Elucidation of a previously unknown mode of interaction between antibody and Fc receptor toward development of novel strategies for antibody engineering

• Project/Area Number: 18K14892
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
• Research Institution: Institute for Molecular Science
• Principal Investigator: Yanaka Saeko 分子科学研究所, 生命・錯体分子科学研究領域, 助教 (80722777)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 免疫グロブリンG (IgG) / Fc受容体 / MDシミュレーション / 核磁気共鳴法 / 量子ビーム溶液散乱 / 高速原子間力顕微鏡 / 中性子溶液散乱 / 抗体 / NMR

Outline of Final Research Achievements

Antibody functions are divided into antigen recognition by Fab and effector function promotion by Fc. The Fc receptors interact with the Fc portion of the antibody, thereby triggering the effector functions, and are therefore collectively called Fc receptors. This study is based on a working model in which both Fab and Fc synergistically contribute to Fc receptor binding. The biophysical data obtained in this study supported this hypothesis and, moreover, uncovered previously unidentified interaction sites in antibody and Fc receptors. The knowledge gained in this study will provide basis for designing antibodies with higher affinities for Fc receptor.

Academic Significance and Societal Importance of the Research Achievements

抗体医薬品は高い特異性と親和性から分子標的薬として幅広い疾患に使用されており、特に抗体が司るエフェクター機能である抗体依存性細胞介在性細胞傷害活性を利用した抗がん剤の開発が進められてきている。こうしたなかで、これまでの抗体医薬の分子設計においては、分子標的に対するFab部分の親和性を向上することと、Fc受容体とFc部分との親和性を向上することがそれぞれ独立に検討されてきた。しかしながら、抗体全体の動的構造を考慮して機能を最適化することが、今後の重要な課題である。本研究成果は、抗体の作動メカニズムに関する分子免疫学の常識に一石を投じるとともに抗体医薬の開発に新たな可能性をもたらすものである。

Research Products

• [Int'l Joint Research] National Inst. of Standards and Tech.(米国)
• [Int'l Joint Research] National Inst. of Standards and Tech.(米国)
• [Journal Article] Dynamic Views of the Fc Region of Immunoglobulin G Provided by Experimental and Computational Observations (2019)
  • Author(s): Yanaka Saeko、Yogo Rina、Inoue Rintaro、Sugiyama Masaaki、Itoh Satoru G.、Okumura Hisashi、Miyanoiri Yohei、Yagi Hirokazu、Satoh Tadashi、Yamaguchi Takumi、Kato Koichi
  • Journal Title: Antibodies Volume: 8 Issue: 3 Pages: 39-39
  • DOI: 10.3390/antib8030039
  • Peer Reviewed / Open Access
• [Journal Article] The Fab portion of immunoglobulin G contributes to its binding to Fcγ receptor III. (2019)
  • Author(s): [Rina Yogo,Yuki Yamaguchi,Hiroki Watanabe,Hirokazu Yagi,Tadashi Satoh,Mahito Nakanishi,Masayoshi Onitsuka,Takeshi Omasa,Mari Shimada,Takahiro Maruno,Tetsuo Torisu,Shio Watanabe,Daisuke Higo,Takayuki Uchihashi,Saeko Yanaka,Susumu Uchiyama,Koichi Kato]
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 11957-11957
  • DOI: 10.1038/s41598-019-48323-w
  • NAID: 120006875664
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural and thermodynamic basis for the recognition of the substrate-binding cleft on hen egg lysozyme by a single-domain antibody (2019)
  • Author(s): Akiba Hiroki、Tamura Hiroko、Kiyoshi Masato、Yanaka Saeko、Sugase Kenji、Caaveiro Jose M. M.、Tsumoto Kouhei
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 15481-15481
  • DOI: 10.1038/s41598-019-50722-y
  • NAID: 120006822517
  • Peer Reviewed / Open Access
• [Journal Article] On-Membrane Dynamic Interplay between Anti-GM1 IgG Antibodies and Complement Component C1q. (2019)
  • Author(s): Saeko Yanaka,Rina Yogo,Hiroki Watanabe,Yuki Taniguchi,Tadashi Satoh,Naoko Komura,Hiromune Ando,Hirokazu Yagi,Nobuhiro Yuki,Takayuki Uchihashi,Koichi Kato
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 1 Pages: 147-147
  • DOI: 10.3390/ijms21010147
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Newly developed Laboratory-based Size exclusion chromatography Small-angle x-ray scattering System (La-SSS) (2019)
  • Author(s): R. Inoue, T. Nakagawa, K. Morishima, N. Sato, A. Okuda, R. Urade, R. Yogo, S. Yanaka, M. Yagi-Utsumi, K. Kato, K. Omoto, K. Ito, M. Sugiyama
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41598-019-48911-w
  • NAID: 120006799252
  • Peer Reviewed / Open Access
• [Journal Article] Enabling adoption of 2D-NMR for the higher order structure assessment of monoclonal antibody therapeutics (2018)
  • Author(s): Brinson RG.、Marino JP.、Delaglio F、Arbogast LW.、Evans RM.、Kearsley A、Gingras G、Ghasriani H、Aubin Y、Pierens GK.、Jia X、Mobli M、Grant HG.、Keizer DW.、Schweimer K、Sthle J、Widmalm G、Zartler ER.、Lawrence CW.、Reardon PN.、Cort JR.、Xu P、Ni F、Yanaka S、Kato K、et al.
  • Journal Title: mAbs Volume: 11 Issue: 1 Pages: 94-105
  • DOI: 10.1080/19420862.2018.1544454
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structure and Dynamics of Immunoglobulin G Glycoproteins (2018)
  • Author(s): Yagi Hirokazu、Yanaka Saeko、Kato Koichi
  • Journal Title: Advances in experimental medicine and biology Volume: 1104 Pages: 219-235
  • DOI: 10.1007/978-981-13-2158-0_11
  • ISBN: 9789811321573, 9789811321580
  • Peer Reviewed / Open Access
• [Presentation] IgG のフコシル化による Fc のダイナミクスの変化が Fc γ受容体との相互 作用に及ぼす影響 Dynamic conformational effects of IgG fucosylation for interaction between Fc and Fcγ receptor (2019)
  • Author(s): 谷中冴子，與語理那，矢木宏和，伊藤 暁，奥村久士，山口拓実，加藤晃一
  • Organizer: 第19回日本蛋白質科学会年会、第71回日本細胞生物学会大会 合同年次大会
• [Presentation] Dynamic Views of the Fc Portion of Immunoglobulin G Provided by Experimental and Computational Observations (2019)
  • Author(s): Saeko Yanaka, Rina Yogo, Rintaro Inoue, Masaaki Sugiyama, Satoru G. Itoh, Hisashi Okumura, Yohei Miyanoiri, Hirokazu Yagi, Tadashi Satoh, Takumi Yamaguchi and Koichi Kato
  • Organizer: Frontier Bioorganization Forum 2019
  • Int'l Joint Research / Invited
• [Presentation] 抗体の構造研究から学ぶ、研究者ってどんな職業？ (2019)
  • Author(s): 谷中冴子
  • Organizer: 中高生のための未来教室‐ホンネで語るライフサイエンスの道！
  • Invited
• [Presentation] Experimental and computational observations of the dynamics of the Fc region of immunoglobulin G (2019)
  • Author(s): Saeko Yanaka
  • Organizer: Satellite meeting for PF Workshop“Marriage of Computational and Experimental Techniques for Solution Small-angle Scattering”
  • Int'l Joint Research / Invited
• [Presentation] Dynamic structures and interactions of antibodies under physiologically relevant conditions (2019)
  • Author(s): Saeko Yanaka, Rina Yogo, Hirokazu Yagi, and Koichi Kato
  • Organizer: 第57回日本生物物理学会年会
  • Invited
• [Presentation] 安定同位体標識を利用したNMRによる抗体の「品質」の解析 (2019)
  • Author(s): 谷中冴子，與語理那，矢木宏和，加藤晃一
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] Fcの構造ダイナミクスがFcγ受容体との相互作用に及ぼす影響の解明 (2019)
  • Author(s): 谷中冴子、與語理那、矢木宏和、伊藤暁、奥村久士、加藤晃一
  • Organizer: 日本薬学会第139年会
  • Invited
• [Presentation] 血清環境下における抗体の相互作用解析 (2018)
  • Author(s): 谷中冴子，與語理那，矢木宏和，加藤晃一
  • Organizer: 第18回日本蛋白質科学会年会
  • Invited
• [Presentation] 部位選択的重水素化を活用した抗体の血清中での相互作用解析 (2018)
  • Author(s): 谷中冴子
  • Organizer: 第19回若手NMR研究会
  • Invited
• [Presentation] Structural characterization of antibody interactions in situ (2018)
  • Author(s): S. Yanaka, H. Watanabe, R. Yogo, H. yagi, T. Uchihashi and K. Kato
  • Organizer: 第56回日本生物物理学会年会
  • Invited
• [Presentation] 抗体研究から学ぶこと (2018)
  • Author(s): 谷中冴子
  • Organizer: 第91回日本生化学会大会 生化学若い研究者の会創立60周年記念シンポジウム「生命科学の来し方行く末」
  • Invited
• [Remarks] EurekAlert
  • URL: https://www.eurekalert.org/pub_releases/2020-01/nion-aga010620.php
• [Remarks] 免疫学の常識を覆す！抗体と受容体の新たな結合部位の発見
  • URL: http://www.excells.orion.ac.jp/pr/20190816pr.html