]. However, as EGFR is also expressed in normal cells [ 102 ], enhancing the effect of ADCC or CDC of these monoclonal antibodies could potentially increase the toxicity.…”

Section: Targeted Therapy Reverses Immunotherapy Tolerancementioning

confidence: 99%

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

et al. 2020

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Cancer treatment has evolved tremendously in the last few decades. Immunotherapy has been considered to be the forth pillar in cancer treatment in addition to conventional surgery, radiotherapy, and chemotherapy. Though immunotherapy has resulted in impressive response, it is generally limited to a small subset of patients. Understanding the mechanisms of resistance toward cancer immunotherapy may shed new light to counter that resistance. In this review, we highlighted and summarized two major hurdles (recognition and attack) of cancer elimination by the immune system. The mechanisms of failure of some available immunotherapy strategies were also described. Moreover, the significance role of immune compartment for various established cancer treatments were also elucidated in this review. Then, the mechanisms of combinatorial treatment of various conventional cancer treatment with immunotherapy were discussed. Finally, a strategy to improve immune cancer killing by characterizing cancer immune landscape, then devising treatment based on that cancer immune landscape was put forward.

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ADCC responses and blocking of EGFR-mediated signaling and cell growth by combining the anti-EGFR antibodies imgatuzumab and cetuximab in NSCLC cells

Cited by 23 publications

References 32 publications

FcγRIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by Human Neutrophils

FcγRIIIb Restricts Antibody-Dependent Destruction of Cancer Cells by Human Neutrophils

The multi-functionality of N-809, a novel fusion protein encompassing anti-PD-L1 and the IL-15 superagonist fusion complex

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

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