#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Glycosylation as an Important Regulator of Antibody Function


Authors: L. Uhrík;  L. Hernychová;  B. Vojtěšek
Authors‘ workplace: Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno
Published in: Klin Onkol 2019; 32(Supplementum 3): 46-55
Category: Review
doi: https://doi.org/10.14735/amko20193S

Overview

Background: The glycosylation of constant regions of antibodies significantly affects their interaction capabilities with immune cells. It is a modification that, in addition to the bio­logical activity of antibodies, has an impact on their conformation, stability, solubility, secretion, pharmaco­kinetics, and immunogenicity. The location of glycosylations on the molecule is essential for the proper function of the antibody, as is the structure of the individual glycans. Changes in the glycosylation profiles of antibodies have been described in some physiological processes like pregnancy or ageing, but also in many pathological conditions such as rheumatoid arthritis or gastric, lung and prostate tumours. There are still several unexplained mechanisms that control the glycosylation of antibodies or immune responses, which in turn are regulated by these modifications. Multiple sources describe the importance of some specific glycosylations as potential bio­markers.

Purpose: The aim of this review is to summarise and present the knowledge of the glycosylation of antibodies and to highlight their influence on immune responses and their role dur­ing dis­ease. Their importance is also underlined by the fact that the most of these therapeutic antibodies used and developed are modified by glycosylation. The targeted introduction of appropriate glycosylations, which can promote activities such as antibody-­dependent cellular cytotoxicity, antibody­-dependent cellular phagocytosis or complement­-dependent cytotoxicity, have improved the ability of these antibodies to kill pathogens or tumour cells. Therefore, more attention is be­ing paid to this area. In the future, more effective tools for dia­gnos­ing and treat­ing certain dis­eases can be created with better knowledge.

Keywords:

Antibodies – glycosylation – pharmacology – immune system – therapeutics


Sources

10.4049/ jimmunol.1402025.

56. Takahashi N, Tetaert D, Debuire B et al. Complete amino acid sequence of the delta heavy chain of human immunoglobulin D. Proc Natl Acad Sci USA 1982; 79(9): 2850– 2854. doi: 10.1073/ pnas.79.9.2850.

57. Pucić M, Knezevic A, Vidic J et al. High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations. Mol Cell Proteomics 2011; 10(10): M111. doi: 10.1074/ mcp.M111.010090.

58. Kapur R, Kustiawan I, Vestrheim A et al. A prominent lack of IgG1-Fc fucosylation of platelet alloantibodies in pregnancy. Blood 2014; 123(4): 471– 480. doi: 10.1182/ blood-2013-09-527978.

59. Menni C, Keser T, Mangino M et al. Glycosylation of immunoglobulin g: role of genetic and epigenetic influences. PLoS One 2013; 8(12): e82558. doi: 10.1371/ journal.pone.0082558.

60. Krištić J, Vučković F, Menni C et al. Glycans are a novel bio­marker of chronological and bio­logical ages. J Gerontol A Biol Sci Med Sci 2014; 69(7): 779– 789. doi: 10.1093/ gerona/ glt190.

61. Ercan A, Kohrt WM, Cui J et al. Estrogens regulate glycosylation of IgG in women and men. JCI Insight 2017; 2(4): e89703. doi: 10.1172/ jci.insight.89703.

62. Ruhaak LR, Uh HW, Beekman M et al. Decreased levels of bisect­ing GlcNAc glycoforms of IgG are associated with human longevity. PLoS One 2010; 5(9): e12566. doi: 10.1371/ journal.pone.0012566.

63. van de Geijn FE, Wuhrer M, Selman MH et al. Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: results from a large prospective cohort study. Arthritis Res Ther 2009; 11(6): R193. doi: 10.1186/ ar2892.

64. Bondt A, Selman MH, Deelder AM et al. Association between galactosylation of immunoglobulin G and improvement of rheumatoid arthritis dur­ing pregnancy is independent of sialylation. J Proteome Res 2013; 12(10): 4522– 4531. doi: 10.1021/ pr400589m.

65. Novokmet M, Lukic E, Vuckovic F et al. Changes in IgG and total plasma protein glycomes in acute systemic inflammation. Sci Rep 2014; 4: 4347. doi: 10.1038/ srep04347.

66. Troelsen LN, Jacobsen S, Abrahams JL et al. IgG glycosylation changes and MBL2 polymorphisms: associations with markers of systemic inflammation and joint destruction in rheumatoid arthritis. J Rheumatol 2012; 39(3): 463– 469. doi: 10.3899/ jrheum.110584.

67. Pezer M, Stambuk J, Perica M et al. Effects of allergic dis­eases and age on the composition of serum IgG glycome in children. Sci Rep 2016; 6: 33198. doi: 10.1038/ srep33198.

68. de Jong SE, Selman MH, Adegnika AA et al. IgG1 Fc N-glycan galactosylation as a bio­marker for immune activation. Sci Rep 2016; 6: 28207. doi: 10.1038/ srep28207.

69. Mittermayr S, Le GN, Clarke C et al. Polyclonal immunoglobulin G N-glycosylation in the pathogenesis of plasma cell disorders. J Proteome Res 2017; 16(2): 748– 762. doi: 10.1021/ acs.jproteome.6b00768.

70. Kodar K, Stadlmann J, Klaamas K, Sergeyev B, Kurtenkov O. Immunoglobulin G Fc N-glycan profil­ing in patients with gastric cancer by LC-ESI-MS: relation to tumor progression and survival. Glycoconj J 2012; 29(1): 57– 66. doi: 10.1007/ s10719-011-9364-z.

71. Bones J, Mittermayr S, O’Donoghue N et al. Ultra performance liquid chromatographic profil­ing of serum N-glycans for fast and efficient identification of cancer associated alterations in glycosylation. Anal Chem 2010; 82(24): 10208– 10215. doi: 10.1021/ ac102860w.

72. Kanoh Y, Mashiko T, Danbara M et al. Analysis of the oligosaccharide chain of human serum immunoglobulin G in patients with localized or metastatic cancer. Oncology 2004; 66(5): 365– 370. doi: 10.1159/ 000079484.

73. Arnold JN, Saldova R, Galligan MC et al. Novel glycan bio­markers for the detection of lung cancer. J Proteome Res 2011; 10(4): 1755– 1764. doi: 10.1021/ pr101034t.

74. Markiewski MM, DeAngelis RA, Benencia F et al. Modulation of the antitumor immune response by complement. Nat Immunol 2008; 9(11): 1225– 1235. doi: 10.1038/ ni.1655.

75. Vuckovic F, Theodoratou E, Thaci K et al. IgG glycome in colorectal cancer. Clin Cancer Res 2016; 22(12): 3078– 3086. doi: 10.1158/ 1078-0432.CCR-15-1867.

76. Theodoratou E, Thaci K, Agakov F et al. Glycosylation of plasma IgG in colorectal cancer prognosis Sci Rep 2016; 6: 28098. doi: 10.1038/ srep28098.

77. Kanoh Y, Ohara T, Tadano T et al. Changes to N-linked oligosaccharide chains of human serum immunoglobulin G and matrix metalloproteinase-2 with cancer progres­sion. Anticancer Res 2008; 28(2A): 715– 720.

78. Qian Y, Wang Y, Zhang X et al. Quantitative analysis of serum IgG galactosylation assists differential dia­gnosis of ovarian cancer. J Proteome Res 2013; 12(9): 4046– 4055. doi: 10.1021/ pr4003992.

79. Beck A, Wurch T, Bailly C et al. Strategies and challenges for the next generation of therapeutic antibodies. Nat Rev Immunol 2010; 10(5): 345– 352. doi: 10.1038/ nri2747.

80. Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs 2018; 10(2): 183– 203. doi: 10.1080/ 19420862. 2018.1415671.

81. Kaplon H, Reichert JM. Antibodies to watch in 2019. MAbs 2019; 11(2): 219– 238. doi: 10.1080/ 19420862.2018. 1556465.

82. Kirchhoff CF, Wang XM, Conlon HD et al. Biosimilars: key regulatory considerations and similarity assessment tools. Biotechnol Bioeng 2017; 114(12): 2696– 2705. doi: 10.1002/ bit.26438.

83. Jefferis R. Glycosylation of recombinant antibody therapeutics. Biotechnol Prog 2005; 21(1): 11– 16. doi: 10.1021/ bp040016j.

84. Raju S. Glycosylation variations with expression systems and their impact on bio­logical activity of therapeutic immunoglobulins. BioProcess International 2003; 1: 44– 53.

85. Yoo EM, Chintalacharuvu KR, Penichet MLet al. Myeloma expression systems. J Immunol Methods 2002; 261(1– 2): 1– 20. doi: 10.1016/ s0022-1759(01)00559-2.

86. Liu CP, Tsai TI, Cheng T et al. Glycoengineer­ing of antibody (Herceptin) through yeast expression and in vitro enzymatic glycosylation. Proc Natl Acad Sci USA 2018; 115(4): 720– 725. doi: 10.1073/ pnas.1718172115.

87. Li H, Sethuraman N, Stadheim TA et al. Optimization of humanized IgGs in glycoengineered Pichia pastoris. Nat Biotechnol 2006; 24(2): 210– 215. doi: 10.1038/ nbt1178.

88. Durocher Y, Butler M. Expression systems for therapeutic glycoprotein production. Curr Opin Biotechnol 2009; 20(6): 700– 707. doi: 10.1016/ j.copbio­.2009.10.008.

89. Ha S, Wang Y, Rustandi RR. Biochemical and bio­physical characterization of humanized IgG1 produced in Pichia pastoris. MAbs 2011; 3(5): 453– 460. doi: 10.4161/ mabs.3.5.16891.

90. Sehn LH, Assouline SE, Stewart DA et al. A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood 2012; 119(22): 5118– 5125. doi: 10.1182/ blood-2012-02-408773.

91. Ashwell G, Harford J. Carbohydrate-specific receptors of the liver. Annu Rev Biochem 1982; 51: 531– 554. doi: 10.1146/ annurev.bi.51.070182.002531.

92. Mi Y, Lin A, Fiete D et al. Modulation of mannose and asialoglycoprotein receptor expression determines glycoprotein hormone half-life at critical points in the reproductive cycle. J Biol Chem 2014; 289(17): 12157– 12167. doi: 10.1074/ jbc.M113.544973.

93. Baenziger JU, Fiete D. Galactose and N-acetylgalactosamine-specific endocytosis of glycopeptides by isolated rat hepatocytes. Cell 1980; 22(2 Pt 2): 611– 620. doi: 10.1016/ 0092-8674(80)90371-2.

94. Park EI, Manzella SM, Baenziger JU. Rapid clearance of sialylated glycoproteins by the asialoglycoprotein receptor. J Biol Chem 2003; 278(7): 4597– 4602. doi: 10.1074/ jbc.M210612200.

95. Taylor ME, Drickamer K. Structural requirements for high affinity bind­ing of complex ligands by the macrophage mannose receptor. J Biol Chem 1993; 268(1): 399– 404.

96. Zhou Q, Qiu H. The mechanistic impact of N-glycosylation on stability, pharmacokinetics, and immunogenicity of therapeutic proteins. J Pharm Sci 2019; 108(4): 1366– 1377. doi: 10.1016/ j.xphs.2018.11.029.

97. Liu L, Stadheim A, Hamuro L et al. Pharmacokinetics of IgG1 monoclonal antibodies produced in humanized Pichia pastoris with specific glycoforms: a comparative study with CHO produced materials. Biologicals 2011; 39(4): 205– 210. doi: 10.1016/ j.bio­logicals.2011.06.002.

98. Leabman MK, Meng YG, Kelley RF et al. Effects of altered FcgammaR bind­ing on antibody pharmacokinetics in cynomolgus monkeys. MAbs 2013; 5(6): 896– 903. doi: 10.4161/ mabs.26436.

99. Endo T, Wright A, Morrison SL et al. Glycosylation of the variable region of immunoglobulin G-site specific maturation of the sugar chains. Mol Immunol 1995; 32(13): 931– 940. doi: 10.1016/ 0161-5890(95)00078-s.

100. Mimura Y, Katoh T, Saldova R et al. Glycosylation engineer­ing of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy. Protein Cell 2018; 9(1): 47– 62. doi: 10.1007/ s13238-017-0433-3.

101. Goetze AM, Liu YD, Zhang Z et al. High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobio­logy 2011; 21(7): 949– 959. doi: 10.1093/ glycob/ cwr027.

102. Malhotra R, Wormald MR, Rudd PM et al. Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-bind­ing protein. Nat Med 1995; 1(3): 237– 243.

103. Ju MS, Jung ST. Aglycosylated full-length IgG antibodies: steps toward next-generation immunotherapeutics. Curr Opin Biotechnol 2014; 30: 128– 139. doi: 10.1016/ j.copbio­.2014.06.013.

104. Jung ST, Kang TH, Kelton W et al. Bypass­ing glycosylation: engineer­ing aglycosylated full-length IgG antibodies for human ther­apy. Curr Opin Biotechnol 2011; 22(6): 858– 867. doi: 10.1016/ j.copbio­.2011.03.002.

105. Simmons LC, Reilly D, Klimowski L et al. Expression of full-length immunoglobulins in Escherichia coli: rapid and efficient production of aglycosylated antibodies. J Immunol Methods 2002; 263(1– 2): 133– 147. doi: 10.1016/ s0022-1759(02)00036-4.

106. Sazinsky SL, Ott RG, Silver NW et al. Aglycosylated immunoglobulin G1 variants productively engage activat­ing Fc receptors. Proc Natl Acad Sci USA 2008; 105(51): 20167– 20172. doi: 10.1073/ pnas.0809257105.

107. Jung ST, Reddy ST, Kang TH et al. Aglycosylated IgG variants expressed in bacteria that selectively bind FcgammaRI potentiate tumor cell kill­ing by monocyte-dendritic cells. Proc Natl Acad Sci USA 2010; 107(2): 604– 609. doi: 10.1073/ pnas.0908590107.

108. Jafari R, Zolbanin NM, Rafatpanah H et al. Fc-fusion proteins in ther­apy: an updated view. Curr Med Chem 2017; 24(12): 1228– 1237. doi: 10.2174/ 0929867324666170113112759.

109. Plosker GL, Figgitt DP. Rituximab: a review of its use in non-Hodgkin‘s lymphoma and chronic lymphocytic leukaemia. Drugs 2003; 63(8): 803– 843. doi: 10.2165/ 00003495-200363080-00005.

110. Weiner GJ. Rituximab: mechanism of action. Semin Hematol 2010; 47(2): 115– 123. doi: 10.1053/ j.seminhematol.2010.01.011.

111. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350(23): 2335– 2342. doi: 10.1056/ NEJMoa032691.

112. Velcheti V, Viswanathan A, Govindan R: The proportion of patients with metastatic non-small cell lung cancer potentially eligible for treatment with bevacizumab: a single institutional survey. J Thorac Oncol 2006 Jun; 1(5): 501.

113. von Minckwitz G, Eidtmann H, Rezai M et al. Neoadjuvant chemother­apy and bevacizumab for HER2-negative breast cancer. N Engl J Med 2012; 366(4): 299– 309. doi: 10.1056/ NEJMoa1111065.

114. Gibiansky L, Sutjandra L, Doshi S et al. Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. Clin Pharmacokinet 2012; 51(4): 247– 260. doi: 10.2165/ 11598090-000000000-00000.

115. de Weers M, Tai YT, van der Veer MS et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces kill­ing of multiple myeloma and other hematological tumors. J Immunol 2011; 186(3): 1840– 1848. doi: 10.4049/ jimmunol.1003032.

116. Jonker DJ, O’Callaghan CJ, Karapetis CS et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007; 357(20): 2040– 2048. doi: 10.1056/ NEJMoa071834.

117. Bonner JA, Harari PM, Giralt J et al. Radiother­apy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354(6): 567– 578. doi: 10.1056/ NEJMoa053422.

118. Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res 2014; 16(2): 209. doi: 10.1186/ bcr3621.

119. Verma S, Miles D, Gianni L et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367(19): 1783– 1791. doi: 10.1056/ NEJMoa1209124.

120. Boyerinas B, Jochems C, Fantini M et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res 2015; 3(10): 1148– 1157. doi: 10.1158/ 2326-6066.CIR-15-0059.

121. Nahta R, Hung MC, Esteva FJ. The HER-2-target­ing antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004; 64(7): 2343– 2346.

122. Swain SM, Baselga J, Kim SB et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372(8): 724– 734. doi: 10.1056/ NEJMoa1413513.

123. Dienstmann R, Tabernero J. Necitumumab, a fully human IgG1 mAb directed against the EGFR for the potential treatment of cancer. Curr Opin Investig Drugs 2010; 11(12): 1434– 1441.

124. Garnock-Jones KP. Necitumumab: first global approval. Drugs 2016; 76(2): 283– 289. doi: 10.1007/ s40265-015-0537-0.

125. Ribas A, Hamid O, Daud A et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 2016; 315(15): 1600– 1609. doi: 10.1001/ jama.2016.4059.

126. Borcoman E, Le Tourneau C. Pembrolizumab in cervical cancer: latest evidence and clinical usefulness. Ther Adv Med Oncol 2017; 9(6): 431– 439. doi: 10.1177/ 1758834017708742.

127. Gandhi L, Rodriguez-Abreu D, Gadgeel S et al. Pembrolizumab plus chemother­apy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378(22): 2078– 2092. doi: 10.1056/ NEJMoa1801005.

128. Markham A, Duggan S. Cemiplimab: first global approval. Drugs 2018; 78(17): 1841– 1846. doi: 10.1007/ s40265-018-1012-5.

129. Migden MR, Rischin D, Schmults CD et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018; 379(4): 341– 351. doi: 10.1056/ NEJMoa1805131.

Labels
Paediatric clinical oncology Surgery Clinical oncology
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#