Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins.

Nature Biotechnology
Darius GhaderiAjit Varki

Abstract

Recombinant glycoprotein therapeutics produced in nonhuman mammalian cell lines and/or with animal serum are often modified with the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc; refs. 1,2). This documented contamination has generally been ignored in drug development because healthy individuals were not thought to react to Neu5Gc (ref. 2). However, recent findings indicate that all humans have Neu5Gc-specific antibodies, sometimes at high levels. Working with two monoclonal antibodies in clinical use, we demonstrate the presence of covalently bound Neu5Gc in cetuximab (Erbitux) but not panitumumab (Vectibix). Anti-Neu5Gc antibodies from healthy humans interact with cetuximab in a Neu5Gc-specific manner and generate immune complexes in vitro. Mice with a human-like defect in Neu5Gc synthesis generate antibodies to Neu5Gc after injection with cetuximab, and circulating anti-Neu5Gc antibodies can promote drug clearance. Finally, we show that the Neu5Gc content of cultured human and nonhuman cell lines and their secreted glycoproteins can be reduced by adding a human sialic acid to the culture medium. Our findings may be relevant to improving the half-life, efficacy and immunogenicity of glycoprotein therapeutics.

References

Apr 1, 1987·Infection and Immunity·A A CampagnariM A Apicella
Sep 16, 1985·European Journal of Biochemistry·P DebeireJ F Vliegenthart
Mar 4, 2000·Proceedings of the National Academy of Sciences of the United States of America·D B AxworthyA R Fritzberg
Oct 3, 2003·Proceedings of the National Academy of Sciences of the United States of America·Pam TangvoranuntakulElaine Muchmore
Nov 24, 2004·The Journal of Biological Chemistry·Muriel BardorAjit Varki
Feb 3, 2005·Nature Medicine·Maria J MartinAjit Varki
Jul 30, 2005·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Catherine DelbaldoEric Raymond
Aug 6, 2005·European Journal of Immunology·Lorenzo BenatuilJohn Iacomini
Oct 13, 2006·Annual Review of Immunology·James N ArnoldRaymond A Dwek
Mar 16, 2007·The Annals of Pharmacotherapy·Claire E Saadeh, H Stephen Lee
Apr 11, 2007·Molecular and Cellular Biology·Maria HedlundAjit Varki
Mar 14, 2008·The New England Journal of Medicine·Christine H ChungThomas A E Platts-Mills
Nov 11, 2008·Nature Biotechnology·Saurabh Aggarwal
Nov 20, 2008·Proceedings of the National Academy of Sciences of the United States of America·Maria HedlundAjit Varki
May 9, 2009·Science·James M Wilson
Jun 6, 2009·New Biotechnology·Eva-Maria Jahn, Christian K Schneider
Nov 6, 2009·Glycoconjugate Journal·Elizabeth Higgins
Nov 6, 2009·Current Opinion in Biotechnology·Yves Durocher, Michael Butler
Feb 23, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Hiroyuki TaharaHideki Ohdan

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Citations

Apr 25, 2012·Applied Microbiology and Biotechnology·Yanhong Li, Xi Chen
Jul 24, 2012·Applied Microbiology and Biotechnology·Jae Seong LeeGyun Min Lee
Nov 1, 2011·Journal of Inherited Metabolic Disease·Patrick B Deegan
Dec 26, 2012·Glycoconjugate Journal·Jarkko Räbinä
Aug 6, 2013·Applied Biochemistry and Biotechnology·Haitham A BadrLeyla B Djansugurova
Mar 27, 2013·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Gustavo Grampp, Sundar Ramanan
May 8, 2013·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Jan VisserMartin Schiestl
Apr 1, 2014·Carbohydrate Research·Ron AmonVered Padler-Karavani
Aug 2, 2011·Nature Biotechnology·Xun XuJun Wang
Feb 2, 2011·Nature Reviews. Drug Discovery·Xu-Rong JiangMark Schenerman
Jun 30, 2012·Nature Reviews. Drug Discovery·Steven A BerkowitzGraham B Jones
Mar 29, 2013·Nature Reviews. Drug Discovery·Jean G SathishB Kevin Park
Nov 2, 2012·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Troy E BargerDaniel T Mytych
Nov 11, 2011·BMC Clinical Pharmacology·Dohan WeeraratneMarta Starcevic
Feb 15, 2014·Applied Microbiology and Biotechnology·Daniel HopkinsStephen R Hamilton
Jan 14, 2011·Bioscience, Biotechnology, and Biochemistry·Hitomi KajiwaraTakeshi Yamamoto
Aug 1, 2014·Analytical and Bioanalytical Chemistry·Trina FormoloKaren W Phinney
Jul 16, 2015·Expert Opinion on Biological Therapy·Martina Dicker, Richard Strasser
Oct 26, 2013·Critical Reviews in Biotechnology·Timo RathRichard S Blumberg
Sep 19, 2015·Critical Reviews in Biotechnology·Jennifer DumontRashmi Kshirsagar
Nov 26, 2015·MAbs·Lei ZhangBaolin Zhang
Aug 29, 2012·Journal of Pharmaceutical Sciences·Yuefeng LuHimanshu Gadgil
Feb 13, 2016·Frontiers in Immunology·Murli Krishna, Steven G Nadler
Jan 30, 2016·The AAPS Journal·Boris GorovitsLi Xue
Dec 20, 2014·Journal of Immunological Methods·Alison E MahanGalit Alter
Dec 31, 2014·Proceedings of the National Academy of Sciences of the United States of America·Annie N SamrajAjit Varki
Nov 1, 2015·Glycobiology·Oliver M T Pearce, Heinz Läubli
Aug 13, 2015·Glycobiology·Dietmar Reusch, Max L Tejada
Oct 3, 2012·Biotechnology Journal·Miranda M C van Beers, Muriel Bardor
Nov 23, 2012·Biotechnology Progress·Seshu TummalaAnthony Rossomando

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