The performance of biophysical methods used for the characterization of protein higher order structure (HOS) is key to ensure reliable structural data for drug applications, as these methods are not routinely validated. To assess the analytical performance characteristics, the impact of increasing amounts of heat-denatured material (HDM) on HOS data obtained for a monoclonal antibody (mAb) and its cysteine-conjugated antibody-drug conjugate (ADC) by a set of biophysical methods routinely used in the pharmaceutical industry was evaluated. Relationships between structural data generated by these methods were established using statistical correlation analysis. Most individual methods revealed a linear correlation with increasing amounts of HDM, in the presence of intact mAb or ADC. Overall, Pearson correlation analysis showed strong correlations between the biophysical data obtained. Moreover, biophysical methods that are generally claimed to be orthogonal, were confirmed to provide similar structural insights based on the data obtained. Some methods were capable of differentiating the impact of structural change and/or onset of protein aggregation between the mAb and the ADC. Our results underline the capabilities and performance of the biophysical characterization methods investigated, thereby substantiating these are 'scientifically sound' and 'fit for purpose': the interrogation of protein HOS as part of pharmaceutical development.
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| http://dx.doi.org/10.1016/j.ab.2021.114331 | DOI Listing |
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