Glycoform-dependent conformational alteration of the Fc region of human immunoglobulin G1 as revealed by NMR spectroscopy

Yamaguchi, Yoshiki; Nishimura, Mamiko; Nagano, Mayumi; Yagi, Hirokazu; Sasakawa, Hiroaki; Uchida, Kazuaki; Shitara, Kenya; Kato, Koichi

doi:10.1016/j.bbagen.2005.10.002

Cited by 187 publications

(186 citation statements)

References 66 publications

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“…2, both degalactosylated 6A6 IgG subclasses bound Ϸ2-fold better to MBL, whereas binding to C1q was decreased, consistent with earlier observations (15,25). Previous studies dealing with the effect of the lack of galactose on FcR binding were inconclusive, with some studies finding reduced binding (25)(26)(27), whereas others found only slight or no major changes (28)(29)(30)(31). Importantly, many of these studies used different methods, FcRs, and antibody isotypes, which might explain some of these contradictory results.…”

Section: Binding Of Igg-g0 Glycovariants To Fcrs and Complement Protementioning

confidence: 66%

Agalactosylated IgG antibodies depend on cellular Fc receptors forin vivoactivity

Nimmerjahn

Anthony²,

Ravetch³

2007

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

237

178

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IgG antibodies are glycoproteins containing a branched sugar moiety attached to the asparagine 297 residue in the antibody constant region (Fc). This glycan is essential for maintaining a functional Fc structure, which is a prerequisite for antibodymediated effector functions, such as the interaction with cellular Fc receptors or the complement component C1q. Variations in the composition of the sugar moiety can dramatically influence antibody activity. Moreover, humans and mice with autoimmune disorders, such as rheumatoid arthritis, have altered IgG glycosylation patterns with increased levels of antibodies lacking terminal sialic acid and galactose residues (IgG-G0). There is great interest in understanding whether this altered glycosylation pattern influences antibody-mediated effector functions. In vitro studies have suggested that IgG-G0 antibodies gain the capacity to activate the complement pathway via mannose-binding lectin (MBL), which could contribute to antibody-mediated inflammation. We have analyzed the activity of IgG-G0 antibodies in mice with a genetic deletion of MBL (MBL-null mice) and demonstrate that IgG-G0 antibodies are unimpaired in MBL-null mice. In contrast, the activity of these antibody glycovariants is fully dependent on the presence of activating Fc receptors.galactose ͉ glycosylation ͉ sialic acid ͉ inflammation

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Section: Binding Of Igg-g0 Glycovariants To Fcrs and Complement Protementioning

confidence: 66%

Agalactosylated IgG antibodies depend on cellular Fc receptors forin vivoactivity

Nimmerjahn

Anthony²,

Ravetch³

2007

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

237

178

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“…[10][11][12] In this report, we focus on deglycosylated antibodies. Changes in a product's glycosylation pattern may significantly alter its intrinsic properties and stability, [13][14][15][16][17][18][19] thereby adding challenges for downstream process development. Thus, a good understanding of the impact of glycosylation on protein properties is useful during process development.…”

Section: Introductionmentioning

confidence: 99%

The impact of glycosylation on monoclonal antibody conformation and stability

Zheng

Bantog

Bayer

2011

mAbs

280

210

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“…Interestingly, these consensus sequences are mostly not germline encoded but result from somatic mutation -suggestive of positive selection for improved antigen binding. Analysis of polyclonal human IgG-Fab reveals the presence of diantennary oligosaccharides that are extensively galactosylated and substantially sialylated, in contrast to the oligosaccharides released from IgG-Fc (4,10,(36)(37)(38)(39). This pattern was maintained for IgG-Fab prepared from hypogalactosylated IgG isolated from the sera of patients with Wegner's granulomatosis or microscopic polyangiitis (38).…”

Section: F Glycosylation Of Igg-fabmentioning

confidence: 95%

“…Truncation of the sugar residues results in the mutual approach of CH2 domains with the generation of a``closed'' conformation; in contrast to thè`o pen'' conformation observed for the fully galactosylated IgG-Fc (16). A truncated glycoform bearing only a fucosylated primary GlcNAc was shown not to bind soluble recombinant FcgRa and NMR studies indicated conformational alterations of the lower hinge region that contributes to FcgR binding sites (36).…”

Section: E the Impact Of Glycosylation On Structure And Stabilitymentioning

confidence: 99%

“…It is established that ¿30z of polyclonal human IgG molecules bear N-linked oligosaccharides within the IgG-Fab region, in addition to the conserved glycosylation site at Asn 297 in the IgG-Fc (4,10,(36)(37)(38)(39). When present they are attached within the variable regions of the kappa (Vk), lambda (Vl) or heavy (VH) chains; sometimes both.…”

Section: F Glycosylation Of Igg-fabmentioning

confidence: 99%

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Glycoforms of Human IgG in Health and Disease

Jefferis¹

2009

TIGG

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More than twenty recombinant antibody molecules are now licensed for treatment of a variety of cancers and chronic diseases. In addition there are, literally, hundreds in development and early phase clinical trials. Initially, the attraction of antibodies was their speciˆcity for target antigens; however, it is now appreciated that the immune complexes formed trigger downstream biological activities that are critical to clinical success. It has been demonstrated that, although accounting for only 2-3z of antibody mass, glycosylation of the IgG-Fc is essential to the activation of such biologic mechanisms (eŠector functions). Additionally the precise structure of the attached oligosaccharide can determine protein conformation and stability and hence downstream biologic e‹cacy. Cellular engineering has been embraced to generate cell lines that synthesise selected homogeneous antibody glycoforms that may be optimal for a given disease indication. The advantage of being able to formulate therapeutic antibody preparations at high concentration might be aided by additional glycosylation within the IgG-Fab region. Novel production vehicles are also being developed that oŠer the possibility of lower production costs, with consequent lower cost of goods.

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Glycoform-dependent conformational alteration of the Fc region of human immunoglobulin G1 as revealed by NMR spectroscopy

Cited by 187 publications

References 66 publications

Agalactosylated IgG antibodies depend on cellular Fc receptors forin vivoactivity

Agalactosylated IgG antibodies depend on cellular Fc receptors forin vivoactivity

The impact of glycosylation on monoclonal antibody conformation and stability

Glycoforms of Human IgG in Health and Disease

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