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An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence
Cited 44 time in
Web of Science
Cited 45 time in Scopus
- Authors
- Issue Date
- 2019-12
- Publisher
- Nature Publishing Group
- Citation
- Nature Communications, Vol.10 No.1, p. 5031
- 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 hFc gamma Rs 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.
- ISSN
- 2041-1723
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