Impact of Glycosylation on Effector Functions of Therapeutic IgG

Abès, Riad; Teillaud, Jean‐Luc

doi:10.3390/ph3010146

Cited by 111 publications

(89 citation statements)

References 48 publications

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“…First, the enhanced effect may be due to an increased Fc affinity for Fcγ receptors [24] . Second, the improved ADCC activity may also result from a better specific binding of Fab to antigen-positive cells, which initiates the process of ADCC and target cell lysis [25] .…”

Section: Wwwchinapharcom Yi Ch Et Almentioning

confidence: 99%

Function characterization of a glyco-engineered anti-EGFR monoclonal antibody cetuximab in vitro

Ruan

Wang

et al. 2014

Acta Pharmacol Sin

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Aim: To evaluate the biochemical features and activities of a glyco-engineered form of the anti-human epidermal growth factor receptor monoclonal antibody (EGFR mAb) cetuximab in vitro. Methods: The genes encoding the Chinese hamster bisecting glycosylation enzyme (GnTIII) and anti-human EGFR mAb were cloned and coexpressed in CHO DG44 cells. The bisecting-glycosylated recombinant EGFR mAb (bisec-EGFR mAb) produced by these cells was characterized with regard to its glycan profile, antiproliferative activity, Fc receptor binding affinity and cell lysis capability. The content of galactose-α-1,3-galactose (α-Gal) in the bisec-EGFR mAb was measured using HPAEC-PAD. Results: The bisec-EGFR mAb had a higher content of bisecting N-acetylglucosamine residues. Compared to the wild type EGFR mAb, the bisec-EGFR mAb exhibited 3-fold higher cell lysis capability in the antibody-dependent cellular cytotoxicity assay, and 1.36-fold higher antiproliferative activity against the human epidermoid carcinoma line A431. Furthermore, the bisec-EGFR mAb had a higher binding affinity for human FcγRIa and FcγRIIIa-158F than the wild type EGFR mAb. Moreover, α-Gal, which was responsible for cetuximab-induced hypersensitivity reactions, was not detected in the bisec-EGFR mAb. Conclusion: The glyco-engineered EGFR mAb with more bisecting modifications and lower α-Gal content than the approved therapeutic antibody Erbitux shows improved functionality in vitro, and requires in vivo validations.

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Section: Wwwchinapharcom Yi Ch Et Almentioning

confidence: 99%

Function characterization of a glyco-engineered anti-EGFR monoclonal antibody cetuximab in vitro

Ruan

Wang

et al. 2014

Acta Pharmacol Sin

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“…14 Likewise, neutral glycan moieties can cause changes in solvation and structure of a protein, which can contribute to differences in retention, particularly in CEX. 29,30 Lastly, cyclization of N-terminal glutamate to pyroglutamate (pyro-E) is a common PTM that results in a mass change of ¡18 Da and a decrease in positive charge. 28 This is observed in the case of infliximab where the pyroE-modified F(ab') 2 fragment elutes much earlier than the unmodified F(ab') 2 fragment (see peaks IxA.8 and IxA.9 in Fig.…”

Section: Discussionmentioning

confidence: 99%

Comparison of originator and biosimilar therapeutic monoclonal antibodies using comprehensive two-dimensional liquid chromatography coupled with time-of-flight mass spectrometry

Sorensen

Harmes

Stoll

et al. 2016

mAbs

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As research, development, and manufacturing of biosimilar protein therapeutics proliferates, there is great interest in the continued development of a portfolio of complementary analytical methods that can be used to efficiently and effectively characterize biosimilar candidate materials relative to the respective reference (i.e., originator) molecule. Liquid phase separation techniques such as liquid chromatography and capillary electrophoresis are powerful tools that can provide both qualitative and quantitative information about similarities and differences between reference and biosimilar materials, especially when coupled with mass spectrometry. However, the inherent complexity of these protein materials challenges even the most modern one-dimensional (1D) separation methods. Two-dimensional (2D) separations present a number of potential advantages over 1D methods, including increased peak capacity, 2D peak patterns that can facilitate unknown identification, and improvement in the compatibility of some separation methods with mass spectrometry. In this study, we demonstrate the use of comprehensive 2D-LC separations involving cation-exchange (CEX) and reversed-phase (RP) separations in the first and second dimensions to compare 3 reference/biosimilar pairs of monoclonal antibodies (cetuximab, trastuzumab and infliximab) that cover a range of similarity/disimilarity in a middle-up approach. The second dimension RP separations are coupled to time-of-flight mass spectrometry, which enables direct identification of features in the chromatograms obtained from mAbs digested with the IdeS enzyme, or digestion with IdeS followed by reduction with dithiothreitol. As many as 23 chemically unique mAb fragments were detected in a single sample. Our results demonstrate that these rich datasets enable facile assesment of the degree of similarity between reference and biosimilar materials.

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“…In many autoimmune and infectious diseases (rheumatoid arthritis (RA), active Crohn's disease, tuberculosis, Lyme disease, sarcoidosis, etc. ), an increased amount of low-galactosecontaining IgG antibodies (G0 glycoform), which have a pro-inflammatory effect, has been observed [60].…”

Section: Sialylation α-13-galactosylation and Microorganismsmentioning

confidence: 99%

“Lost sugars” — reality of their biological and medical applications

Talafová¹,

Nahálka²

2012

Open Life Sciences

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The glycan chains attached to cell surfaces or to single proteins are highly dynamic structures with various functions. The glycan chains of mammals and of some microorganisms often terminate in sialic acids or α-1,3-galactose. Although these two sugars are completely distinct, there are several similarities in their biological and medical importance. First, one type of sialic acid, N-glycolylneuraminic acid, and the galactose bound by an α-1,3-linkage to LacNAc, that forms an α-gal epitope, were both eliminated in human evolution, resulting in the production of antibodies to these sugars. Both of these evolutionary events have consequences connected with the consumption of foods of mammalian origin, causing medical complications of varying severity. In terms of ageing, sialic acids prevent the clearance of glycoproteins and circulating blood cells, whereas cryptic α-gal epitopes on senescent red blood cells contribute to their removal from circulation. The efficiency of therapeutic proteins can be increased by sialylation. Another common feature is the connection with microorganisms since sialic acids and α-gal epitopes serve as receptors on host cells and can also be expressed on the surfaces of some microorganisms. Whereas, the sialylation of IgG antibodies may help to treat inflammation, the expression of the α-gal epitope on microbial antigens increases the immunogenicity of the corresponding vaccines. Finally, sialic acids and the α-gal epitope have applications in cancer immunotherapy. N-glycolylneuraminic acid is a powerful target for cancer immunotherapy, and the α-gal epitope increases the efficiency of cancer vaccines. The final section of this article contains a brief overview of the methods for oligosaccharide chain synthesis and the characteristics of sialyltransferases and α-1,3-galactosyltransferase.

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Impact of Glycosylation on Effector Functions of Therapeutic IgG

Cited by 111 publications

References 48 publications

Function characterization of a glyco-engineered anti-EGFR monoclonal antibody cetuximab in vitro

Function characterization of a glyco-engineered anti-EGFR monoclonal antibody cetuximab in vitro

Comparison of originator and biosimilar therapeutic monoclonal antibodies using comprehensive two-dimensional liquid chromatography coupled with time-of-flight mass spectrometry

“Lost sugars” — reality of their biological and medical applications

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