NMR Spectral Fingerprinting of Biological Therapeutics without NMR Spectra
April 25, 2017 –
Room 0112, Marker Seminar Room, Chemistry Building (091)
Dr. Frank Delaglio, NIST/IBBR
Growth of biologic therapeutics is outpacing that of small-molecule drugs, and the development, manufacture, and delivery of biologics presents very different challenges. The efficacy and safety of biologics depends critically on their High Order Structure (HOS), and changes to HOS during manufacture or storage can render them inactive or promote dangerous immune responses. Methods to measure and characterize HOS are essential for development of new biotherapeutics, for evaluating less expensive “biosimilar” replacements, and for monitoring and improving manufacturing, formulation, and stability.
Nuclear Magnetic Resonance (NMR), which can provide detailed information on structure and dynamics at atomic resolution, is a powerful tool to probe HOS, but typical biomolecular applications use isotopic enrichment, long measurement times, and require extensive and often subjective interactive analysis by an expert.
We have shown previously that fast measurement techniques combined with Non-Uniform Sampling (NUS) strategies can generate practical two-dimensional 1H/13C spectra at natural isotopic abundance for molecules as large as intact monoclonal antibodies. We now demonstrate that HOS attributes can be classified by direct computational analysis of the shapes of such spectra, or even of NMR data without complete spectral reconstruction, as an alternative to interactive analysis and assignment of spectral features. This paves the way for NMR HOS characterization via chemometrics and machine learning that is both objective and automated.