1. Department of Clinical Research, NHO Yamaguchi-Ube Medical Center, 685 Higashi-Kiwa, Ube 755-0241, Japan 2. Laboratory of Molecular Biology and Bioresponse, Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kitashirakawa, Oiwake-Cho, Sakyo-Ku, Kyoto 606-8502, Japan 3. NIBRT GlycoScience Group, National Institute for Bioprocessing Research and Training, Mount Merrion, Blackrock, Dublin 4, Ireland 4. Center for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube 755-8505, Japan 5. Center for Gene Research, Yamaguchi University, 1-1-1 Minami-Kogushi, Ube 755-8505, Japan 6. Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, 1-308 Suematsu, Nonoichi, Ishikawa 921-8836, Japan
Glycosylation of the Fc region of IgG has a profound impact on the safety and clinical efficacy of therapeutic antibodies. While the biantennary complex-type oligosaccharide attached to Asn297 of the Fc is essential for antibody effector functions, fucose and outer-arm sugars attached to the core heptasaccharide that generate structural heterogeneity (glycoforms) exhibit unique biological activities. Hence, efficient and quantitative glycan analysis techniques have been increasingly important for the development and quality control of therapeutic antibodies, and glycan profiles of the Fc are recognized as critical quality attributes. In the past decade our understanding of the influence of glycosylation on the structure/function of IgG-Fc has grown rapidly through X-ray crystallographic and nuclear magnetic resonance studies, which provides possibilities for the design of novel antibody therapeutics. Furthermore, the chemoenzymatic glycoengineering approach using endoglycosidase-based glycosynthases may facilitate the development of homogeneous IgG glycoforms with desirable functionality as nextgeneration therapeutic antibodies. Thus, the Fc glycans are fertile ground for the improvement of the safety, functionality, and efficacy of therapeutic IgG antibodies in the era of precision medicine.
Ahmed AA, Giddens J, Pincetic A, Lomino JV, Ravetch JV, Wang LX, Bjorkman PJ (2014) Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. J Mol Biol 426:3166–3179
2
Albert H, Collin M, Dudziak D, Ravetch JV, Nimmerjahn F (2008) In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner. Proc Natl Acad Sci USA 105:15005–15009
3
Allhorn M, Collin M (2009) Sugar-free antibodies—the bacterial solution to autoimmunity? Ann N Y Acad Sci 1173:664–669
4
Anthony RM, Kobayashi T, Wermeling F, Ravetch JV (2011) Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature 475:110–113
5
Anthony RM, Nimmerjahn F, Ashline DJ, Reinhold VN, Paulson JC, Ravetch JV (2008a) Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science 320:373–376
6
Anthony RM, Wermeling F, Karlsson MC, Ravetch JV (2008b) Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci USA 105:19571–19578
7
Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA (2006) The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol 25:21–50
8
Ashwell G, Harford J (1982) Carbohydrate-specific receptors of the liver. Annu Rev Biochem 51:531–554
9
Barb AW, Brady EK, Prestegard JH (2009) Branch-specific sialylation of IgG-Fc glycans by ST6Gal-I. Biochemistry 48:9705–9707
10
Barb AW, Meng L, Gao Z, Johnson RW, Moremen KW, Prestegard JH (2012) NMR characterization of immunoglobulin G Fc glycan motion on enzymatic sialylation. Biochemistry 51:4618–4626
11
Baruah K, Bowden TA, Krishna BA, Dwek RA, Crispin M, Scanlan CN (2012) Selective deactivation of serum IgG: a general strategy for the enhancement of monoclonal antibody receptor interactions. J Mol Biol 420:1–7
12
Bazin R, Lemieux R, Tremblay T (2006) Reversal of immune thrombocytopenia in mice by cross-linking human immunoglobulin G with a high-affinity monoclonal antibody. Br J Haematol 135:97–100
13
Bones J, Mittermayr S, O’Donoghue N, Guttman A, Rudd PM (2010) Ultra performance liquid chromatographic profiling of serum N-glycans for fast and efficient identification of cancer associated alterations in glycosylation. Anal Chem 82:10208–10215
14
Borrok MJ, Jung ST, Kang TH, Monzingo AF, Georgiou G (2012) Revisiting the role of glycosylation in the structure of human IgG Fc. ACS Chem Biol 7:1596–1602
15
Bruhns P, Samuelsson A, Pollard JW, Ravetch JV (2003) Colonystimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease. Immunity 18:573–581
16
Campbell IK, Miescher S, Branch DR, Mott PJ, Lazarus AH, Han D, Maraskovsky E, Zuercher AW, Neschadim A, Leontyev Det al. (2014) Therapeutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of sialylation or basophils. J Immunol 192:5031–5038
17
Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro Det al. (2008) Cetuximabinduced anaphylaxis and IgE specific for galactose-alpha-1,3- galactose. N Engl J Med 358:1109–1117
18
Collin M, Shannon O, Bjorck L (2008) IgG glycan hydrolysis by a bacterial enzyme as a therapy against autoimmune conditions. Proc Natl Acad Sci USA 105:4265–4270
19
Crispin M, Yu X, Bowden TA (2013) Crystal structure of sialylated IgG Fc: implications for the mechanism of intravenous immunoglobulin therapy. Proc Natl Acad Sci USA 110:E3544–3546
20
Davies AM, Jefferis R, Sutton BJ (2014a) Crystal structure of deglycosylated human IgG4-Fc. Mol Immunol 62:46–53
21
Davies AM, Rispens T, Ooijevaar-de Heer P, Gould HJ, Jefferis R, Aalberse RC, Sutton BJ (2014b) Structural determinants of unique properties of human IgG4-Fc. J Mol Biol 426:630–644
22
Debre M, Bonnet MC, Fridman WH, Carosella E, Philippe N, Reinert P, Vilmer E, Kaplan C, Teillaud JL, Griscelli C (1993) Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 342:945–949
23
Deisenhofer J (1981) Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-A resolution. Biochemistry 20:2361–2370
24
Delord JP, Tabernero J, Garcia-Carbonero R, Cervantes A, Gomez-Roca C, Berge Y, Capdevila J, Paz-Ares L, Roda D, Delmar Pet al.(2014) Open-label, multicentre expansion cohort to evaluate imgatuzumab in pre-treated patients with KRAS-mutant advanced colorectal carcinoma. Eur J Cancer 50:496–505
25
Doherty M, McManus CA, Duke R, Rudd PM (2012) High-throughput quantitative N-glycan analysis of glycoproteins. Methods Mol Biol 899:293–313
26
Dwek RA (1998) Biological importance of glycosylation. Dev Biol Stand 96:43–47
27
Fan SQ, Huang W, Wang LX (2012) Remarkable transglycosylation activity of glycosynthase mutants of endo-D, an endo-beta-Nacetylglucosaminidase from Streptococcus pneumoniae. J Biol Chem 287:11272–11281
28
Feige MJ, Nath S, Catharino SR, Weinfurtner D, Steinbacher S, Buchner J (2009) Structure of the murine unglycosylated IgG1 Fc fragment. J Mol Biol 391:599–608
29
Ferrara C, Grau S, Jager C, Sondermann P, Brunker P, Waldhauer I, Hennig M, Ruf A, Rufer AC, Stihle Met al. (2011) Unique carbohydrate–carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose. Proc Natl Acad Sci USA 108:12669–12674
30
Ferrara C, Stuart F, Sondermann P, Brunker P, Umana P (2006) The carbohydrate at FcgammaRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J Biol Chem 281:5032–5036
31
Fujita K, Kobayashi K, Iwamatsu A,Takeuchi M, Kumagai H, Yamamoto K (2004) Molecular cloning of Mucor hiemalis endobeta-N-acetylglucosaminidase and some properties of the recombinant enzyme. Arch Biochem Biophys 432:41–49
32
Gala FA, Morrison SL (2004) V region carbohydrate and antibody expression. J Immunol 172:5489–5494
33
Galili U, Anaraki F, Thall A, Hill-Black C, Radic M (1993) One percent of human circulating B lymphocytes are capable of producing the natural anti-Gal antibody. Blood 82:2485–2493
34
Ghirlando R, Keown MB, Mackay GA, Lewis MS, Unkeless JC, Gould HJ (1995) Stoichiometry and thermodynamics of the interaction between the Fc fragment of human IgG1 and its lowaffinity receptor Fc gamma RIII. Biochemistry 34:13320–13327
35
Giddens JP, Wang LX (2015) Chemoenzymatic Glyco-engineering of Monoclonal Antibodies. Methods Mol Biol 1321:375–387
36
Goetze AM, Liu YD, Zhang Z, Shah B, Lee E, Bondarenko PV, Flynn GC (2011) High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology 21:949–959
37
Grey AA, Narasimhan S, Brisson JR, Schachter H, Carver JP (1982) Structure of the glycopeptides of a human gamma 1-immunoglobulin G (Tem) myeloma protein as determined by 360-megahertz nuclear magnetic resonance spectroscopy. Can J Biochem 60:1123–1131
38
Guhr T, Bloem J, Derksen NI, Wuhrer M, Koenderman AH, Aalberse RC, Rispens T (2011) Enrichment of sialylated IgG by lectin fractionation does not enhance the efficacy of immunoglobulinGin a murine model of immune thrombocytopenia. PloS One 6:e21246
39
Ha S, Wang Y, Rustandi RR (2011) Biochemical and biophysical characterization of humanized IgG1 produced in Pichia pastoris. MAbs 3:453–460
40
Higel F, Seidl A, Sorgel F, Friess W (2016) N-glycosylation heterogeneity and the influence on structure, function and pharmacokinetics of monoclonal antibodies and Fc fusion proteins. Eur J Pharm Biopharm 100:94–100
41
Holland M, Yagi H, Takahashi N, Kato K, Savage CO, Goodall DM, Jefferis R (2006) Differential glycosylation of polyclonal IgG, IgG-Fc and IgG-Fab isolated from the sera of patients with ANCAassociated systemic vasculitis. Biochim Biophys Acta 1760:669–677
42
Huang W, Giddens J, Fan SQ, Toonstra C, Wang LX (2012) Chemoenzymatic glycoengineering of intact IgG antibodies for gain of functions. J Am Chem Soc 134:12308–12318
43
Iida S, Misaka H, Inoue M, Shibata M, Nakano R, Yamane-Ohnuki N, Wakitani M, Yano K, Shitara K, Satoh M (2006) Nonfucosylated therapeutic IgG1 antibody can evade the inhibitory effect of serum immunoglobulinGon antibody-dependent cellular cytotoxicity through its high binding to FcgammaRIIIa. Clin Cancer Res 12:2879–2887
44
Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S, Saburi Y, Miyamoto T, Takemoto S, Suzushima Het al.(2012) Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol 30:837–842
45
Iwamoto T, Okamoto A, Ishinaga H, Shimizu K, Gayle AA, Arai N, Takeuchi K, Okuda M (2016) A novel approach to predict cetuximab-induced hypersensitivity reaction: detection of drugspecific IgE on basophils. Cancer Med 5:1004–1012
46
Jefferis R (2009) Glycosylation as a strategy to improve antibodybased therapeutics. Nat Rev Drug Discov 8:226–234
47
Jefferis R (2012) Isotype and glycoform selection for antibody therapeutics. Arch Biochem Biophys 526:159–166
48
Jefferis R (2017) Characterization of biosimilar biologics: the link between structure and functions. In: Endrenyi L, Declerck P, Chow S-C (eds) Drugs and the pharmaceutical sciences. CRC Press, Boca Raton, pp 109–149
49
Ju MS, Jung ST (2014) Aglycosylated full-length IgG antibodies: steps toward next-generation immunotherapeutics. Curr Opin Biotechnol 30:128–139
50
Ju MS, Na JH, Yu YG, Kim JY, Jeong C, Jung ST (2015) Structural consequences of aglycosylated IgG Fc variants evolved for FcgammaRI binding. Mol Immunol 67:350–356
51
Jung ST, Kang TH, Kelton W, Georgiou G (2011) Bypassing glycosylation: engineering aglycosylated full-length IgG antibodies for human therapy. Curr Opin Biotechnol 22:858–867
52
Jung ST, Reddy ST, Kang TH, Borrok MJ, Sandlie I, Tucker PW, Georgiou G(2010) Aglycosylated IgG variants expressed in bacteria that selectively bind FcgammaRI potentiate tumor cell killing by monocyte-dendritic cells. Proc Natl Acad Sci USA 107:604–609
53
Kanda Y,Yamada T, Mori K, Okazaki A, Inoue M, Kitajima-Miyama K, Kuni-Kamochi R, Nakano R, Yano K, Kakita Set al. (2007) Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. Glycobiology 17:104–118
54
Kaneko Y,Nimmerjahn F, Ravetch JV (2006) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–673
55
Kao D, Danzer H, Collin M, Gross A, Eichler J, Stambuk J,Lauc G, Lux A, Nimmerjahn F (2015) A monosaccharide residue is sufficient to maintain mouse and human IgG subclass activity and directs IgG effector functions to cellular Fc receptors. Cell Rep 13:2376–2385
56
Kato T, Fujita K, Takeuchi M, Kobayashi K, Natsuka S, Ikura K, Kumagai H, Yamamoto K (2002) Identification of an endo-beta-Nacetylglucosaminidase gene in Caenorhabditis elegans and its expression in Escherichia coli. Glycobiology 12:581–587
57
Kobayashi S, Kiyosada T, Shoda S-I (1996) Enzymatic synthesis of chondroitin and its derivatives catalyzed by hyaluronidase. J Am Chem Soc 118:13113–13114
58
Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AE, de Haas M (1997) Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype. Blood 90:1109–1114
59
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
60
Kurogochi M, Mori M, Osumi K, Tojino M, Sugawara S, Takashima S, Hirose Y, Tsukimura W, Mizuno M, Amano Jet al. (2015) Glycoengineered monoclonal antibodies with homogeneous glycan (M3, G0, G2, and A2) using a chemoenzymatic approach have different affinities for FcgammaRIIIa and Variable antibodydependent cellular cytotoxicity activities. PloS One 10:e0132848
61
Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J,Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC (2002) Mannose receptormediated regulation of serum glycoprotein homeostasis. Science 295:1898–1901
62
Leontyev D,Katsman Y, Branch DR (2012a) Mouse background and IVIG dosage are critical in establishing the role of inhibitory Fcgamma receptor for the amelioration of experimental ITP. Blood 119:5261–5264
63
Leontyev D, Katsman Y,Ma XZ, Miescher S, Kasermann F, Branch DR (2012b) Sialylation-independent mechanism involved in the amelioration of murine immune thrombocytopenia using intravenous gammaglobulin. Transfusion 52:1799–1805
64
Li B, Zeng Y, Hauser S, Song H, Wang LX (2005) Highly efficient endoglycosidase-catalyzed synthesis of glycopeptides using oligosaccharide oxazolines as donor substrates. J Am Chem Soc 127:9692–9693
65
Li H, Sethuraman N, Stadheim TA, Zha D, Prinz B, Ballew N, Bobrowicz P, Choi BK, Cook WJ, Cukan Met al.(2006) Optimization of humanized IgGs in glycoengineered Pichia pastoris. Nat Biotechnol 24:210–215
66
Li T,Tong X, Yang Q, Giddens JP, Wang LX (2016) Glycosynthase mutants of endoglycosidase S2 show potent transglycosylation activity and remarkably relaxed substrate specificity for antibody glycosylation remodeling. J Biol Chem 291:16508–16518
67
Lin CW, Tsai MH, Li ST, Tsai TI, Chu KC, Liu YC, Lai MY, Wu CY, Tseng YC, Shivatare SSet al. (2015) A common glycan structure on immunoglobulin G for enhancement of effector functions. Proc Natl Acad Sci USA 112:10611–10616
68
Liu L (2015) Antibody glycosylation and its impact on the pharmacokinetics and pharmacodynamics of monoclonal antibodies and Fc-fusion proteins. J Pharm Sci 104:1866–1884
Liu L, Stadheim A, Hamuro L, Pittman T, Wang W, Zha D, Hochman J, Prueksaritanont T (2011) Pharmacokinetics of IgG1 monoclonal antibodies produced in humanized Pichia pastoris with specific glycoforms: a comparative study with CHO produced materials. Biologicals 39:205–210
71
Lund J, Tanaka T, Takahashi N, Sarmay G, Arata Y, Jefferis R (1990) A protein structural change in aglycosylated IgG3 correlates with loss of huFc gamma R1 and huFc gamma R111 binding and/or activation. Mol Immunol 27:1145–1153
72
Maenaka K, van der Merwe PA, Stuart DI, Jones EY, Sondermann P (2001) The human low affinity Fcgamma receptors IIa, IIb, and III bind IgG with fast kinetics and distinct thermodynamic properties. J Biol Chem 276:44898–44904
73
Mariotte D, Dupont B, Gervais R, Galais MP, Laroche D, Tranchant A, Comby E, Bouhier-Leporrier K, Reimund JM, Le Mauff B (2011) Anti-cetuximab IgE ELISA for identification of patients at a high risk of cetuximab-induced anaphylaxis. MAbs 3:396–401
74
Matsumiya S, Yamaguchi Y, Saito J, Nagano M, Sasakawa H, Otaki S, Satoh M, Shitara K, Kato K (2007) Structural comparison of fucosylated and nonfucosylated Fc fragments of human immunoglobulin G1. J Mol Biol 368:767–779
75
Mimura Y, Ashton PR, Takahashi N, Harvey DJ, Jefferis R (2007) Contrasting glycosylation profiles between Fab and Fc of a human IgG protein studied by electrospray ionization mass spectrometry. J Immunol Methods 326:116–126
76
Mimura Y, Church S, Ghirlando R, Ashton PR,Dong S, Goodall M, Lund J, Jefferis R(2000) The influence of glycosylation on the thermal stability and effector function expression of human IgG1-Fc: properties of a series of truncated glycoforms. Mol Immunol 37:697–706
77
Mimura Y, Jefferis R, Mimura-Kimura Y, Abrahams J,Rudd PM (2009) Glycosylation of therapeutic IgGs. In: An Z (ed) Therapeutic monoclonal antibodies: from the Bench to the Clinic. Wiley, Hoboken, pp 67–89
78
Mimura Y, Kelly RM, Unwin L, Albrecht S, Jefferis R,Goodall M, Mizukami Y,Mimura-Kimura Y, Matsumoto T, Ueoka Het al. (2016) Enhanced sialylation of a human chimeric IgG1 variant produced in human and rodent cell lines. J Immunol Methods 428:30–36
79
Mimura Y, Sondermann P, Ghirlando R, Lund J, Young SP, Goodall M, Jefferis R (2001) Role of oligosaccharide residues of IgG1-Fc in Fc gamma RIIb binding. J Biol Chem 276:45539–45547
80
Mizushima T, Yagi H, Takemoto E, Shibata-Koyama M, Isoda Y, Iida S, Masuda K, Satoh M, Kato K (2011) Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans. Genes Cells 16:1071–1080
81
Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek Eet al. (2010) Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115:4393–4402
82
Muramatsu H, Tachikui H, Ushida H, Song X, Qiu Y, Yamamoto S, Muramatsu T (2001) Molecular cloning and expression of endobeta-N-acetylglucosaminidase D, which acts on the core structure of complex type asparagine-linked oligosaccharides. J Biochem 129:923–928
83
Niwa R, Natsume A,Uehara A ,Wakitani M, Iida S, Uchida K,Satoh M, Shitara K (2005) IgG subclass-independent improvement of antibody-dependent cellular cytotoxicity by fucose removal from Asn297-linked oligosaccharides. J ImmunolMethods 306:151–160
84
Noguchi M, Fujieda T, Huang WC, Ishihara M, Kobayashi A, Shoda S-I (2012) A practical one-step synthesis of 1,2-oxazoline derivatives from unprotected sugars and its application to chemoenzymatic beta-N-acetylglucosaminidation of disialooligosaccharide. Helv. Chim. Acta 95:1928–1936
85
Noguchi M, Tanaka T, Gyakushi H, Kobayashi A, Shoda S (2009) Efficient synthesis of sugar oxazolines from unprotected N-acetyl-2-amino sugars by using chloroformamidinium reagent in water. J Org Chem 74:2210–2212
86
Nose M, Wigzell H (1983) Biological significance of carbohydrate chains on monoclonal antibodies. Proc Natl Acad Sci USA 80:6632–6636
87
Okazaki A, Shoji-Hosaka E,Nakamura K , Wakitani M, Uchida K, Kakita S, Tsumoto K, Kumagai I, Shitara K (2004) Fucose depletion from human IgG1 oligosaccharide enhances binding enthalpy and association rate between IgG1 and FcgammaRIIIa. J Mol Biol 336:1239–1249
88
Othy S, Topcu S, Saha C, Kothapalli P, Lacroix-Desmazes S, Kasermann F, Miescher S, Bayry J, Kaveri SV (2014) Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin. Eur J Immunol 44:2059–2063
89
Padlan EA (1990) X-ray diffraction studies of antibody constant regions. In: Metzger H (ed) Fc receptors and the action of antibodies. American Society for Microbiology, Washington, DC, pp 12–30
90
Pound JD, Lund J, Jefferis R (1993) Aglycosylated chimaeric human IgG3 can trigger the human phagocyte respiratory burst. Mol Immunol 30:233–241
91
Pucic M, Knezevic A, Vidic J, Adamczyk B, Novokmet M, Polasek O, Gornik O, Supraha-Goreta S, Wormald MR, Redzic Iet al. (2011) High throughput isolation and glycosylation analysis of IgGvariability and heritability of the IgG glycome in three isolated human populations. Mol Cell Proteomics 10(M111):010090
92
Qian J, Liu T, Yang L, Daus A, Crowley R, Zhou Q (2007) Structural characterization of N-linked oligosaccharides on monoclonal antibody cetuximab by the combination of orthogonal matrixassisted laser desorption/ionization hybrid quadrupole–quadrupole time-of-flight tandem mass spectrometry and sequential enzymatic digestion. Anal Biochem 364:8–18
93
Quast I, Keller CW, Maurer MA, Giddens JP, Tackenberg B, Wang LX, Munz C, Nimmerjahn F, Dalakas MC, Lunemann JD (2015) Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity. J Clin Invest 125:4160–4170
94
Radaev S, Motyka S, Fridman WH, Sautes-Fridman C, Sun PD (2001) The structure of a human type III Fcgamma receptor in complex with Fc. J Biol Chem 276:16469–16477
95
Radcliffe CM, Arnold JN, Suter DM, Wormald MR, Harvey DJ, Royle L, Mimura Y, Kimura Y,Sim RB , Inoges Set al. (2007) Human follicular lymphoma cells contain oligomannose glycans in the antigen-binding site of the B-cell receptor. J Biol Chem 282:7405–7415
96
Raju TS, Briggs JB, Borge SM, Jones AJ (2000) Species-specific variation in glycosylation of IgG: evidence for the species-specific sialylation and branch-specific galactosylation and importance for engineering recombinant glycoprotein therapeutics. Glycobiology 10:477–486
97
Raymond C, Robotham A, Spearman M, Butler M, Kelly J, Durocher Y (2015) Production of alpha2,6-sialylated IgG1 in CHO cells. MAbs 7:571–583
98
Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7:715–725
99
Royle L, Radcliffe CM, Dwek RA, Rudd PM (2006) Detailed structural analysis of N-glycans released from glycoproteins in SDS-PAGE gel bands using HPLC combined with exoglycosidase array digestions. Methods Mol Biol 347:125–143
100
Rudd PM, Dwek RA (1997) Glycosylation: heterogeneity and the 3D structure of proteins. Crit Rev Biochem Mol Biol 32:1–100
101
Sarmay G, Lund J, Rozsnyay Z, Gergely J, Jefferis R (1992) Mapping and comparison of the interaction sites on the Fc region of IgG responsible for triggering antibody dependent cellular cytotoxicity (ADCC) through different types of human Fc gamma receptor. Mol Immunol 29:633–639
102
Sazinsky SL, Ott RG, Silver NW, Tidor B, Ravetch JV, Wittrup KD (2008) Aglycosylated immunoglobulin G1 variants productively engage activating Fc receptors. Proc Natl Acad Sci USA 105:20167–20172
103
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
104
Sehn LH, Assouline SE, Stewart DA, Mangel J, Gascoyne RD, Fine G, Frances-Lasserre S, Carlile DJ, Crump M (2012) A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood 119:5118–5125
105
Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LEet al. (2015) Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-Cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol 33:3467–3474
106
Shibata-Koyama M, Iida S, Okazaki A, Mori K, Kitajima-Miyama K, Saitou S, Kakita S, Kanda Y, Shitara K,Kato Ket al. (2009) The N-linked oligosaccharide at Fc gamma RIIIa Asn-45: an inhibitory element for high Fc gamma RIIIa binding affinity to IgG glycoforms lacking core fucosylation. Glycobiology 19:126–134
107
Shields RL, Lai J, Keck R, O’Connell LY, Hong K, Meng YG, Weikert SH, Presta LG (2002) Lack of fucose on human IgG1N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J BiolChem 277:26733–26740
108
Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J, Xie D, Lai J, Stadlen A, Li Bet al. (2001) High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem 276:6591–6604
109
Shinkawa T, Nakamura K, Yamane N, Shoji-Hosaka E, Kanda Y, Sakurada M, Uchida K, Anazawa H, Satoh M, Yamasaki Met al. (2003) The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibodydependent cellular cytotoxicity. J Biol Chem 278:3466–3473
110
Simmons LC, Reilly D, Klimowski L, Raju TS, Meng G, Sims P, Hong K, Shields RL, Damico LA, Rancatore Pet al. (2002) Expression of full-length immunoglobulins in Escherichia coli: rapid and efficient production of aglycosylated antibodies. J Immunol Methods 263:133–147
111
Sondermann P, Huber R, Jacob U (1999) Crystal structure of the soluble form of the human fcgamma-receptor IIb: a new member of the immunoglobulin superfamily at 1.7 A resolution. EMBO J 18:1095–1103
112
Sondermann P,Huber R, Oosthuizen V, Jacob U (2000) The 3.2-A crystal structure of the human IgG1 Fc fragment-Fc gammaRIII complex. Nature 406:267–273
113
Sondermann P, Jacob U (1999) Human Fcgamma receptor IIb expressed in Escherichia coli reveals IgG binding capability. Biol Chem 380:717–721
114
Sun B, Bao W, Tian X, Li M, Liu H, Dong J, Huang W (2014) A simplified procedure for gram-scale production of sialylglycopeptide (SGP) from egg yolks and subsequent semi-synthesis of Man3GlcNAc oxazoline. Carbohydr Res 396:62–69
115
Takegawa K, Tabuchi M, Yamaguchi S, Kondo A, Kato I, Iwahara S (1995) Synthesis of neoglycoproteins using oligosaccharidetransfer activity with endo-beta-N-acetylglucosaminidase. J Biol Chem 270:3094–3099
116
Takegawa K, Yamabe K, Fujita K, Tabuchi M, Mita M, Izu H, Watanabe A, Asada Y, Sano M, Kondo Aet al. (1997) Cloning, sequencing, and expression of Arthrobacter protophormiae endobeta-N-acetylglucosaminidase in Escherichia coli. Arch Biochem Biophys 338:22–28
117
Takeuchi M, Takasaki S, Miyazaki H, Kato T, Hoshi S, Kochibe N, Kobata A (1988) Comparative study of the asparagine-linked sugar chains of human erythropoietins purified from urine and the culture medium of recombinant Chinese hamster ovary cells. J Biol Chem 263:3657–3663
118
Tangvoranuntakul P, Gagneux P, Diaz S, Bardor M, Varki N, Varki A, Muchmore E (2003) Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid. Proc Natl Acad Sci USA 100:12045–12050
119
Tao MH, Morrison SL (1989) Studies of aglycosylated chimeric mouse-human IgG. Role of carbohydrate in the structure and effector functions mediated by the human IgG constant region. J Immunol 143:2595–2601
120
Trinath J, Hegde P, Sharma M, Maddur MS, Rabin M, Vallat JM, Magy L, Balaji KN, Kaveri SV, Bayry J (2013) Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxygenase-2-dependent prostaglandin E2 in human dendritic cells. Blood 122:1419–1427
121
Umana P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE (1999) Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol 17:176–180
122
Umekawa M, Li C, Higashiyama T, Huang W, Ashida H, Yamamoto K, Wang LX (2010) Efficient glycosynthase mutant derived from Mucor hiemalis endo-beta-N-acetylglucosaminidase capable of transferring oligosaccharide from both sugar oxazoline and natural N-glycan. J Biol Chem 285:511–521
123
van den Eijnden DH, Joziasse DH, Dorland L, van Halbeek H, Vliegenthart JF, Schmid K (1980) Specificity in the enzymic transfer of sialic acid to the oligosaccharide branches of b1- and triantennary glycopeptides of alpha 1-acid glycoprotein. Biochem Biophys Res Commun 92:839–845
124
Wang B, Yan L, Yao Z, Roskos LK (2017) Population pharmacokinetics and pharmacodynamics of benralizumab in healthy volunteers and patients with asthma. CPT Pharmacomet Syst Pharmacol. 6(4):249–257
125
Wei Y, Li C, Huang W, Li B, Strome S, Wang LX (2008) Glycoengineering of human IgG1-Fc through combined yeast expression and in vitro chemoenzymatic glycosylation. Biochemistry 47:10294–10304
126
Woof JM, Burton DR (2004) Human antibody-Fc receptor interactions illuminated by crystal structures. Nat Rev Immunol 4:89–99
127
Wright A, Tao MH, Kabat EA, Morrison SL (1991) Antibody variable region glycosylation: position effects on antigen binding and carbohydrate structure. EMBO J 10:2717–2723
128
Wu J, Edberg JC, Redecha PB, Bansal V, Guyre PM, Coleman K, Salmon JE, Kimberly RP (1997) A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 100:1059–1070
129
Wu SJ, Luo J, O’Neil KT, Kang J, Lacy ER, Canziani G, Baker A, Huang M, Tang QM, Raju TSet al. (2010) Structure-based engineering of a monoclonal antibody for improved solubility. Protein Eng Des Sel 23:643–651
130
Yamaguchi Y, Nishimura M, Nagano M, Yagi H, Sasakawa H, Uchida K, Shitara K, Kato K (2006) Glycoform-dependent conformational alteration of the Fc region of human immunoglobulin G1 as revealed by NMR spectroscopy. Biochim Biophys Acta 1760:693–700
131
Yamamoto K, Kadowaki S, Fujisaki M, Kumagai H, Tochikura T (1994) Novel specificities of Mucor hiemalis endo-beta-N-acetylglucosaminidase acting complex asparagine-linked oligosaccharides. Biosci Biotechnol Biochem 58:72–77
132
Yamamoto K, Utsunomiya A, Tobinai K, Tsukasaki K, Uike N, Uozumi K, Yamaguchi K, Yamada Y, Hanada S, Tamura Ket al. (2010) Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. J Clin Oncol 28:1591–1598
133
Yamane-Ohnuki N, Kinoshita S, Inoue-Urakubo M, Kusunoki M, Iida S, Nakano R, Wakitani M, Niwa R, Sakurada M, Uchida Ket al. (2004) Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity. Biotechnol Bioeng 87:614–622
134
Yu X, Vasiljevic S, Mitchell DA, Crispin M, Scanlan CN (2013) Dissecting the molecular mechanism of IVIg therapy: the interaction between serum IgG and DC-SIGN is independent of antibody glycoform or Fc domain. J Mol Biol 425:1253–1258
135
Zhang P, Woen S, Wang T, Liau B, Zhao S, Chen C, Yang Y, Song Z, Wormald MR, Yu Cet al. (2016) Challenges of glycosylation analysis and control: an integrated approach to producing optimal and consistent therapeutic drugs. Drug Discov Today 21:740–765
136
Zhu A, Hurst (2002) Anti-N-glycolylneuraminic acid antibodies identified in healthy human serum. Xenotransplantation 9:376–381
