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

Tae Hyun Kang (1) , Chang-Han Lee (1) , Tae Hyun Kang (1) , Ophélie Godon (2) , Makiko Watanabe (1) , George Delidakis (1) , Caitlin Gillis (2) , Delphine Sterlin (2) , David Hardy (3) , Michel Cogné (4) , Lynn E Macdonald (5) , Andrew J Murphy (5) , Naxin Tu (5) , Jiwon Lee (6) , Jonathan R Mcdaniel (1) , Emily Makowski (7) , Peter Tessier (7) , Aaron S Meyer (8) , Pierre Bruhns (2) , George Georgiou (1)

1 University of Texas at Austin [Austin]
2 Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology
3 Neuropathologie expérimentale - Experimental neuropathology
4 UNILIM - Université de Limoges
5 Regeneron Pharmaceuticals [Tarrytown]
6 Dartmouth College [Hanover]
7 University of Michigan [Ann Arbor]
8 UCLA - University of California [Los Angeles]

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.

Domains: Immunology

Tae Hyun 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, 2019, 10 (1), pp.5031. ⟨10.1038/s41467-019-13108-2⟩. ⟨pasteur-02448624⟩