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

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, Jiwon Lee, Jonathan R. McDaniel, Emily Makowski, Peter M. Tessier, Aaron S. Meyer, Pierre Bruhns () and George Georgiou ()
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Chang-Han Lee: University of Texas at Austin
Tae Hyun Kang: University of Texas at Austin
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
Aaron S. Meyer: University of California at Los Angeles
Pierre Bruhns: Institut Pasteur
George Georgiou: University of Texas at Austin

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13108-2

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DOI: 10.1038/s41467-019-13108-2

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