An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.
Lee, C-H
Kang, TH
Godon, O
Watanabe, M
Delidakis, G
Gillis, CM
Sterlin, D
Hardy, D
Cogné, M
Macdonald, LE
Murphy, AJ
Tu, N
Lee, J
McDaniel, JR
Makowski, E
Tessier, PM
Meyer, AS
Bruhns, P
Georgiou, G
- Publication Type:
- Journal Article
- Citation:
- Nat Commun, 2019, 10 (1), pp. 5031 - ?
- Issue Date:
- 2019-11-06
Open Access
Copyright Clearance Process
- Recently Added
- In Progress
- Open Access
This item is open access.
Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author |
Lee, C-H |
en_US |
dc.contributor.author |
Kang, TH |
en_US |
dc.contributor.author | Godon, O | en_US |
dc.contributor.author |
Watanabe, M |
en_US |
dc.contributor.author |
Delidakis, G |
en_US |
dc.contributor.author |
Gillis, CM |
en_US |
dc.contributor.author | Sterlin, D | en_US |
dc.contributor.author | Hardy, D | en_US |
dc.contributor.author | Cogné, M | en_US |
dc.contributor.author | Macdonald, LE | en_US |
dc.contributor.author |
Murphy, AJ |
en_US |
dc.contributor.author | Tu, N | en_US |
dc.contributor.author |
Lee, J |
en_US |
dc.contributor.author | McDaniel, JR | en_US |
dc.contributor.author | Makowski, E | en_US |
dc.contributor.author | Tessier, PM | en_US |
dc.contributor.author |
Meyer, AS |
en_US |
dc.contributor.author | Bruhns, P | en_US |
dc.contributor.author | Georgiou, G | en_US |
dc.date.accessioned | 2020-04-16T23:07:13Z | |
dc.date.available | 2019-10-16 | en_US |
dc.date.available | 2020-04-16T23:07:13Z | |
dc.date.issued | 2019-11-06 | en_US |
dc.identifier.citation | Nat Commun, 2019, 10 (1), pp. 5031 - ? | en_US |
dc.identifier.uri | http://hdl.handle.net/10453/140049 | |
dc.description.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. | en_US |
dc.language | eng | en_US |
dc.relation.ispartof | Nat Commun | en_US |
dc.relation.isbasedon | 10.1038/s41467-019-13108-2 | en_US |
dc.subject.mesh | Animals | en_US |
dc.subject.mesh | Mice, Inbred BALB C | en_US |
dc.subject.mesh | Mice, Inbred C57BL | en_US |
dc.subject.mesh | Mice, Transgenic | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Mice | en_US |
dc.subject.mesh | Immunoglobulin G | en_US |
dc.subject.mesh | Receptors, Fc | en_US |
dc.subject.mesh | Recombinant Proteins | en_US |
dc.subject.mesh | Histocompatibility Antigens Class I | en_US |
dc.subject.mesh | Genetic Engineering | en_US |
dc.subject.mesh | Protein Engineering | en_US |
dc.subject.mesh | Pharmacokinetics | en_US |
dc.subject.mesh | Hydrogen-Ion Concentration | en_US |
dc.subject.mesh | Half-Life | en_US |
dc.subject.mesh | Protein Domains | en_US |
dc.title | An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence. | en_US |
dc.type | Journal Article | |
utslib.citation.volume | 1 | en_US |
utslib.citation.volume | 10 | en_US |
utslib.location.activity | England | en_US |
pubs.embargo.period | Not known | en_US |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science/School of Life Sciences | |
utslib.copyright.status | open_access | |
pubs.issue | 1 | en_US |
pubs.publication-status | Published online | en_US |
pubs.volume | 10 | en_US |
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.
Please use this identifier to cite or link to this item:
Download statistics for the last 12 months
Not enough data to produce graph