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Understanding the efficacy of therapeutic antibodies through their interaction with cellular receptors.

Research Project

Project/Area Number 20H03228
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 43040:Biophysics-related
Research InstitutionKyushu University

Principal Investigator

CAAVEIRO Jose  九州大学, 薬学研究院, 教授 (00536732)

Co-Investigator(Kenkyū-buntansha) 高橋 大輔  九州大学, 薬学研究院, 講師 (70791523)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2022: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2021: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2020: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
KeywordsAntibody / Fc receptor / hinge / structure / immunology / glycosylation / bnAbs / HIV-1 / antibody / fc receptor / Antobody / protein expression / Mechanism / Molecular interactios / molecular interactions / mechanism
Outline of Research at the Start

Therapeutic antibodies are improving human healthcare.
To improve their efficacy and safety we need to understand how they work in a more precise manner.
The binding of antibodies to Fc receptors starts a strong cellular response.
We aim to understand how that happens at the molecular level.

Outline of Final Research Achievements

We advanced the understanding of the interaction between antibodies of the IgG family and their cellular receptors at the molecular level. We have described the less-than expected effect of mutations in the middle hinge region to the strength of the interaction with receptors (the middle hinge is where the disulfide bond is located). However, residues in close proximity to the binding interface had a profound effect. Our studies support the engineering of antibodies in the hinge region without major effect in the potency of Abs.
Additionally, we made an important contribution to improve the potency of Abs. This process was patented and consist on (i) the introduction of a CYS residue in a strategic location and (2) chemical modification of the CYS residue by a yodo acetamide molecule of specific atomic structure. Using this approach we have improved the potency of anti-HIV-1 Abs by more than 500-fold.

Academic Significance and Societal Importance of the Research Achievements

From a scientific point, we have advanced the basic knowledge of the interaction between antibodies and their cellular receptors. From a social point of view, the technology discovered herein improves the potency of antibodies and might save the lives of people suffering from infectious diseases.

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (8 results)

All 2022 2021 2020

All Journal Article (8 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 8 results,  Open Access: 6 results)

  • [Journal Article] Antibody recognition of complement Factor H reveals a flexible loop involved in Atypical Hemolytic Uremic Syndrome pathogenesis2022

    • Author(s)
      Yokoo Takanori、Tanabe Aki、Yoshida Yoko、Caaveiro Jose M.M.、Nakakido Makoto、Ikeda Yoichiro、Fujimura Yoshihiro、Matsumoto Masanori、Entzminger Kevin、Maruyama Toshiaki、Okumura C.J.、Nangaku Masaomi、Tsumoto Kouhei
    • Journal Title

      Journal of Biological Chemistry

      Volume: - Issue: 6 Pages: 101962-101962

    • DOI

      10.1016/j.jbc.2022.101962

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Functional Delineation of a Protein?Membrane Interaction Hotspot Site on the HIV-1 Neutralizing Antibody 10E82022

    • Author(s)
      Insausti Sara、Garcia-Porras Miguel、Torralba Johana、Morillo Izaskun、Ramos-Caballero Ander、de la Arada Igor、Apellaniz Beatriz、Caaveiro Jose M. M.、Carravilla Pablo、Eggeling Christian、Rujas Edurne、Nieva Jose L.
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 18 Pages: 10767-10767

    • DOI

      10.3390/ijms231810767

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular recognition of a membrane-anchored HIV-1 pan-neutralizing epitope2022

    • Author(s)
      Torralba Johana、de la Arada Igor、Partida-Hanon Angelica、Rujas Edurne、Arribas Madalen、Insausti Sara、Valotteau Claire、Valle Javier、Andreu David、Caaveiro Jose M. M.、Jimenez Maria Angeles、Apellaniz Beatriz、Redondo-Morata Lorena、Nieva Jose L.
    • Journal Title

      Communications Biology

      Volume: 5 Issue: 1 Pages: 1-14

    • DOI

      10.1038/s42003-022-04219-6

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular basis for thermal stability and affinity in a VHH: Contribution of the framework region and its influence in the conformation of the CDR32022

    • Author(s)
      Kinoshita Seisho、Nakakido Makoto、Mori Chinatsu、Kuroda Daisuke、Caaveiro Jose M.M.、Tsumoto Kouhei
    • Journal Title

      Protein Science

      Volume: 31 Issue: 11 Pages: 1-12

    • DOI

      10.1002/pro.4450

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Focal accumulation of aromaticity at the CDRH3 loop mitigates 4E10 polyreactivity without altering its HIV neutralization profile2021

    • Author(s)
      Rujas Edurne、Leaman Daniel P.、Insausti Sara、Carravilla Pablo、Garc?a-Porras Miguel、Largo Eneko、Morillo Izaskun、S?nchez-Eugenia Rub?n、Zhang Lei、Cui Hong、Iloro Ibon、Elortza F?lix、Julien Jean-Philippe、Eggeling Christian、Zwick Michael B.、Caaveiro Jose M.M.、Nieva Jos? L.
    • Journal Title

      iScience

      Volume: 24 Issue: 9 Pages: 102987-102987

    • DOI

      10.1016/j.isci.2021.102987

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Abolition of aggregation of CH2 domain of human IgG1 when combining glycosylation and protein stabilization2021

    • Author(s)
      Oyama Kosuke、Ohkuri Takatoshi、Ochi Jinta、Caaveiro Jose M.M.、Ueda Tadashi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 558 Pages: 114-119

    • DOI

      10.1016/j.bbrc.2021.04.070

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] High-level expression of human CH2 domain from the Fc region in <i>Pichia pastoris</i> and preparation of anti-CH2 antibodies2021

    • Author(s)
      Oyama Kosuke、Ohkuri Takatoshi、Inoue Mao、Caaveiro Jose M M、Ueda Tadashi
    • Journal Title

      The Journal of Biochemistry

      Volume: 170 Issue: 2 Pages: 289-297

    • DOI

      10.1093/jb/mvab039

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Affinity for the Interface Underpins Potency of Antibodies Operating In Membrane Environments2020

    • Author(s)
      Rujas Edurne、various authors, Ojida Akio、Domene Carmen、Caaveiro Jose M.M.、Nieva Jose L.
    • Journal Title

      Cell Reports

      Volume: 32 Issue: 7 Pages: 108037-108037

    • DOI

      10.1016/j.celrep.2020.108037

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research

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Published: 2020-04-28   Modified: 2024-01-30  

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