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      Enabling adoption of 2D-NMR for the higher order structure assessment of monoclonal antibody therapeutics

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      a , a , a , a , b , b , c , c , c , d , d , d , e , e , f , g , g , h , i , i , i , j , j , k , k , l , m , n , n , o , o , p , q , r , r , s , t , t , u , v , u , v , w , x , y , z , aa , bb , bb , cc , dd
      mAbs
      Taylor & Francis
      monoclonal antibody (mAb) therapeutics, NISTmAb, higher order structure, nuclear magnetic resonance spectroscopy (NMR), comparability, chemometrics

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          ABSTRACT

          The increased interest in using monoclonal antibodies (mAbs) as a platform for biopharmaceuticals has led to the need for new analytical techniques that can precisely assess physicochemical properties of these large and very complex drugs for the purpose of correctly identifying quality attributes (QA). One QA, higher order structure (HOS), is unique to biopharmaceuticals and essential for establishing consistency in biopharmaceutical manufacturing, detecting process-related variations from manufacturing changes and establishing comparability between biologic products. To address this measurement challenge, two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) methods were introduced that allow for the precise atomic-level comparison of the HOS between two proteins, including mAbs. Here, an inter-laboratory comparison involving 26 industrial, government and academic laboratories worldwide was performed as a benchmark using the NISTmAb, from the National Institute of Standards and Technology (NIST), to facilitate the translation of the 2D-NMR method into routine use for biopharmaceutical product development. Two-dimensional 1H, 15N and 1H, 13C NMR spectra were acquired with harmonized experimental protocols on the unlabeled Fab domain and a uniformly enriched- 15N, 20%- 13C-enriched system suitability sample derived from the NISTmAb. Chemometric analyses from over 400 spectral maps acquired on 39 different NMR spectrometers ranging from 500 MHz to 900 MHz demonstrate spectral fingerprints that are fit-for-purpose for the assessment of HOS. The 2D-NMR method is shown to provide the measurement reliability needed to move the technique from an emerging technology to a harmonized, routine measurement that can be generally applied with great confidence to high precision assessments of the HOS of mAb-based biotherapeutics.

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          Most cited references28

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          NMRFAM-SPARKY: enhanced software for biomolecular NMR spectroscopy

          Summary: SPARKY (Goddard and Kneller, SPARKY 3) remains the most popular software program for NMR data analysis, despite the fact that development of the package by its originators ceased in 2001. We have taken over the development of this package and describe NMRFAM-SPARKY, which implements new functions reflecting advances in the biomolecular NMR field. NMRFAM-SPARKY has been repackaged with current versions of Python and Tcl/Tk, which support new tools for NMR peak simulation and graphical assignment determination. These tools, along with chemical shift predictions from the PACSY database, greatly accelerate protein side chain assignments. NMRFAM-SPARKY supports automated data format interconversion for interfacing with a variety of web servers including, PECAN , PINE, TALOS-N, CS-Rosetta, SHIFTX2 and PONDEROSA-C/S. Availability and implementation: The software package, along with binary and source codes, if desired, can be downloaded freely from http://pine.nmrfam.wisc.edu/download_packages.html. Instruction manuals and video tutorials can be found at http://www.nmrfam.wisc.edu/nmrfam-sparky-distribution.htm. Contact: whlee@nmrfam.wisc.edu or markley@nmrfam.wisc.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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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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              Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars.

              Biologics such as monoclonal antibodies are much more complex than small-molecule drugs, which raises challenging questions for the development and regulatory evaluation of follow-on versions of such biopharmaceutical products (also known as biosimilars) and their clinical use once patent protection for the pioneering biologic has expired. With the recent introduction of regulatory pathways for follow-on versions of complex biologics, the role of analytical technologies in comparing biosimilars with the corresponding reference product is attracting substantial interest in establishing the development requirements for biosimilars. Here, we discuss the current state of the art in analytical technologies to assess three characteristics of protein biopharmaceuticals that regulatory authorities have identified as being important in development strategies for biosimilars: post-translational modifications, three-dimensional structures and protein aggregation.
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                Author and article information

                Journal
                MAbs
                MAbs
                KMAB
                kmab20
                mAbs
                Taylor & Francis
                1942-0862
                1942-0870
                January 2019
                22 December 2018
                22 December 2018
                : 11
                : 1
                : 94-105
                Affiliations
                [a ]Institute of Bioscience and Biotechnology Research, National Institute of Standards and Technology and the University of Maryland , Rockville, MD, USA
                [b ]Applied and Computational Mathematics Division, National Institute of Standards and Technology , Gaithersburg, MD, USA
                [c ]Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada , Ottawa, ON, Canada
                [d ]The Centre for Advanced Imaging, The University of Queensland , St Lucia, QLD, Australia
                [e ]Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne , Victoria, Australia
                [f ]Lehrstuhl Biopolymere, Universitaet Bayreuth , Bayreuth, Germany
                [g ]Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University , Stockholm, Sweden
                [h ]Analytical R&D, Pfizer Essential Health , Lake Forest, IL, USA
                [i ]Pacific Northwest National Laboratory, Earth and Biological Sciences Directorate , Richland, DC, USA
                [j ]Department of Downstream Processing and Analytics, Human Health Therapeutics Research Centre, National Research Council of Canada , Montreal, Quebec, Canada
                [k ]Institute for Molecular Science and Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences , Myodaiji, Okazaki, Japan
                [l ]Department of Biochemistry and Molecular Biology, Medical University of South Carolina , Charleston, SC, USA
                [m ]Analytical Development, Momenta Pharmaceuticals , Cambridge, MA, USA
                [n ]Laboratory Unit, Swedish Medical Products Agency, Laboratory , Uppsala, Sweden
                [o ]NMR-supported Structural Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) , Berlin, Germany
                [p ]Roche Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel , Basel, Switzerland
                [q ]Analytical Operations, Genentech , South San Francisco, CA, USA
                [r ]Center for Drug Evaluation and Research, Food and Drug Administration , Maryland, USA
                [s ]Center for Biologics Evaluation and Research, Food and Drug Administration , Maryland, USA
                [t ]Department of Biology, Institute of Molecular Biology and Biophysics , ETH Zurich, Zurich, Switzerland
                [u ]NMR Centre, EN-FIST Centre of Excellence , Ljubljana, Slovenia
                [v ]NMR Centre, National Institute of Chemistry , Ljubljana, Slovenia
                [w ]Eli Lilly and Company, Lilly Corporate Center , Indianapolis, IN, USA
                [x ]MRS – Application Science, Bruker BioSpin Corporation , Billerica, MA, USA
                [y ]Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM) , Campinas, Brazil
                [z ]Brazilian Synchrotron Light Laboratory (LNLS), Brazilian Center for Research in Energy and Materials (CNPEM) , Campinas, Brazil, CEP
                [aa ]Protein Product Development, Biogen Inc ., Cambridge, MA, USA
                [bb ]Baxter Pharmaceuticals R&D, Baxter Healthcare , Round Lake, IL, USA
                [cc ]Global Regulatory and R&D Policy, Amgen Inc ., Thousand Oaks, CA, USA
                [dd ]Higher Order Structure, Attribute Sciences, Amgen Inc ., Thousand Oaks, CA, USA
                Author notes
                CONTACT Robert G. Brinson robert.brinson@ 123456nist.gov
                [†]

                Present address: Oregon State University, Corvallis, Oregon 97331, United States

                Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kmab.

                Author information
                http://orcid.org/0000-0001-6871-450X
                http://orcid.org/0000-0002-9646-0006
                http://orcid.org/0000-0002-8554-0297
                http://orcid.org/0000-0002-2831-4605
                http://orcid.org/0000-0003-2420-4262
                http://orcid.org/0000-0001-5657-8635
                http://orcid.org/0000-0002-6858-0086
                http://orcid.org/0000-0001-6342-6461
                http://orcid.org/0000-0002-8205-5827
                http://orcid.org/0000-0001-8171-4678
                http://orcid.org/0000-0001-9004-7272
                http://orcid.org/0000-0002-3530-9273
                http://orcid.org/0000-0003-0276-2474
                http://orcid.org/0000-0002-7767-7904
                http://orcid.org/0000-0003-1991-5174
                http://orcid.org/0000-0003-1570-8602
                http://orcid.org/0000-0003-0403-6337
                http://orcid.org/0000-0003-1644-8689
                Article
                1544454
                10.1080/19420862.2018.1544454
                6343768
                30570405
                5caf3b58-191f-4f74-a49e-8fdac22b3402
                © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                History
                : 12 July 2018
                : 18 October 2018
                : 31 October 2018
                Page count
                Figures: 4, Tables: 2, References: 44, Pages: 12
                Funding
                Funded by: Alice Wallenberg Foundation
                Award ID: JP25102001
                NIST acknowledges the support by NIST Biomanufacturing Program and NIST and W.M. Keck Foundation for support of biomolecular NMR instrumentation. The work at Stockholm University was supported by a grant from the Knut and Alice Wallenberg Foundation. The Brazilian Center for Research in Energy and Materials acknowledge the support by the Brazilian Ministry of Science, Technology, Innovation and Communication (MCTIC). A portion of the research was performed using NMR instrumentation at EMSL, a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory. This work at Health Canada was supported by Government of Canada. The work at NRC Canada was supported by the NRC Biologics and Biomanufacturing Program and by the Department of Downstream Processing and Analytics (for Protein NMR instrumentation), for which this paper is assigned the NRCC Publication No. NRC_HHT_53378. The work at the University of Queensland was supported by the Australian Research Council and The National Health and Medical Research Council as well as the University of Queensland. BNSP (Biomolecular NMR Spectroscopy Platform) ETH Zürich, is acknowledged for providing equipment and infrastructure. The NMR facility used for this work is supported by the Office of the Vice President for Research at the Medical University of South Carolina. The NMR maintenance was supported in part by the Nanotechnology Platform Program (Molecule and Material Synthesis) and by the grants (JP25102001, JP25102008, JP15K21708 and JP15H02491 to K.K.; JP17H05893 and 18K14892 to S.Y.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.
                Categories
                Report

                Immunology
                monoclonal antibody (mab) therapeutics,nistmab,higher order structure,nuclear magnetic resonance spectroscopy (nmr),comparability,chemometrics

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