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Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria

Author

Listed:
  • Stian Foss

    (Oslo University Hospital
    University of Oslo
    University of Oslo)

  • Siri A. Sakya

    (Oslo University Hospital
    University of Oslo
    University of Oslo)

  • Leire Aguinagalde

    (University Medical Center Utrecht, Utrecht University)

  • Marta Lustig

    (Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein)

  • Jutamas Shaughnessy

    (University of Massachusetts Chan Medical School)

  • Ana Rita Cruz

    (University Medical Center Utrecht, Utrecht University)

  • Lisette Scheepmaker

    (University Medical Center Utrecht, Utrecht University)

  • Line Mathiesen

    (University of Copenhagen)

  • Fulgencio Ruso-Julve

    (Oslo University Hospital
    University of Oslo
    University of Oslo)

  • Aina Karen Anthi

    (Oslo University Hospital
    University of Oslo
    University of Oslo)

  • Torleif Tollefsrud Gjølberg

    (Oslo University Hospital
    University of Oslo
    University of Oslo)

  • Simone Mester

    (Oslo University Hospital
    University of Oslo
    University of Oslo)

  • Malin Bern

    (Oslo University Hospital
    University of Oslo
    University of Oslo)

  • Mitchell Evers

    (University Medical Center Utrecht)

  • Diane B. Bratlie

    (Norwegian Institute of Public Health)

  • Terje E. Michaelsen

    (Norwegian Institute of Public Health
    University of Oslo)

  • Tilman Schlothauer

    (Roche Innovation Center Munich)

  • Devin Sok

    (International AIDS Vaccine Initiative (IAVI))

  • Jayanta Bhattacharya

    (NCR Biotech Science Cluster)

  • Jeanette Leusen

    (University Medical Center Utrecht)

  • Thomas Valerius

    (Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein)

  • Sanjay Ram

    (University of Massachusetts Chan Medical School)

  • Suzan H. M. Rooijakkers

    (University Medical Center Utrecht, Utrecht University)

  • Inger Sandlie

    (University of Oslo)

  • Jan Terje Andersen

    (Oslo University Hospital
    University of Oslo
    University of Oslo)

Abstract

Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.

Suggested Citation

  • Stian Foss & Siri A. Sakya & Leire Aguinagalde & Marta Lustig & Jutamas Shaughnessy & Ana Rita Cruz & Lisette Scheepmaker & Line Mathiesen & Fulgencio Ruso-Julve & Aina Karen Anthi & Torleif Tollefsru, 2024. "Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46321-9
    DOI: 10.1038/s41467-024-46321-9
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    as
    1. Sung-Youl Ko & Amarendra Pegu & Rebecca S. Rudicell & Zhi-yong Yang & M. Gordon Joyce & Xuejun Chen & Keyun Wang & Saran Bao & Thomas D. Kraemer & Timo Rath & Ming Zeng & Stephen D. Schmidt & John-Pau, 2014. "Enhanced neonatal Fc receptor function improves protection against primate SHIV infection," Nature, Nature, vol. 514(7524), pages 642-645, October.
    2. Algirdas Grevys & Jeannette Nilsen & Kine M. K. Sand & Muluneh B. Daba & Inger Øynebråten & Malin Bern & Martin B. McAdam & Stian Foss & Tilman Schlothauer & Terje E. Michaelsen & Gregory J. Christian, 2018. "A human endothelial cell-based recycling assay for screening of FcRn targeted molecules," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    3. Chang-Han Lee & Tae Hyun Kang & Ophélie Godon & Makiko Watanabe & George Delidakis & Caitlin M. Gillis & Delphine Sterlin & David Hardy & Michel Cogné & Lynn E. Macdonald & Andrew J. Murphy & Naxin Tu, 2019. "An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    4. Chang-Han Lee & Tae Hyun Kang & Ophélie Godon & Makiko Watanabe & George Delidakis & Caitlin M. Gillis & Delphine Sterlin & David Hardy & Michel Cogné & Lynn E. Macdonald & Andrew J. Murphy & Naxin Tu, 2019. "Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence," Nature Communications, Nature, vol. 10(1), pages 1-1, December.
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