IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab

Patel, Dhaval; Guo, Xuemei; Ng, Stanley; Melchior, Maxine; Balderes, Paul; Burtrum, Douglas; Persaud, Kris; Luna, Xenia; Ludwig, Dale L.; Kang, Xiaoqiang

doi:10.3233/hab-2010-0232

Cited by 72 publications

(50 citation statements)

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“…Secondary effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), mediated by the Fc region of the antibody are part of cetuximab's antitumor activity in patients, but the relative contribution is unknown (26)(27)(28). It is likely that the above-described mechanism of cetuximab action is insufficient for efficient EGFR targeting due to the plasticity/promiscuity of the receptor.…”

Section: Introductionmentioning

confidence: 99%

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

Kjær

Lindsted

Fröhlich

et al. 2016

Molecular Cancer Therapeutics

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Squamous cell carcinomas (SCC) arising in upper parts of the aerodigestive tract are among the leading causes of death worldwide. EGFR has been found to play an essential role in driving the malignancy of SCC of the upper aerodigestive tract (SCCUAT), but, despite this, clinical results using a range of different EGFR-targeted agents have been disappointing. Cetuximab is currently the only EGFR-targeted agent approved by the FDA for treatment of SCCUAT. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics. In order to better understand the underlying mechanisms of cetuximab resistance in SCCUAT, we established from cetuximab-sensitive models cell lines with acquired resistance to cetuximab by continuous selective pressure in vitro and in vivo. Our results show that resistant clones maintain partial dependency on EGFR and that receptor tyrosine kinase plasticity mediated by HER3 and IGF1R plays an essential role. A multitarget mAb mixture against EGFR, HER3, and IGF1R was able to overcome cetuximab resistance in vitro. To our surprise, these findings could be extended to include SCCUAT cell lines with intrinsic resistance to cetuximab, suggesting that the triad consisting of EGFR, HER3, and IGF1R plays a key role in SCCUAT. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in SCCUAT. Mol Cancer Ther; 15(7); 1614-26. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

Kjær

Lindsted

Fröhlich

et al. 2016

Molecular Cancer Therapeutics

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“…[1][2][3] For example, antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) are triggered when the Fc domain interacts with the Fcg receptors (FcgR) present at the surface of immune cells or the complement molecule C1q, respectively. The Fc domain of immunoglobulin (Ig) G possesses 2 N-glycans, one on each heavy chain (HC) at Asparagine 297, which are necessary for its binding to FcgRs [4][5][6] or C1q. 7,8 N-glycosylation is a very common co-translational modification initiated in the endoplasmic reticulum (ER) and completed in the Golgi apparatus.…”

Section: Introductionmentioning

confidence: 99%

Production of α2,6-sialylated IgG1 in CHO cells

Raymond

Robotham

Spearman

et al. 2015

mAbs

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The presence of a2,6-sialic acids on the Fc N-glycan provides anti-inflammatory properties to the IgGs through a mechanism that remains unclear. Fc-sialylated IgGs are rare in humans as well as in industrial host cell lines such as Chinese hamster ovary (CHO) cells. Facilitated access to well-characterized a2,6-sialylated IgGs would help elucidate the mechanism of this intriguing IgG's effector function. This study presents a method for the efficient Fc glycan a2,6-sialylation of a wild-type and a F243A IgG1 mutant by transient co-expression with the human a2,6-sialyltransferase 1 (ST6) and b1,4-galactosyltransferase 1 (GT) in CHO cells. Overexpression of ST6 alone only had a moderate effect on the glycoprofiles, whereas GT alone greatly enhanced Fc-galactosylation, but not sialylation. Overexpression of both GT and ST6 was necessary to obtain a glycoprofile dominated by a2,6-sialylated glycans in both antibodies. The wild-type was composed of the G2FS(6)1 glycan (38%) with remaining unsialylated glycans, while the mutant glycoprofile was essentially composed of G2FS(6)1 (25%), G2FS(3,6)2 (16%) and G2FS(6,6)2 (37%). The a2,6-linked sialic acids represented over 85% of all sialic acids in both antibodies. We discuss how the limited sialylation level in the wild-type IgG1 expressed alone or with GT results from the glycan interaction with Fc's amino acid residues or from intrinsic galactosyl-and sialyl-transferases substrate specificities.

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“…Among mAbs, the robustness of ADCC may be an important component of therapeutic activity in SCCHN. IgG1 mAbs have greater ADCC potential compared with IgG2 agents; therefore, cetuximab may have greater activity than panitumumab [85]. Enhanced ADCC and improvements in clinical efficacy have been observed in patients with polymorphisms of the fragment C (Fc) receptor of immune cells that enhances their affinity for the Fc region [86].…”

Section: Discussionmentioning

confidence: 99%

Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck

Iberri

Colevas

2015

The Oncologist

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The epidermal growth factor receptor (EGFR) is overexpressed in more than 80% of squamous cell cancers of the head and neck (SCCHN). An evolving understanding of the role of EGFR in tumorigenesis has made the receptor an important therapeutic target in SCCHN. Several EGFR inhibitors (EGFRIs) are active in SCCHN, and their use is associated with improvement in progression-free survival and overall survival in various treatment settings. Nevertheless, EGFR inhibition is associated with significant mucocutaneous toxicity that must be balanced against its anticipated efficacy. This review summarizes the relevant clinical trial experience with EGFRIs, with attention to efficacy, toxicity, and methods of selecting patients most likely to benefit from therapy.

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IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab

Abstract: Cetuximab elicits effective ADCC activity against a wide range of tumor cells in vitro. This activity is dependent on antibody glycosylation and IgG1 isotype as well as tumor-cell EGFR expression. These findings suggest that ADCC may contribute to the antitumor activity of cetuximab.

Cited by 72 publications

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Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

Production of α2,6-sialylated IgG1 in CHO cells

Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck

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