An Engineered Human Fc Domain that Behaves like a pH-Toggle Switch for Ultra-Long Circulation Persistence
Résumé
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.
Domaines
Immunologie
Fichier principal
Lee et al., Nat Comm 2019 manuscript (final version).pdf (4.63 Mo)
Télécharger le fichier
41467_2019_13108_MOESM1_ESM.pdf (13.14 Mo)
Télécharger le fichier
Loading...
