Structural Biological Approach to Biopharmaceuticals

• Kato Koichi

  Graduate School of Pharmaceutical Sciences, Nagoya City University Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences Institute for Molecular Science, National Institutes of Natural Sciences

• Yanaka Saeko

  Graduate School of Pharmaceutical Sciences, Nagoya City University Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences Institute for Molecular Science, National Institutes of Natural Sciences

• Yagi Hirokazu

  Graduate School of Pharmaceutical Sciences, Nagoya City University

Bibliographic Information

Other Title

• バイオ医薬品への構造生物学的アプローチ
• Symposium Review バイオ医薬品への構造生物学的アプローチ
• Symposium Review バイオ イヤクヒン エ ノ コウゾウ セイブツガクテキ アプローチ

Abstract

Detailed structural characterization of protein biopharmaceuticals is a critical step in research and development; however, this step is often hampered by the structural complexities associated with glycosylation. Most protein biopharmaceuticals are modified with structurally heterogeneous and dynamic oligosaccharides which govern the physicochemical properties, functionality, pharmacokinetics, and potential pathogenicity of these glycoproteins. Considering this, we have developed a structural biological approach to describe the dynamic three-dimensional structures and interactions of glycoproteins as biopharmaceuticals. We developed an NMR technique assisted by metabolic stable-isotope labeling that can provide useful atomic-level probes for detecting and characterizing structural perturbations of glycoproteins caused by alterations in solution conditions and production protocols, as well as by mutagenesis. We have applied this method in conjunction with X-ray crystallography to investigate the structural impacts of varying glycoforms of the Fc region of immunoglobulin G (IgG), thereby elucidating the functional roles of the Fc glycans. In particular, we have successfully elucidated the structural mechanisms by which defucosylation of the IgG-Fc region increases its affinity for Fcγ receptor IIIa, leading to an improvement in ameliorating antibody-dependent cell-mediated cytotoxicity. In addition, we applied our stable-isotope-assisted NMR method to analyzing biomolecular interactions in serum environments, which are characterized by molecular crowding and promiscuous intermolecular interactions. An integrative structural biological approach combining NMR spectroscopy, X-ray crystallography, neutron scattering, atomic force microscopy, and molecular dynamics simulation will provide new research tools that will enable the visualization of dynamic structures and interactions of glycoproteins of pharmaceutical interest, thereby providing valuable insights for the development of biopharmaceuticals.

Journal

• YAKUGAKU ZASSHI

  YAKUGAKU ZASSHI 138 (12), 1495-1502, 2018-12-01

  The Pharmaceutical Society of Japan

Keywords

• immunoglobulin G
• NMR spectroscopy
• X-ray crystallography

Details

• CRID: 1390282763072349184
• NII Article ID: 130007539077
• NII Book ID: AN00284903
• DOI: 10.1248/yakushi.18-00020-3
• ISSN: 13475231
• ISSN: 00316903
• NDL BIB ID: 029386817
• PubMed: 30504663
• Web Site: http://id.ndl.go.jp/bib/029386817
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I029386817
• Web Site: https://www.jstage.jst.go.jp/article/yakushi/138/12/138_18-00020-3/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2019209131
• Text Lang: ja
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• Abstract License Flag: Disallowed