한빛사논문
- 조회2,540
Chang-Han Lee1,14, Tae Hyun Kang1,13,14, Ophélie Godon2, Makiko Watanabe1, George Delidakis1, Caitlin M. Gillis2, Delphine Sterlin2, David Hardy3, Michel Cogné4, Lynn E. Macdonald5, Andrew J. Murphy5, Naxin Tu5, Jiwon Lee6, Jonathan R. McDaniel1, Emily Makowski7, Peter M. Tessier8,9, Aaron S. Meyer10, Pierre Bruhns2,15,* & George Georgiou1,11,12,15,*
1 Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA.
2 Unit of Antibodies in Therapy and Pathology, Institut Pasteur, UMR1222 INSERMF-75015, Paris, France.
3 Experimental Neuropathology Unit, Infection and Epidemiology Department, Institut Pasteur, 25, rue du Docteur Roux, 75015 Paris, France.
4 Limoges University, Limoges, France.
5 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
6 Thayer School of Engineering, Dartmouth College, Hanover, NH, USA.
7 Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA.
8 Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
9 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
10 Department of Bioengineering, University of California at Los Angeles, Los Angeles, CA, USA.
11 Department of Molecular Bioscience, University of Texas at Austin, Austin, TX, USA.
12 Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA.
13 Present address: Department of Applied Chemistry, Kookmin University, Seoul, Republic of Korea.
14 These authors contributed equally: Chang-Han Lee, Tae Hyun Kang.
15 These authors jointly supervised this work: Pierre Bruhns, George Georgiou.
*Correspondence to Pierre Bruhns or George Georgiou
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.
논문정보
- Research article
- 2019년 11월 (BRIC 등록일 2019-11-21)
- 국내+국외 연구진
- 의약학 > 약학
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