Terminal sugars of Fc glycans influence antibody effector functions of IgGs

Raju, T. Shantha

doi:10.1016/j.coi.2008.06.007

Cited by 486 publications

(398 citation statements)

References 50 publications

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“…The h-13F6 binding results for FcγRI and c1q are consistent with previous reports demonstrating that the absence of fucose does not affect the binding of IgG 1 (4,18). Similar to other reports (8), elimination of core fucose from h-13F6 (h-13F6 ΔXF ) resulted in an improved affinity for FcγRIII.…”

Section: Discussionsupporting

confidence: 91%

Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant

Zeitlin

Pettitt

Scully

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

212

195

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No countermeasures currently exist for the prevention or treatment of the severe sequelae of Filovirus (such as Ebola virus; EBOV) infection. To overcome this limitation in our biodefense preparedness, we have designed monoclonal antibodies (mAbs) which could be used in humans as immunoprotectants for EBOV, starting with a murine mAb (13F6) that recognizes the heavily glycosylated mucin-like domain of the virion-attached glycoprotein (GP). Point mutations were introduced into the variable region of the murine mAb to remove predicted human T-cell epitopes, and the variable regions joined to human constant regions to generate a mAb (h-13F6) appropriate for development for human use. We have evaluated the efficacy of three variants of h-13F6 carrying different glycosylation patterns in a lethal mouse EBOV challenge model. The pattern of glycosylation of the various mAbs was found to correlate to level of protection, with aglycosylated h-13F6 providing the least potent efficacy (ED 50 = 33 μg). A version with typical heterogenous mammalian glycoforms (ED 50 = 11 μg) had similar potency to the original murine mAb. However, h-13F6 carrying complex N-glycosylation lacking core fucose exhibited superior potency (ED 50 = 3 μg). Binding studies using Fcγ receptors revealed enhanced binding of nonfucosylated h-13F6 to mouse and human FcγRIII. Together the results indicate the presence of Fc N-glycans enhances the protective efficacy of h-13F6, and that mAbs manufactured with uniform glycosylation and a higher potency glycoform offer promise as biodefense therapeutics.passive immunization | antibody glycosylation | antibody-dependent cellular cytotoxicity | antiviral

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Section: Discussionsupporting

confidence: 91%

Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant

Zeitlin

Pettitt

Scully

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

212

195

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“…Though this appears to be a somewhat convoluted mechanism to explain the observations, it has been shown that there is contact between the two glycans through the two core mannose residues and that in the absence of this interaction the structure of the CH 2 domains are perturbed, highlighting the interaction between the glycans and this region of the Fc. [24][25][26] Now we consider the possibility that the effect observed was due to oxidation of Met430. Residues HC[247-253] have been shaded dark red in Figure 3, it can be seen that in the crystal structure these residues form an a-helix, which is located adjacent to methionines 253 and 430.…”

Section: Resultsmentioning

confidence: 99%

Conformational changes in oxidatively stressed monoclonal antibodies studied by hydrogen exchange mass spectrometry

Burkitt¹,

Domann²,

O’Connor³

2010

Protein Science

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Oxidation of methionine residues in biopharmaceuticals is a common and often unwanted modification that frequently occurs during their manufacture and storage. It often results in a lack of stability and biological function of the product, necessitating continuous testing for the modification throughout the product shelf life. A major class of biopharmaceutical products are monoclonal antibodies (mAbs), however, techniques for their detailed structural analysis have until recently been limited. Hydrogen/deuterium exchange mass spectrometry (HXMS) has recently been successfully applied to the analysis of mAbs. Here we used HXMS to identify and localise the structural changes that occurred in a mAb (IgG1) after accelerated oxidative stress. Structural alterations in a number of segments of the Fc region were observed and these related to oxidation of methionine residues. These included a large change in the hydrogen exchange profile of residues 247-253 of the heavy chain, while smaller changes in hydrogen exchange profile were identified for peptides that contained residues in the interface of the C H 2 and C H 3 domains.

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“…Sialic acid is fully dispensable for classical complement pathway activation. 95 Galactose and bisecting GlcNAc residues however have a more controversial role. [96][97][98] This may be due in part to the fact that IgG1 lacking galactose (G 0 ) can bind to mannose binding lectin (MBL) and activate the lectin pathway of complement instead of the classical pathway.…”

Section: Glycosylation In Insect Cellsmentioning

confidence: 99%

Lepidopteran cells, an alternative for the production of recombinant antibodies?

Cérutti

Golay

2012

mAbs

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Terminal sugars of Fc glycans influence antibody effector functions of IgGs

Cited by 486 publications

References 50 publications

Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant

Enhanced potency of a fucose-free monoclonal antibody being developed as an Ebola virus immunoprotectant

Conformational changes in oxidatively stressed monoclonal antibodies studied by hydrogen exchange mass spectrometry

Lepidopteran cells, an alternative for the production of recombinant antibodies?

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