4q74 › Citations

Structural characterization of anti-inflammatory immunoglobulin G Fc proteins.

Ahmed AA, Giddens J, Pincetic A, Lomino JV, Ravetch JV, Wang LX, Bjorkman PJ
J Mol Biol 426 3166-3179 (2014)
Related entries: 4q6y, 4q7d

Cited: 89 times
EuropePMC logo PMID: 25036289

Abstract

Immunoglobulin G (IgG) is a central mediator of host defense due to its ability to recognize and eliminate pathogens. The recognition and effector responses are encoded on distinct regions of IgGs. The diversity of the antigen recognition Fab domains accounts for IgG's ability to bind with high specificity to essentially any antigen. Recent studies have indicated that the Fc effector domain also displays considerable heterogeneity, accounting for its complex effector functions of inflammation, modulation, and immune suppression. Therapeutic anti-tumor antibodies, for example, require the pro-inflammatory properties of the IgG Fc to eliminate tumor cells, while the anti-inflammatory activity of intravenous IgG requires specific Fc glycans for activity. In particular, the anti-inflammatory activity of intravenous IgG is ascribed to a small population of IgGs in which the Asn297-linked complex N-glycans attached to each Fc CH2 domain include terminal α2,6-linked sialic acids. We used chemoenzymatic glycoengineering to prepare fully disialylated IgG Fc and solved its crystal structure. Comparison of the structures of asialylated Fc, sialylated Fc, and F241A Fc, a mutant that displays increased glycan sialylation, suggests that increased conformational flexibility of the CH2 domain is associated with the switch from pro-inflammatory to anti-inflammatory activity of the Fc.

Articles - 4q74 mentioned but not cited (2)

  1. Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. Ahmed AA, Giddens J, Pincetic A, Lomino JV, Ravetch JV, Wang LX, Bjorkman PJ. J Mol Biol 426 3166-3179 (2014)
  2. Solution structure of deglycosylated human IgG1 shows the role of CH2 glycans in its conformation. Spiteri VA, Doutch J, Rambo RP, Gor J, Dalby PA, Perkins SJ. Biophys J 120 1814-1834 (2021)


Reviews citing this publication (42)

  1. IgG subclasses and allotypes: from structure to effector functions. Vidarsson G, Dekkers G, Rispens T. Front Immunol 5 520 (2014)
  2. Biological roles of glycans. Varki A. Glycobiology 27 3-49 (2017)
  3. The Immunoregulatory Roles of Antibody Glycosylation. Jennewein MF, Alter G. Trends Immunol 38 358-372 (2017)
  4. Intravenous immunoglobulin in neurology--mode of action and clinical efficacy. Lünemann JD, Nimmerjahn F, Dalakas MC. Nat Rev Neurol 11 80-89 (2015)
  5. The role of Fc-FcγR interactions in IgG-mediated microbial neutralization. Bournazos S, DiLillo DJ, Ravetch JV. J Exp Med 212 1361-1369 (2015)
  6. Human IgG4: a structural perspective. Davies AM, Sutton BJ. Immunol Rev 268 139-159 (2015)
  7. Understanding Fc Receptor Involvement in Inflammatory Diseases: From Mechanisms to New Therapeutic Tools. Ben Mkaddem S, Benhamou M, Monteiro RC. Front Immunol 10 811 (2019)
  8. Differential antibody glycosylation in autoimmunity: sweet biomarker or modulator of disease activity? Seeling M, Brückner C, Nimmerjahn F. Nat Rev Rheumatol 13 621-630 (2017)
  9. Fcγ receptor pathways during active and passive immunization. Bournazos S, Ravetch JV. Immunol Rev 268 88-103 (2015)
  10. Glycosylation engineering of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy. Mimura Y, Katoh T, Saldova R, O'Flaherty R, Izumi T, Mimura-Kimura Y, Utsunomiya T, Mizukami Y, Yamamoto K, Matsumoto T, Rudd PM. Protein Cell 9 47-62 (2018)
  11. The Ligands for Human IgG and Their Effector Functions. de Taeye SW, Rispens T, Vidarsson G. Antibodies (Basel) 8 E30 (2019)
  12. The Role and Function of Fcγ Receptors on Myeloid Cells. Bournazos S, Wang TT, Ravetch JV. Microbiol Spectr 4 (2016)
  13. The history of IgG glycosylation and where we are now. Cobb BA. Glycobiology 30 202-213 (2020)
  14. Functional diversification of IgGs through Fc glycosylation. Wang TT, Ravetch JV. J Clin Invest 129 3492-3498 (2019)
  15. Chemoenzymatic Methods for the Synthesis of Glycoproteins. Li C, Wang LX. Chem Rev 118 8359-8413 (2018)
  16. Glycoengineering of Antibodies for Modulating Functions. Wang LX, Tong X, Li C, Giddens JP, Li T. Annu Rev Biochem 88 433-459 (2019)
  17. Novel Concepts of Altered Immunoglobulin G Galactosylation in Autoimmune Diseases. Dekkers G, Rispens T, Vidarsson G. Front Immunol 9 553 (2018)
  18. Structural analysis of Fc/FcγR complexes: a blueprint for antibody design. Caaveiro JM, Kiyoshi M, Tsumoto K. Immunol Rev 268 201-221 (2015)
  19. FcγRIIB and autoimmunity. Espéli M, Smith KG, Clatworthy MR. Immunol Rev 269 194-211 (2016)
  20. Anti-retroviral antibody FcγR-mediated effector functions. Bournazos S, Ravetch JV. Immunol Rev 275 285-295 (2017)
  21. Improving Antibody-Based Cancer Therapeutics Through Glycan Engineering. Yu X, Marshall MJE, Cragg MS, Crispin M. BioDrugs 31 151-166 (2017)
  22. Using glyco-engineering to produce therapeutic proteins. Dicker M, Strasser R. Expert Opin Biol Ther 15 1501-1516 (2015)
  23. Immune recruitment or suppression by glycan engineering of endogenous and therapeutic antibodies. Le NP, Bowden TA, Struwe WB, Crispin M. Biochim Biophys Acta 1860 1655-1668 (2016)
  24. Glycosylation of IgG-Fc: a molecular perspective. Kiyoshi M, Tsumoto K, Ishii-Watabe A, Caaveiro JMM. Int Immunol 29 311-317 (2017)
  25. A synopsis of recent developments defining how N-glycosylation impacts immunoglobulin G structure and function. Yamaguchi Y, Barb AW. Glycobiology 30 214-225 (2020)
  26. Analytical comparability study of recombinant monoclonal antibody therapeutics. Ambrogelly A, Gozo S, Katiyar A, Dellatore S, Kune Y, Bhat R, Sun J, Li N, Wang D, Nowak C, Neill A, Ponniah G, King C, Mason B, Beck A, Liu H. MAbs 10 513-538 (2018)
  27. Macro- and Micro-Heterogeneity of Natural and Recombinant IgG Antibodies. Beck A, Liu H. Antibodies (Basel) 8 E18 (2019)
  28. Breaking the Glyco-Code of HIV Persistence and Immunopathogenesis. Colomb F, Giron LB, Trbojevic-Akmacic I, Lauc G, Abdel-Mohsen M. Curr HIV/AIDS Rep 16 151-168 (2019)
  29. Impact of IgG Fc-Oligosaccharides on Recombinant Monoclonal Antibody Structure, Stability, Safety, and Efficacy. Liu H, Nowak C, Andrien B, Shao M, Ponniah G, Neill A. Biotechnol Prog 33 1173-1181 (2017)
  30. In Silico Methods in Antibody Design. Zhao J, Nussinov R, Wu WJ, Ma B. Antibodies (Basel) 7 E22 (2018)
  31. Sialylated immunoglobulin G: a promising diagnostic and therapeutic strategy for autoimmune diseases. Li D, Lou Y, Zhang Y, Liu S, Li J, Tao J. Theranostics 11 5430-5446 (2021)
  32. Glycobiology of rheumatic diseases. Kissel T, Toes REM, Huizinga TWJ, Wuhrer M. Nat Rev Rheumatol 19 28-43 (2023)
  33. Recombinant Proteins and Monoclonal Antibodies. Jefferis R. Adv Biochem Eng Biotechnol 175 281-318 (2021)
  34. The therapeutic potential of sialylated Fc domains of human IgG. Pleass RJ. MAbs 13 1953220 (2021)
  35. Importance and Monitoring of Therapeutic Immunoglobulin G Glycosylation. Mimura Y, Saldova R, Mimura-Kimura Y, Rudd PM, Jefferis R. Exp Suppl 112 481-517 (2021)
  36. Sweet Rules: Linking Glycosylation to Antibody Function. Nimmerjahn F, Werner A. Exp Suppl 112 365-393 (2021)
  37. Antibody class-switching as a strategy to improve HIV-1 neutralization. Scheepers C, Richardson SI, Moyo-Gwete T, Moore PL. Trends Mol Med 28 979-988 (2022)
  38. Harnessing IgG Fc glycosylation for clinical benefit. Archer EJ, Gonzalez JC, Ghosh D, Mellins ED, Wang TT. Curr Opin Immunol 77 102231 (2022)
  39. Immunoglobulin Glycosylation - An Unexploited Potential for Immunomodulatory Strategies in Farm Animals. Zlatina K, Galuska SP. Front Immunol 12 753294 (2021)
  40. Polyfunctional antibodies: a path towards precision vaccines for vulnerable populations. Purcell RA, Theisen RM, Arnold KB, Chung AW, Selva KJ. Front Immunol 14 1183727 (2023)
  41. Effect of posttranslational modifications and subclass on IgG activity: from immunity to immunotherapy. Nimmerjahn F, Vidarsson G, Cragg MS. Nat Immunol 24 1244-1255 (2023)
  42. Multifaceted roles of Fcγ receptors in COVID-19 and vaccine responses. Bouayad A. Am J Transl Res 15 3040-3059 (2023)

Articles citing this publication (45)

  1. Decoding the Human Immunoglobulin G-Glycan Repertoire Reveals a Spectrum of Fc-Receptor- and Complement-Mediated-Effector Activities. Dekkers G, Treffers L, Plomp R, Bentlage AEH, de Boer M, Koeleman CAM, Lissenberg-Thunnissen SN, Visser R, Brouwer M, Mok JY, Matlung H, van den Berg TK, van Esch WJE, Kuijpers TW, Wouters D, Rispens T, Wuhrer M, Vidarsson G. Front Immunol 8 877 (2017)
  2. Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity. Quast I, Keller CW, Maurer MA, Giddens JP, Tackenberg B, Wang LX, Münz C, Nimmerjahn F, Dalakas MC, Lünemann JD. J Clin Invest 125 4160-4170 (2015)
  3. Anti-HA Glycoforms Drive B Cell Affinity Selection and Determine Influenza Vaccine Efficacy. Wang TT, Maamary J, Tan GS, Bournazos S, Davis CW, Krammer F, Schlesinger SJ, Palese P, Ahmed R, Ravetch JV. Cell 162 160-169 (2015)
  4. The Structural Role of Antibody N-Glycosylation in Receptor Interactions. Subedi GP, Barb AW. Structure 23 1573-1583 (2015)
  5. Structural basis for binding of human IgG1 to its high-affinity human receptor FcγRI. Kiyoshi M, Caaveiro JM, Kawai T, Tashiro S, Ide T, Asaoka Y, Hatayama K, Tsumoto K. Nat Commun 6 6866 (2015)
  6. Multi-level glyco-engineering techniques to generate IgG with defined Fc-glycans. Dekkers G, Plomp R, Koeleman CA, Visser R, von Horsten HH, Sandig V, Rispens T, Wuhrer M, Vidarsson G. Sci Rep 6 36964 (2016)
  7. Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs. Fiebiger BM, Maamary J, Pincetic A, Ravetch JV. Proc Natl Acad Sci U S A 112 E2385-94 (2015)
  8. Glycoengineered Monoclonal Antibodies with Homogeneous Glycan (M3, G0, G2, and A2) Using a Chemoenzymatic Approach Have Different Affinities for FcγRIIIa and Variable Antibody-Dependent Cellular Cytotoxicity Activities. Kurogochi M, Mori M, Osumi K, Tojino M, Sugawara S, Takashima S, Hirose Y, Tsukimura W, Mizuno M, Amano J, Matsuda A, Tomita M, Takayanagi A, Shoda S, Shirai T. PLoS One 10 e0132848 (2015)
  9. Enhanced Effector Functions Due to Antibody Defucosylation Depend on the Effector Cell Fcγ Receptor Profile. Bruggeman CW, Dekkers G, Bentlage AEH, Treffers LW, Nagelkerke SQ, Lissenberg-Thunnissen S, Koeleman CAM, Wuhrer M, van den Berg TK, Rispens T, Vidarsson G, Kuijpers TW. J Immunol 199 204-211 (2017)
  10. Transient Glyco-Engineering to Produce Recombinant IgA1 with Defined N- and O-Glycans in Plants. Dicker M, Tschofen M, Maresch D, König J, Juarez P, Orzaez D, Altmann F, Steinkellner H, Strasser R. Front Plant Sci 7 18 (2016)
  11. Antigen binding allosterically promotes Fc receptor recognition. Zhao J, Nussinov R, Ma B. MAbs 11 58-74 (2019)
  12. Monocyte recruitment by HLA IgG-activated endothelium: the relationship between IgG subclass and FcγRIIa polymorphisms. Valenzuela NM, Trinh KR, Mulder A, Morrison SL, Reed EF. Am J Transplant 15 1502-1518 (2015)
  13. Processing of complex N-glycans in IgG Fc-region is affected by core fucosylation. Castilho A, Gruber C, Thader A, Oostenbrink C, Pechlaner M, Steinkellner H, Altmann F. MAbs 7 863-870 (2015)
  14. Fc Sialylation Prolongs Serum Half-Life of Therapeutic Antibodies. Bas M, Terrier A, Jacque E, Dehenne A, Pochet-Béghin V, Beghin C, Dezetter AS, Dupont G, Engrand A, Beaufils B, Mondon P, Fournier N, de Romeuf C, Jorieux S, Fontayne A, Mars LT, Monnet C. J Immunol 202 1582-1594 (2019)
  15. Role of sialylation in the anti-inflammatory activity of intravenous immunoglobulin - F(ab')₂ versus Fc sialylation. Schwab I, Nimmerjahn F. Clin Exp Immunol 178 Suppl 1 97-99 (2014)
  16. Structural characterization of GASDALIE Fc bound to the activating Fc receptor FcγRIIIa. Ahmed AA, Keremane SR, Vielmetter J, Bjorkman PJ. J Struct Biol 194 78-89 (2016)
  17. Assessing the Heterogeneity of the Fc-Glycan of a Therapeutic Antibody Using an engineered FcγReceptor IIIa-Immobilized Column. Kiyoshi M, Caaveiro JMM, Tada M, Tamura H, Tanaka T, Terao Y, Morante K, Harazono A, Hashii N, Shibata H, Kuroda D, Nagatoishi S, Oe S, Ide T, Tsumoto K, Ishii-Watabe A. Sci Rep 8 3955 (2018)
  18. Pro-inflammatory State in Monoclonal Gammopathy of Undetermined Significance and in Multiple Myeloma Is Characterized by Low Sialylation of Pathogen-Specific and Other Monoclonal Immunoglobulins. Bosseboeuf A, Allain-Maillet S, Mennesson N, Tallet A, Rossi C, Garderet L, Caillot D, Moreau P, Piver E, Girodon F, Perreault H, Brouard S, Nicot A, Bigot-Corbel E, Hermouet S, Harb J. Front Immunol 8 1347 (2017)
  19. Clinical severity of visceral leishmaniasis is associated with changes in immunoglobulin g fc N-glycosylation. Gardinassi LG, Dotz V, Hipgrave Ederveen A, de Almeida RP, Nery Costa CH, Costa DL, de Jesus AR, Mayboroda OA, Garcia GR, Wuhrer M, de Miranda Santos IK. mBio 5 e01844 (2014)
  20. Gp120 on HIV-1 Virions Lacks O-Linked Carbohydrate. Stansell E, Panico M, Canis K, Pang PC, Bouché L, Binet D, O'Connor MJ, Chertova E, Bess J, Lifson JD, Haslam SM, Morris HR, Desrosiers RC, Dell A. PLoS One 10 e0124784 (2015)
  21. IgG subclass and vaccination stimulus determine changes in antigen specific antibody glycosylation in mice. Kao D, Lux A, Schaffert A, Lang R, Altmann F, Nimmerjahn F. Eur J Immunol 47 2070-2079 (2017)
  22. Human DC-SIGN and CD23 do not interact with human IgG. Temming AR, Dekkers G, van de Bovenkamp FS, Plomp HR, Bentlage AEH, Szittner Z, Derksen NIL, Wuhrer M, Rispens T, Vidarsson G. Sci Rep 9 9995 (2019)
  23. Fcab-HER2 Interaction: a Ménage à Trois. Lessons from X-Ray and Solution Studies. Lobner E, Humm AS, Göritzer K, Mlynek G, Puchinger MG, Hasenhindl C, Rüker F, Traxlmayr MW, Djinović-Carugo K, Obinger C. Structure 25 878-889.e5 (2017)
  24. Impact of Fc N-glycan sialylation on IgG structure. Zhang Z, Shah B, Richardson J. MAbs 11 1381-1390 (2019)
  25. From Rhesus macaque to human: structural evolutionary pathways for immunoglobulin G subclasses. Tolbert WD, Subedi GP, Gohain N, Lewis GK, Patel KR, Barb AW, Pazgier M. MAbs 11 709-724 (2019)
  26. Impact of N-glycosylation on Fcγ receptor / IgG interactions: unravelling differences with an enhanced surface plasmon resonance biosensor assay based on coiled-coil interactions. Cambay F, Henry O, Durocher Y, De Crescenzo G. MAbs 11 435-452 (2019)
  27. The Impact of Immunoglobulin G1 Fc Sialylation on Backbone Amide H/D Exchange. Kuhne F, Bonnington L, Malik S, Thomann M, Avenal C, Cymer F, Wegele H, Reusch D, Mormann M, Bulau P. Antibodies (Basel) 8 E49 (2019)
  28. Weak protein interactions and pH- and temperature-dependent aggregation of human Fc1. Wu H, Truncali K, Ritchie J, Kroe-Barrett R, Singh S, Robinson AS, Roberts CJ. MAbs 7 1072-1083 (2015)
  29. CH2 domain orientation of human immunoglobulin G in solution: Structural comparison of glycosylated and aglycosylated Fc regions using small-angle X-ray scattering. Yageta S, Imamura H, Shibuya R, Honda S. MAbs 11 453-462 (2019)
  30. Enhanced Immunomodulatory Effect of Intravenous Immunoglobulin by Fc Galactosylation and Nonfucosylation. Mimura Y, Mimura-Kimura Y, Saldova R, Rudd PM, Jefferis R. Front Immunol 13 818382 (2022)
  31. Solid-Phase Enzymatic Remodeling Produces High Yields of Single Glycoform Antibodies. Tayi VS, Butler M. Biotechnol J 13 e1700381 (2018)
  32. Two-faced Fcab prevents polymerization with VEGF and reveals thermodynamics and the 2.15 Å crystal structure of the complex. Lobner E, Humm AS, Mlynek G, Kubinger K, Kitzmüller M, Traxlmayr MW, Djinović-Carugo K, Obinger C. MAbs 9 1088-1104 (2017)
  33. Cyanovirin-N Binds Viral Envelope Proteins at the Low-Affinity Carbohydrate Binding Site without Direct Virus Neutralization Ability. Maier I, Schiestl RH, Kontaxis G. Molecules 26 3621 (2021)
  34. Impact of IgG1 N-glycosylation on their interaction with Fc gamma receptors. Cambay F, Raymond C, Brochu D, Gilbert M, Tu TM, Cantin C, Lenferink A, Grail M, Henry O, De Crescenzo G, Durocher Y. Curr Res Immunol 1 23-37 (2020)
  35. Identification of serum glycobiomarkers for Hepatocellular Carcinoma using lectin microarrays. Zhang Y, Zhang S, Liu J, Zhang Y, Liu Y, Shen S, Tian F, Yan G, Gao Y, Qin X. Front Immunol 13 973993 (2022)
  36. Sex effect on the correlation of immunoglobulin G glycosylation with rheumatoid arthritis disease activity. Ercan A. Turk J Biol 44 406-416 (2020)
  37. Synthetic nanobodies as tools to distinguish IgG Fc glycoforms. Kao KS, Gupta A, Zong G, Li C, Kerschbaumer I, Borghi S, Achkar JM, Bournazos S, Wang LX, Ravetch JV. Proc Natl Acad Sci U S A 119 e2212658119 (2022)
  38. The Rapidly Expanding Nexus of Immunoglobulin G N-Glycomics, Suboptimal Health Status, and Precision Medicine. Russell A, Wang W. Exp Suppl 112 545-564 (2021)
  39. Highly sensitive characterization of non-human glycan structures of monoclonal antibody drugs utilizing tandem mass spectrometry. She YM, Dai S, Tam RY. Sci Rep 12 15109 (2022)
  40. Synthesis and Immunological Study of N-Glycan-Bacteriophage Qβ Conjugates Reveal Dominant Antibody Responses to the Conserved Chitobiose Core. Donahue TC, Zong G, O'Brien NA, Ou C, Gildersleeve JC, Wang LX. Bioconjug Chem 33 1350-1362 (2022)
  41. Systematic Analysis of the Expression and Prognosis of Fcγ Receptors in Clear Cell Renal Cell Carcinoma. Nie W, Yao Y, Luo B, Zhu J, Li S, Yang X, Luo T, Liu W, Yan S. Front Oncol 12 755936 (2022)
  42. The Role of IgG Fc Region N-Glycosylation in the Pathomechanism of Rheumatoid Arthritis. Gyebrovszki B, Ács A, Szabó D, Auer F, Novozánszki S, Rojkovich B, Magyar A, Hudecz F, Vékey K, Drahos L, Sármay G. Int J Mol Sci 23 5828 (2022)
  43. Global conformational changes in IgG-Fc upon mutation of the FcRn-binding site are not associated with altered antibody-dependent effector functions. Burvenich IJG, Farrugia W, Liu Z, Makris D, King D, Gloria B, Perani A, Allan LC, Scott AM, Ramsland PA. Biochem J 475 2179-2190 (2018)
  44. Lectin and Liquid Chromatography-Based Methods for Immunoglobulin (G) Glycosylation Analysis. Petrović T, Trbojević-Akmačić I. Exp Suppl 112 29-72 (2021)
  45. The isotype repertoire of antibodies against novel UH-RA peptides in rheumatoid arthritis. De Winter LM, Geusens P, Lenaerts J, Vanhoof J, Stinissen P, Somers V. Arthritis Res Ther 18 130 (2016)


Quick links