Generation of a Double Transgenic Humanised Neonatal Fc Receptor (FcRn)/Albumin Mouse to Study the Pharmacokinetics of Albumin-linked Drugs

Dorthe Viuff, Filipa Antunes, Leslie Evans, Jason Cameron, Hans Dyrnesli, Birgitte Thue Ravn, Magnus Stougaard, Kader Thiam, Birgitte Andersen, Søren Kjærulff, Ken Howard

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Human serum albumin (HSA) is a natural carrier protein possessing multiple ligand binding sites with a plasma half-life ~ 19 days, facilitated by interaction with the human neonatal Fc receptor (FcRn), that promotes it as a highly attractive drug delivery technology. A lack of adequate rodent models, however, is a major challenge in the preclinical development of albumin-linked therapeutics. This work describes the first double transgenic mouse model bearing both human FcRn and HSA genes (hFcRn +/+, hAlb +/+) under the control of an endogenous promoter. Human FcRn was shown by immunohistochemical and qPCR analysis to be ubiquitously expressed in the major organs. Physiological levels of HSA were detected in the blood that exhibited similar FcRn binding kinetics to recombinant or human serum-derived HSA. The circulatory half-life (t 1/2) was shown to be dependent on FcRn binding affinity that increased from low affinity (t 1/2 29 h), to wild type (t 1/2 50 h), to high affinity (t 1/2 80 h) variants, that validates the application of the model for optimizing the pharmacokinetics of drug carriers who's circulatory half-life is dependent in some manner upon interaction with endogenous FcRn. This study presents a novel mouse model that better mimics the human physiological conditions and, thus, has potential wide applications in the development of albumin-linked drugs or conventional drugs whose action is influenced by reversible binding to endogenous HSA.

Original languageEnglish
JournalJournal of Controlled Release
Volume223
Pages (from-to)22-30
Number of pages9
ISSN0168-3659
DOIs
Publication statusPublished - 2016

Keywords

  • Albumin
  • Animal model
  • Drug delivery
  • Drug development
  • Neonatal Fc receptor
  • Protein engineering

Fingerprint

Dive into the research topics of 'Generation of a Double Transgenic Humanised Neonatal Fc Receptor (FcRn)/Albumin Mouse to Study the Pharmacokinetics of Albumin-linked Drugs'. Together they form a unique fingerprint.

Cite this