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An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence

Author

Listed:
  • Chang-Han Lee

    (University of Texas at Austin)

  • Tae Hyun Kang

    (University of Texas at Austin
    Kookmin University)

  • Ophélie Godon

    (Institut Pasteur)

  • Makiko Watanabe

    (University of Texas at Austin)

  • George Delidakis

    (University of Texas at Austin)

  • Caitlin M. Gillis

    (Institut Pasteur)

  • Delphine Sterlin

    (Institut Pasteur)

  • David Hardy

    (Institut Pasteur)

  • Michel Cogné

    (Limoges University)

  • Lynn E. Macdonald

    (Regeneron Pharmaceuticals, Inc.)

  • Andrew J. Murphy

    (Regeneron Pharmaceuticals, Inc.)

  • Naxin Tu

    (Regeneron Pharmaceuticals, Inc.)

  • Jiwon Lee

    (Dartmouth College)

  • Jonathan R. McDaniel

    (University of Texas at Austin)

  • Emily Makowski

    (University of Michigan)

  • Peter M. Tessier

    (University of Michigan
    University of Michigan)

  • Aaron S. Meyer

    (University of California at Los Angeles)

  • Pierre Bruhns

    (Institut Pasteur)

  • George Georgiou

    (University of Texas at Austin
    University of Texas at Austin
    University of Texas at Austin)

Abstract

The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13108-2
    DOI: 10.1038/s41467-019-13108-2
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    Cited by:

    1. 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.
    2. Sasha B. Ebrahimi & Devleena Samanta, 2023. "Engineering protein-based therapeutics through structural and chemical design," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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