Native mass spectrometry combined with enzymatic dissection unravels glycoform heterogeneity of biopharmaceuticals

Therese Wohlschlager, Kai Scheffler, Ines C. Forstenlehner, Wolfgang Skala, Stefan Senn, Eugen Damoc, Johann Holzmann and Christian G. Huber ()
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Therese Wohlschlager: University of Salzburg
Kai Scheffler: University of Salzburg
Ines C. Forstenlehner: University of Salzburg
Wolfgang Skala: University of Salzburg
Stefan Senn: University of Salzburg
Eugen Damoc: Thermo Fisher Scientific GmbH
Johann Holzmann: University of Salzburg
Christian G. Huber: University of Salzburg

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract Robust manufacturing processes resulting in consistent glycosylation are critical for the efficacy and safety of biopharmaceuticals. Information on glycosylation can be obtained by conventional bottom–up methods but is often limited to the glycan or glycopeptide level. Here, we apply high-resolution native mass spectrometry (MS) for the characterization of the therapeutic fusion protein Etanercept to unravel glycoform heterogeneity in conditions of hitherto unmatched mass spectral complexity. Higher spatial resolution at lower charge states, an inherent characteristic of native MS, represents a key component for the successful revelation of glycan heterogeneity. Combined with enzymatic dissection using a set of proteases and glycosidases, assignment of specific glycoforms is achieved by transferring information from subunit to whole protein level. The application of native mass spectrometric analysis of intact Etanercept as a fingerprinting tool for the assessment of batch-to-batch variability is exemplified and may be extended to demonstrate comparability after changes in the biologic manufacturing process.

Date: 2018
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DOI: 10.1038/s41467-018-04061-7

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