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

  • Author(s): Lee, Chang-Han;
  • Kang, Tae Hyun;
  • Godon, Ophélie;
  • Watanabe, Makiko;
  • Delidakis, George;
  • Gillis, Caitlin M;
  • Sterlin, Delphine;
  • Hardy, David;
  • Cogné, Michel;
  • Macdonald, Lynn E;
  • Murphy, Andrew J;
  • Tu, Naxin;
  • Lee, Jiwon;
  • McDaniel, Jonathan R;
  • Makowski, Emily;
  • Tessier, Peter M;
  • Meyer, Aaron S;
  • Bruhns, Pierre;
  • Georgiou, George
  • et al.
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.

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