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An Engineered Human Fc Domain that Behaves like a pH-Toggle Switch for Ultra-Long Circulation Persistence

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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Tae Kang, Chang-Han Lee, Tae Hyun Kang, Ophélie Godon, Makiko Watanabe, et al.. An Engineered Human Fc Domain that Behaves like a pH-Toggle Switch for Ultra-Long Circulation Persistence. Nature Communications, Nature Publishing Group, 2019, 10 (1), pp.5031. ⟨10.1038/s41467-019-13108-2⟩. ⟨pasteur-02448624⟩

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