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

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 thatmore » 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.« less

Authors:
 [1];  [1];  [1]; ORCiD logo [1];  [2];  [2];  [3]; ORCiD logo [3]; ORCiD logo [3];  [4]; ORCiD logo [4]; ORCiD logo [4];  [5];  [5];  [6]; ORCiD logo [7];  [7];  [8];  [9]; ORCiD logo [9] more »; ORCiD logo [9];  [10];  [10];  [11];  [11]; ORCiD logo [12];  [13]; ORCiD logo [14]; ORCiD logo [14]; ORCiD logo [15];  [15];  [16];  [17]; ORCiD logo [18]; ORCiD logo [18]; ORCiD logo [18];  [19];  [19];  [20]; ORCiD logo [20];  [21];  [22];  [23];  [24];  [25]; ORCiD logo [26]; ORCiD logo [26];  [27];  [27] « less
+ Show Author Affiliations
  1. National Institute of Standards and Technology and the University of Maryland, Rockville, MD (United States)
  2. National Inst. of Standards and Technology (NIST), Gaithersburg, MD (United States)
  3. Centre for Biologics Evaluation, Ottawa, ON (Canada)
  4. Univ. of Queensland, St. Lucia, QLD (Australia)
  5. Univ. of Melbourne (Australia)
  6. Univ. of Bayreuth (Germany)
  7. Stockholm Univ. (Sweden)
  8. Analytical R&D, Pfizer Essential Health, Lake Forest, IL (United States)
  9. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
  10. National Research Council of Canada, Montreal, Quebec (Canada)
  11. National Institutes of Natural Sciences, Myodaiji, Okazaki (Japan)
  12. Univ. of South Carolina, Charleston, SC (United States)
  13. Momenta Pharmaceuticals, Cambridge, MA (United States)
  14. Swedish Medical Products Agency, Laboratory, Uppsala (Sweden)
  15. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin (Germany)
  16. Roche Innovation Center Basel (Switzerland)
  17. Genentech, South San Francisco, CA (United States)
  18. Center for Drug Evaluation and Research, Food and Drug Administration, MD (United States)
  19. Institute of Molecular Biology and Biophysics, ETH Zurich (Switzerland)
  20. NMR Centre, Ljubljana (Slovenia)
  21. Eli Lilly and Company, Indianapolis, IN (United States)
  22. Bruker BioSpin Corporation, Billerica, MA (United States)
  23. Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas (Brazil)
  24. Brazilian Synchrotron Light Laboratory (LNLS), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas (Brazil)
  25. Biogen Inc., Cambridge, MA (United States)
  26. Baxter Pharmaceuticals R&D, Baxter Healthcare, Round Lake, IL (United States)
  27. Amgen Inc., Thousand Oaks, CA (United States)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1545065
Report Number(s):
PNNL-SA-131540
Journal ID: ISSN 1942-0862
Grant/Contract Number:  
AC05-76RL01830
Resource Type:
Accepted Manuscript
Journal Name:
mAbs
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 1942-0862
Publisher:
Taylor & Francis
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; monoclonal antibody (mAb) therapeutics; NISTmAb; higher order structure; nuclear magnetic resonance spectroscopy (NMR); comparability; chemometrics

Citation Formats

Brinson, Robert G., Marino, John P., Delaglio, Frank, Arbogast, Luke W., Evans, Ryan M., Kearsley, Anthony, Gingras, Geneviève, Ghasriani, Houman, Aubin, Yves, Pierens, Gregory K., Jia, Xinying, Mobli, Mehdi, Grant, Hamish G., Keizer, David W., Schweimer, Kristian, Ståhle, Jonas, Widmalm, Göran, Zartler, Edward R., Lawrence, Chad W., Reardon, Patrick N., Cort, John R., Xu, Ping, Ni, Feng, Yanaka, Saeko, Kato, Koichi, Parnham, Stuart R., Tsao, Desiree, Blomgren, Andreas, Rundlöf, Torgny, Trieloff, Nils, Schmieder, Peter, Ross, Alfred, Skidmore, Ken, Chen, Kang, Keire, David, Freedberg, Darón I., Suter-Stahel, Thea, Wider, Gerhard, Ilc, Gregor, Plavec, Janez, Bradley, Scott A., Baldisseri, Donna M., Sforça, Mauricio Luis, Zeri, Ana Carolina de Mattos, Wei, Julie Yu, Szabo, Christina M., Amezcua, Carlos A., Jordan, John B., and Wikström, Mats. Enabling adoption of 2D-NMR for the higher order structure assessment of monoclonal antibody therapeutics. United States: N. p., 2018. Web. doi:10.1080/19420862.2018.1544454.
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Brinson, Robert G., Marino, John P., Delaglio, Frank, Arbogast, Luke W., Evans, Ryan M., Kearsley, Anthony, Gingras, Geneviève, Ghasriani, Houman, Aubin, Yves, Pierens, Gregory K., Jia, Xinying, Mobli, Mehdi, Grant, Hamish G., Keizer, David W., Schweimer, Kristian, Ståhle, Jonas, Widmalm, Göran, Zartler, Edward R., Lawrence, Chad W., Reardon, Patrick N., Cort, John R., Xu, Ping, Ni, Feng, Yanaka, Saeko, Kato, Koichi, Parnham, Stuart R., Tsao, Desiree, Blomgren, Andreas, Rundlöf, Torgny, Trieloff, Nils, Schmieder, Peter, Ross, Alfred, Skidmore, Ken, Chen, Kang, Keire, David, Freedberg, Darón I., Suter-Stahel, Thea, Wider, Gerhard, Ilc, Gregor, Plavec, Janez, Bradley, Scott A., Baldisseri, Donna M., Sforça, Mauricio Luis, Zeri, Ana Carolina de Mattos, Wei, Julie Yu, Szabo, Christina M., Amezcua, Carlos A., Jordan, John B., & Wikström, Mats. Enabling adoption of 2D-NMR for the higher order structure assessment of monoclonal antibody therapeutics. United States. doi:https://doi.org/10.1080/19420862.2018.1544454
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Brinson, Robert G., Marino, John P., Delaglio, Frank, Arbogast, Luke W., Evans, Ryan M., Kearsley, Anthony, Gingras, Geneviève, Ghasriani, Houman, Aubin, Yves, Pierens, Gregory K., Jia, Xinying, Mobli, Mehdi, Grant, Hamish G., Keizer, David W., Schweimer, Kristian, Ståhle, Jonas, Widmalm, Göran, Zartler, Edward R., Lawrence, Chad W., Reardon, Patrick N., Cort, John R., Xu, Ping, Ni, Feng, Yanaka, Saeko, Kato, Koichi, Parnham, Stuart R., Tsao, Desiree, Blomgren, Andreas, Rundlöf, Torgny, Trieloff, Nils, Schmieder, Peter, Ross, Alfred, Skidmore, Ken, Chen, Kang, Keire, David, Freedberg, Darón I., Suter-Stahel, Thea, Wider, Gerhard, Ilc, Gregor, Plavec, Janez, Bradley, Scott A., Baldisseri, Donna M., Sforça, Mauricio Luis, Zeri, Ana Carolina de Mattos, Wei, Julie Yu, Szabo, Christina M., Amezcua, Carlos A., Jordan, John B., and Wikström, Mats. Thu . "Enabling adoption of 2D-NMR for the higher order structure assessment of monoclonal antibody therapeutics". United States. doi:https://doi.org/10.1080/19420862.2018.1544454. https://www.osti.gov/servlets/purl/1545065.
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@article{osti_1545065,
title = {Enabling adoption of 2D-NMR for the higher order structure assessment of monoclonal antibody therapeutics},
author = {Brinson, Robert G. and Marino, John P. and Delaglio, Frank and Arbogast, Luke W. and Evans, Ryan M. and Kearsley, Anthony and Gingras, Geneviève and Ghasriani, Houman and Aubin, Yves and Pierens, Gregory K. and Jia, Xinying and Mobli, Mehdi and Grant, Hamish G. and Keizer, David W. and Schweimer, Kristian and Ståhle, Jonas and Widmalm, Göran and Zartler, Edward R. and Lawrence, Chad W. and Reardon, Patrick N. and Cort, John R. and Xu, Ping and Ni, Feng and Yanaka, Saeko and Kato, Koichi and Parnham, Stuart R. and Tsao, Desiree and Blomgren, Andreas and Rundlöf, Torgny and Trieloff, Nils and Schmieder, Peter and Ross, Alfred and Skidmore, Ken and Chen, Kang and Keire, David and Freedberg, Darón I. and Suter-Stahel, Thea and Wider, Gerhard and Ilc, Gregor and Plavec, Janez and Bradley, Scott A. and Baldisseri, Donna M. and Sforça, Mauricio Luis and Zeri, Ana Carolina de Mattos and Wei, Julie Yu and Szabo, Christina M. and Amezcua, Carlos A. and Jordan, John B. and Wikström, Mats},
abstractNote = {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.},
doi = {10.1080/19420862.2018.1544454},
journal = {mAbs},
number = 1,
volume = 11,
place = {United States},
year = {2018},
month = {12}
}
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DOI:  https://doi.org/10.1080/19420862.2018.1544454
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