An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence

Chang-Han Lee; Tae Hyun Kang; Ophélie Godon; Makiko Watanabe; George Delidakis; Caitlin M Gillis; Delphine Sterlin; David Hardy; Michel Cogné; Lynn E Macdonald; Andrew J Murphy; Naxin Tu; Jiwon Lee; Jonathan R McDaniel; Emily Makowski; Peter M Tessier; Aaron S Meyer; Pierre Bruhns; George Georgiou

doi:10.1038/s41467-019-13108-2

An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence

Nat Commun. 2019 Nov 6;10(1):5031. doi: 10.1038/s41467-019-13108-2.

Authors

Chang-Han Lee¹, Tae Hyun Kang^{1

2}, Ophélie Godon³, Makiko Watanabe¹, George Delidakis¹, Caitlin M Gillis³, Delphine Sterlin³, David Hardy⁴, Michel Cogné⁵, Lynn E Macdonald⁶, Andrew J Murphy⁶, Naxin Tu⁶, Jiwon Lee⁷, Jonathan R McDaniel¹, Emily Makowski⁸, Peter M Tessier^{9

10}, Aaron S Meyer¹¹, Pierre Bruhns¹², George Georgiou^{13

14

15}

Affiliations

¹ Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA.
² Department of Applied Chemistry, Kookmin University, Seoul, Republic of Korea.
³ Unit of Antibodies in Therapy and Pathology, Institut Pasteur, UMR1222 INSERMF-75015, Paris, France.
⁴ Experimental Neuropathology Unit, Infection and Epidemiology Department, Institut Pasteur, 25, rue du Docteur Roux, 75015, Paris, France.
⁵ Limoges University, Limoges, France.
⁶ Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
⁷ Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
⁸ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
¹⁰ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
¹¹ Department of Bioengineering, University of California at Los Angeles, Los Angeles, CA, USA.
¹² Unit of Antibodies in Therapy and Pathology, Institut Pasteur, UMR1222 INSERMF-75015, Paris, France. [email protected].
¹³ Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA. [email protected].
¹⁴ Department of Molecular Bioscience, University of Texas at Austin, Austin, TX, USA. [email protected].
¹⁵ Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Genetic Engineering
Half-Life
Histocompatibility Antigens Class I / chemistry*
Histocompatibility Antigens Class I / genetics*
Histocompatibility Antigens Class I / immunology
Histocompatibility Antigens Class I / pharmacology*
Humans
Hydrogen-Ion Concentration
Immunoglobulin G / chemistry
Immunoglobulin G / pharmacology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Pharmacokinetics
Protein Domains
Protein Engineering*
Receptors, Fc / chemistry*
Receptors, Fc / genetics*
Receptors, Fc / immunology
Recombinant Proteins

Substances

Histocompatibility Antigens Class I
Immunoglobulin G
Receptors, Fc
Recombinant Proteins
Fc receptor, neonatal

Abstract

Publication types

MeSH terms

Substances

Grants and funding