On the Analytical Superiority of 1D NMR for Fingerprinting the Higher Order Structure of Protein Therapeutics Compared to Multidimensional NMR Methods
An important aspect in the analytical characterization of protein therapeutics is the comprehensive characterization of higher order structure (HOS). Nuclear magnetic resonance (NMR) is arguably the most sensitive method for fingerprinting HOS of a protein in solution. Traditionally, 1H–15N or 1H–13...
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| Veröffentlicht in: | Analytical chemistry (Washington) 2015-06, Vol.87 (11), p.5539-5545 |
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| container_title | Analytical chemistry (Washington) |
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| creator | Poppe, Leszek Jordan, John B Rogers, Gary Schnier, Paul D |
| description | An important aspect in the analytical characterization of protein therapeutics is the comprehensive characterization of higher order structure (HOS). Nuclear magnetic resonance (NMR) is arguably the most sensitive method for fingerprinting HOS of a protein in solution. Traditionally, 1H–15N or 1H–13C correlation spectra are used as a “structural fingerprint” of HOS. Here, we demonstrate that protein fingerprint by line shape enhancement (PROFILE), a 1D 1H NMR spectroscopy fingerprinting approach, is superior to traditional two-dimensional methods using monoclonal antibody samples and a heavily glycosylated protein therapeutic (Epoetin Alfa). PROFILE generates a high resolution structural fingerprint of a therapeutic protein in a fraction of the time required for a 2D NMR experiment. The cross-correlation analysis of PROFILE spectra allows one to distinguish contributions from HOS vs protein heterogeneity, which is difficult to accomplish by 2D NMR. We demonstrate that the major analytical limitation of two-dimensional methods is poor selectivity, which renders these approaches problematic for the purpose of fingerprinting large biological macromolecules. |
| doi_str_mv | 10.1021/acs.analchem.5b00950 |
| format | Article |
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| subjects | Analytical chemistry Chemistry Techniques, Analytical - standards Chemistry Techniques, Analytical - trends Correlation analysis Fingerprinting Fingerprints Glycosylation Heterogeneity Magnetic Resonance Spectroscopy - standards Mathematical analysis Monoclonal antibodies NMR Nuclear magnetic resonance Protein Conformation Proteins Proteins - chemistry Spectra Two dimensional |
| title | On the Analytical Superiority of 1D NMR for Fingerprinting the Higher Order Structure of Protein Therapeutics Compared to Multidimensional NMR Methods |
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