Hybrid mass spectrometry approaches in glycoprotein analysis and their usage in scoring biosimilarity

Yang Yang, Fan Liu, Vojtech Franc, Liem Andhyk Halim, Huub Schellekens and Albert J. R. Heck ()
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Yang Yang: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht
Fan Liu: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht
Vojtech Franc: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht
Liem Andhyk Halim: Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University
Huub Schellekens: Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University
Albert J. R. Heck: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract Many biopharmaceutical products exhibit extensive structural micro-heterogeneity due to an array of co-occurring post-translational modifications. These modifications often effect the functionality of the product and therefore need to be characterized in detail. Here, we present an integrative approach, combining two advanced mass spectrometry-based methods, high-resolution native mass spectrometry and middle-down proteomics, to analyse this micro-heterogeneity. Taking human erythropoietin and the human plasma properdin as model systems, we demonstrate that this strategy bridges the gap between peptide- and protein-based mass spectrometry platforms, providing the most complete profiling of glycoproteins. Integration of the two methods enabled the discovery of three undescribed C-glycosylation sites on properdin, and revealed in addition unexpected heterogeneity in occupancies of C-mannosylation. Furthermore, using various sources of erythropoietin we define and demonstrate the usage of a biosimilarity score to quantitatively assess structural similarity, which would also be beneficial for profiling other therapeutic proteins and even plasma protein biomarkers.

Date: 2016
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DOI: 10.1038/ncomms13397

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