Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13108-2
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Funding
- Clayton Foundation
- European Research Council (ERC)-Seventh Framework Program [ERC-2013-CoG 616050]
- Institut Pasteur
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- National Institutes of Health [R01GM104130]
- National Science Foundation [CBET 1804313]
- Albert M. Mattocks Chair
- NIH [DP5-OD019815]
- Pasteur-Paris University (PPU) International PhD program
- Institut Carnot Pasteur Maladies Infectieuses
- AP-HP, Paris, France
- Institut Pasteur, Paris, France
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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.
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