title: Generation of a double transgenic humanized neonatal Fc receptor (FcRn)/albumin mouse to study the pharmacokinetics of albumin-linked drugs.
abstract: Human serum albumin (HSA) is a natural carrier protein possessing multiple ligand binding sites with a plasma half-life ~19days, 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 (t1/2) was shown to be dependent on FcRn binding affinity that increased from low affinity (t1/2 29h), to wild type (t1/2 50h), to high affinity (t1/2 80h) 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.
authors.affiliation: Novozymes Biopharma, Novozymes A/S, Brudelysvej 32, 2880 Bagsværd, Denmark.
authors.forename: Dorthe
authors.initials: D
authors.lastname: Viuff
authors.affiliation: Novozymes Biopharma UK Ltd., Castle Court, 59 Castle Boulevard, NG7 1FD Nottingham, United Kingdom.
authors.forename: Filipa
authors.initials: F
authors.lastname: Antunes
authors.affiliation: Novozymes Biopharma UK Ltd., Castle Court, 59 Castle Boulevard, NG7 1FD Nottingham, United Kingdom.
authors.forename: Leslie
authors.initials: L
authors.lastname: Evans
authors.affiliation: Novozymes Biopharma UK Ltd., Castle Court, 59 Castle Boulevard, NG7 1FD Nottingham, United Kingdom.
authors.forename: Jason
authors.initials: J
authors.lastname: Cameron
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Dyrnesli
authors.affiliation: Novozymes Biopharma, Novozymes A/S, Brudelysvej 32, 2880 Bagsværd, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Thue Ravn
authors.affiliation: Pathology Institute, Aarhus University Hospital, 8000 Aarhus C, Denmark.
authors.forename: Magnus
authors.initials: M
authors.lastname: Stougaard
authors.affiliation: genOway, 69362, Lyon, Cedex 07, France.
authors.forename: Kader
authors.initials: K
authors.lastname: Thiam
authors.affiliation: Novozymes Biopharma, Novozymes A/S, Brudelysvej 32, 2880 Bagsværd, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Andersen
authors.affiliation: Novozymes Biopharma, Novozymes A/S, Brudelysvej 32, 2880 Bagsværd, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Kjærulff
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Howard
mesh_terms: D000818:Animals; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011485:Protein Binding; D011961:Receptors, Fc / Q000235:genetics* / Q000378:metabolism*; D012709:Serum Albumin / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D004364:Pharmaceutical Preparations; D011961:Receptors, Fc; D012709:Serum Albumin; C100688:Fc receptor, neonatal
keywords: Albumin; Animal model; Drug delivery; Drug development; Neonatal Fc receptor; Protein engineering