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NDT Advance Access originally published online on February 13, 2007
Nephrology Dialysis Transplantation 2007 22(5):1301-1304; doi:10.1093/ndt/gfl847
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Sialylated therapeutic IgG: a sweet remedy for inflammatory diseases?*

Jordan D. Dimitrov{dagger}, Jagadeesh Bayry{dagger}, Sophie Sibéril and Srini V. Kaveri

INSERM UMRS 872 Equipe 16- Immunopathology and therapeutic immunointervention and Université Pierre et Marie Curie (UPMC-Paris-6), Centre de Recherche des Cordeliers, 15, rue de l’Ecole de Médecine, Paris 75006, France

Correspondence and offprint requests to: Dr Srini V. Kaveri, INSERM UMRS 872 Equipe 16, Centre de Recherche des Cordeliers, 15, rue de l’Ecole de Médecine, Paris 75006, France. Email: srini.kaveri{at}umrs681.jussieu.fr

Keywords: Fc gamma receptor; intravenous immunoglobulin; therapeutic IgG



   Introduction
Top
 Introduction
Overview of the study...
 Discussion
 Perspective
 Acknowledgements
 References
 
Immunoglobulin G (IgG) is the main serum glycoprotein responsible for detection and destruction of pathogens or their noxious products. IgG consists of Fab (‘fragment antigen binding’) regions, that recognize antigenic targets and provide diversity to antibodies, and Fc (‘fragment crystallizable’) regions, that allow antibodies to interact with Fc gamma receptors (Fc{gamma}R) on phagocytes (Fig. 1). Currently, four classes of Fc{gamma}R are identified: Fc{gamma}RI, Fc{gamma}RII, Fc{gamma}RIII and Fc{gamma}RIV [1]. For the initiation of a biological response against the bound antigen, IgGs rely on their constant Fc portion. CH2 domains of the Fc fragment contain complex oligosaccharide structures covalently attached to asparagine 297 of the heavy chain of the IgG [2,3]. The presence of a complex oligosaccharide structure modulates the functions of IgG, especially the activation of complement and binding to Fc{gamma}R [4]. The monosaccharide content of the complex oligosaccharides in antibodies, including monoclonal IgGs (MAbs), is highly variable. More than 30 different glycoforms linked to Fc have been described [4]. The impact of the carbohydrate structure on the biological functions of IgGs remains unresolved.


Figure 1
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  		Fig. 1. (A) The structure of IgG molecule with glycosylation sites. IgG consists of two light and two heavy chains composed of various domains such as variable and constant domains. There are two types of light chains: {kappa} and {lambda}, but only one type is present in each immunoglobulin. The Fab region of an immunoglobulin recognizes a specific antigen unique to its target via antigen-binding site, the structure formed by variable heavy and light chains. The Fc region allows immunoglobulin to interact with and signal through Fc receptors on phagocytes, B cells and other cells as well as with Fc-binding plasma proteins, such as complement. IgGs are known to be variably glycosylated mostly at CH2 domains of heavy chain (indicated by dark arrows). The variable regions of heavy chain also have potential N-glycosylation sites (indicated by light blue arrows). VH, variable heavy domain; CH, constant heavy domain; VL, variable light domain; CL, constant light domain (B) The classification of Fc{gamma}Rs and their function. Currently, four classes of Fc{gamma}R are identified: Fc{gamma}RI, Fc{gamma}RII, Fc{gamma}RIII and Fc{gamma}RIV. Fc{gamma}RI, Fc{gamma}RIIa Fc{gamma}RIIIa and Fc{gamma}RIV are activating receptors while Fc{gamma}RIIB and Fc{gamma}RIIIB are inhibitory receptors. Fc{gamma}RI, Fc{gamma}RIIA and Fc{gamma}RIIIA are characterized by the presence of an immunoreceptor tyrosine-based activation motif (ITAM) either in the cytoplasmic domain of the receptor (Fc{gamma}RIIA) or associated with the receptor as an accessory signalling subunit, the common {gamma} chain. The tyrosine phosphorylation of ITAM leads to activation of cells. Fc{gamma}RIIB is characterized by the presence of an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain and tyrosine phosphorylation of which leads to inhibition of cellular activity. In contrast Fc{gamma}RIIIB is characterized by a glycosyl phosphatidylinositol (GPI) anchor.

 


   Overview of the study by Kaneko et al. [5]
Top
 Introduction
 Overview of the study...
Discussion
 Perspective
 Acknowledgements
 References
 
The study by Kaneko et al. [5] sheds light on the role of the sialic acid-terminating glycan structures on the biological activities of IgG. The authors have compared the properties of IgG with a higher content of sialic acid to those with a lower content. They demonstrate that highly sialylated forms of monoclonal mouse IgGs have reduced affinity for Fc{gamma}R and cytotoxic function. Furthermore, the authors demonstrate that the anti-inflammatory activity of the therapeutic human immunoglobulin G (IVIg) is mediated mainly by a fraction of antibodies with terminal sialic acid on their oligosaccharide structures. The IVIg fraction enriched in sialic acid-containing antibodies showed an Fc{gamma}RIIB-dependent stronger protective effect, while the enzymatic removal of the sialic acid residues abrogated the anti-inflammatory activity of IVIg in a mouse model of rheumatoid arthritis [5]. Using nephrotoxic serum nephritis model, Kaneko et al. also demonstrate that the content of sialic acid in IgG varies during the evolution of the immune responses against antigens. At later stages of the response, during the process of affinity maturation, IgG antibodies switch to variants that lack sialic acid in their oligosaccharide structures.



   Discussion
Top
 Introduction
 Overview of the study...
 Discussion
Perspective
 Acknowledgements
 References
 
Several studies have investigated the influence of the glycan composition on the effector functions of IgG. Using the same clone of the recombinant therapeutic anti-human CD20 mouse/human chimeric IgG1 rituximab, it has been demonstrated that the effector activity of the IgG1 depends strongly on the content of fucose in the glycan structure [6]. Thus, IgG containing non-fucosylated complex oligosaccharide show a substantially greater affinity for binding to Fc{gamma}RIIIA and induce a stronger antibody-dependent cellular cytotoxicity (ADCC). As the therapeutic activity of rituximab is mainly due to ADCC, these results have obvious clinical significance. In addition, the presence of {alpha}2,3-linked sialic acid in the glycans of human IgG3 have a profound inhibitory effect on complement- and on Fc{gamma}R-dependant effector functions [7]. Furthermore, a higher level of sialylation of monoclonal IgG antibodies leads to a decrease in its binding to Fc{gamma}RIIIA and a to considerable reduction of their ADCC activity [8]. These findings together with the results obtained by Kaneko et al. implicate an important role for sialic acid in modifying the biological functions of IgG. Monitoring the sialylation of disease-associated IgG antibodies during different phases of an antibody-mediated disease may have a diagnostic and prognostic potential.

Similar to highly sialylated IgG, IgG exposed to reactive oxygen species has a weaker binding to Fc{gamma} receptors [9]. In addition, oxidized IVIg has an enhanced anti-inflammatory activity and protects mice from experimental sepsis [10].

Initially used as replacement therapy in primary and secondary immune deficiencies, IVIg is also widely used for the treatment of a number of autoimmune and systemic inflammatory diseases [11,12]. The mechanisms of action of IVIg are multiple and mutually non-exclusive [11,13–16]. Some of the mechanisms depend on the interaction between the Fc portion of IVIg and Fc{gamma}R on target cells. Others rely on the variable regions of antibodies. Thus, IVIg represents a very complex and stochastic system, built from microfractions with different (sometimes opposite) immunomodulatory effects. Therefore, some of these microfractions of antibodies may quench the biological effect of others. It is possible to isolate or enrich a fraction of antibodies with particular specificities such as idiotypic determinants, cell-surface molecules including Fas, integrins, CD4, HLA and CD40 [11,17].



   Perspective
Top
 Introduction
 Overview of the study...
 Discussion
 Perspective
Acknowledgements
 References
 
IgGs can mediate pro- and anti-inflammatory activities through the engagement of Fc with distinct Fc{gamma}R. The finding that sialylation of Fc portion of an antibody can determine anti-inflammatory properties provides new opportunities for enhancing the efficacy of current therapeutic immunoglobulins and for the development of new therapeutics. Thus the therapeutic efficacy of MAbs may be optimized by the selection of a glycoform that is best suited. As the current generation of licensed therapeutic MAbs bear oligosaccharides essentially devoid of sialic acid [18], the study by Kaneko et al. [5] may not find an application for the improvement of existing MAbs. However, sialylation of Fc has to be considered while developing new therapeutic MAbs.

The infusion of purified Fc fragments of IVIg ameliorates acute immune thrombocytopenic purpura in children and in murine models, similar to IVIg [13,19]. Kaneko et al [5] demonstrate that sialylation of the Fc portion confers Fc-mediated anti-inflammatory properties to IVIg in experimental models. Thus, sialic acid-enriched IVIg preparations might prove a better therapeutic option. Alternatively, considering the cost involved in additional fractionation steps for enriching sialylated IgG, recombinant sialylated Fc fragments of IgG could be an attractive therapeutic alternative that could contribute to overcoming the shortage of IVIg for several autoimmune diseases [20]. Since the Fc moiety is not diversified as Fab fragments, producing recombinant therapeutic Fc fragments should be a plausible task in the shorter term. However, there is a lack of correspondence between IgG subclasses and Fc receptors in human and mice, and hence the phenomenon described by Kaneko et al. needs to be carefully investigated in humans.



   Acknowledgements
Top
 Introduction
 Overview of the study...
 Discussion
 Perspective
 Acknowledgements
References
 
This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM) and Centre National de la Recherche Scientifique (CNRS), France. We are grateful to Dr. Peter J Spath for inspiring the conception of Figure 1.

Conflict of interest statement. The authors received financial support from the Laboratoire Français du Fractionnement et des Biotechnologies, France; ZLB Behring, Switzerland; Octapharma, Austria and Talecris, USA for the research activities of Equipe 16- Immunopathology and therapeutic immunointervention and Université Pierre et Marie Curie (UPMC-Paris-6), Centre de Recherche des Cordeliers, Paris, France.



   Notes
 
*This article is based on the following basic science article: Kaneko Y, Nimmerjahn F, Ravetch JV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 2006; 313: 670–673. Back

{dagger}The first two authors contributed equally to this manuscript Back



   References
Top
 Introduction
 Overview of the study...
 Discussion
 Perspective
 Acknowledgements
 References
 

  1. Nimmerjahn F and Ravetch JV. (2006) Fcgamma receptors: old friends and new family members. Immunity 24:19–28.[CrossRef][Web of Science][Medline]
  2. Lund J, Takahashi N, Pound JD, Goodall M, Jefferis R. (1996) Multiple interactions of IgG with its core oligosaccharide can modulate recognition by complement and human Fc gamma receptor I and influence the synthesis of its oligosaccharide chains. J Immunol 157:4963–4969.[Abstract]
  3. Krapp S, Mimura Y, Jefferis R, Huber R, Sondermann P. (2003) Structural analysis of human IgG-Fc glycoforms reveals a correlation between glycosylation and structural integrity. J Mol Biol 325:979–989.[CrossRef][Web of Science][Medline]
  4. Burton DR and Dwek RA. (2006) Immunology. Sugar determines antibody activity. Science 313:627–628.[Abstract/Free Full Text]
  5. Kaneko Y, Nimmerjahn F, Ravetch JV. (2006) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–673.[Abstract/Free Full Text]
  6. Kanda Y, Yamada T, Mori K, et al. (2007) Comparison of biological activity among non-fucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. Glycobiology 17:104–118.[Abstract/Free Full Text]
  7. Jassal R, Jenkins N, Charlwood J, Camilleri P, Jefferis R, Lund J. (2001) Sialylation of human IgG-Fc carbohydrate by transfected rat alpha2,6-sialyltransferase. Biochem Biophys Res Commun 286:243–249.[CrossRef][Web of Science][Medline]
  8. Scallon BJ, Tam SH, McCarthy SG, Cai AN, Raju TS. (2007) Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol Immunol 44:1524–1534.[CrossRef][Medline]
  9. Uesugi M, Yoshida K, Jasin HE. (2000) Inflammatory properties of IgG modified by oxygen radicals and peroxynitrite. J Immunol 165:6532–6537.[Abstract/Free Full Text]
  10. Dimitrov JD, Ivanovska ND, Lacroix-Desmazes S, Doltchinkova VR, Kaveri SV, Vassilev TL. (2006) Ferrous ions and reactive oxygen species increase antigen-binding and anti-inflammatory activities of immunoglobulin G. J Biol Chem 281:439–446.[Abstract/Free Full Text]
  11. Kazatchkine MD and Kaveri SV. (2001) Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 345:747–755.[Free Full Text]
  12. Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV. (2004) Intravenous immunoglobulin for infectious diseases: back to the pre-antibiotic and passive prophylaxis era? Trends Pharmacol Sci 25:306–310.[CrossRef][Medline]
  13. Samuelsson A, Towers TL, Ravetch JV. (2001) Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484–486.[Abstract/Free Full Text]
  14. Dalakas MC. (2004) Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA 291:2367–2375.[Abstract/Free Full Text]
  15. Bayry J, Lacroix-Desmazes S, Carbonneil C, et al. (2003) Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 101:758–765.[Abstract/Free Full Text]
  16. Siragam V, Crow AR, Brinc D, Song S, Freedman J, Lazarus AH. (2006) Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells. Nat Med 12:688–692.[CrossRef][Web of Science][Medline]
  17. Bayry J, Lacroix-Desmazes S, Donkova-Petrini V, et al. (2004) Natural antibodies sustain differentiation and maturation of human dendritic cells. Proc Natl Acad Sci USA 101:14210–14215.[Abstract/Free Full Text]
  18. Jefferis R. (2006) A sugar switch for anti-inflammatory antibodies. Nat Biotechnol 24:1230–1231.[CrossRef][Web of Science][Medline]
  19. Debre M, Bonnet MC, Fridman WH, et al. (1993) Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 342:945–949.[CrossRef][Web of Science][Medline]
  20. Bayry J, Kazatchkine MD, Kaveri SV. (2007) Shortage of human intravenous immunoglobulin: reasons and possible solutions. Nat Clin Pract Neurol 3:120–121.[CrossRef][Web of Science][Medline]
Received for publication: 23.11.06
Accepted in revised form: 27.12.06


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This Article
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