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      Biosimilar structural comparability assessment by NMR: from small proteins to monoclonal antibodies

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          Abstract

          Biosimilar drug products must have a demonstrated similarity with respect to the reference product’s molecules in order to ensure both the effectiveness of the drug and the patients’ safety. In this paper the fusion framework of a highly sensitive NMR fingerprinting approach for conformational changes and mathematically-based biosimilarity metrics is introduced. The final goal is to translate the complex spectral information into biosimilarity scores, which are then used to estimate the degree of similarity between the biosimilar and the reference product. The proposed method was successfully applied to a small protein, i.e., filgrastim (neutropenia treatment), which is the first biosimilar approved in the United States, and a relatively large protein, i.e., monoclonal antibody rituximab (lymphoma treatment). This innovative approach introduces a new level of sensitivity to structural changes that are induced by, e.g., a small pH shift or other changes in the protein formulation.

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          Most cited references 32

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          What is principal component analysis?

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            SOFAST-HMQC experiments for recording two-dimensional heteronuclear correlation spectra of proteins within a few seconds.

            Fast multidimensional NMR with a time resolution of a few seconds provides a new tool for high throughput screening and site-resolved real-time studies of kinetic molecular processes by NMR. Recently we have demonstrated the feasibility to record protein 1H-15N correlation spectra in a few seconds of acquisition time using a new SOFAST-HMQC experiment (Schanda and Brutscher (2005) J. Am. Chem. Soc. 127, 8014). Here, we investigate in detail the performance of SOFAST-HMQC to record 1H-15N and 1H-13C correlation spectra of proteins of different size and at different magnetic field strengths. Compared to standard 1H-15N correlation experiments SOFAST-HMQC provides a significant gain in sensitivity, especially for fast repetition rates. Guidelines are provided on how to set up SOFAST-HMQC experiments for a given protein sample. In addition, an alternative pulse scheme, IPAP-SOFAST-HMQC is presented that allows application on NMR spectrometers equipped with cryogenic probes, and fast measurement of one-bond 1H-13C and 1H-15N scalar and residual dipolar coupling constants.
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              Implications of protein flexibility for drug discovery.

              Proteins are in constant motion between different conformational states with similar energies. This has often been ignored in drug design. However, protein flexibility is fundamental to understanding the ways in which drugs exert biological effects, their binding-site location, binding orientation, binding kinetics, metabolism and transport. Protein flexibility allows increased affinity to be achieved between a drug and its target. This is crucial, because the lipophilicity and number of polar interactions allowed for an oral drug is limited by absorption, distribution, metabolism and toxicology considerations.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                31 August 2016
                2016
                : 6
                Affiliations
                [1 ]Protein Biophysics and Bioinformatics Department, Sandoz Biopharmaceuticals , Kolodvorska 27, SI-1234 Mengeš Slovenia
                [2 ]Slovenian NMR Centre, National Institute of Chemistry , Hajdrihova 19, SI-1000 Ljubljana, Slovenia
                [3 ]EN-FIST Centre of Excellence , Trg Osvobodilne fronte 13, SI-1001, Ljubljana, Slovenia
                [4 ]Faculty of Chemistry and Chemical Technology University of Ljubljana , Večna pot 113, SI-1000 Ljubljana, Slovenia
                Author notes
                Article
                srep32201
                10.1038/srep32201
                5006049
                27578487
                Copyright © 2016, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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