Abstract
Albumin is a large, highly abundant protein circulating in the blood stream which is regulated and actively recycled via the neonatal Fc receptor (FcRn). In humans this results in serum albumin having an exceptional long half-life of ~21 days. Some time ago it was realized that these intrinsic properties could be harnessed and albumin could be used as a privileged drug delivery vehicle. However, active development of albumin based therapeutics has been hampered by the lack of economic, relevant experimental models which can accurately recapitulate human albumin metabolism and pharmacokinetics. In mice for example, introduced human albumin is not recycled and is catabolized rapidly. This is mainly due to the failure of mouse FcRn to bind human albumin consequently, human albumin has a half-life of only 2–3 days in mice. To overcome this we developed and characterized a humanized mouse model which is null for mouse FcRn and mouse albumin, but is transgenic for, and expressing functional human FcRn. Published data clearly demonstrate that upon injection of human albumin into this model animal that it accurately recapitulates human albumin FcRn dependent serum recycling, with human albumin now having a half-life ~24 days, closely mimicking that observed in humans. In this practical review we briefly review this model and outline its use for pharmacokinetic studies of human albumin.
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Abbreviations
- B6:
-
C57BL/6J
- FcRn:
-
Neonatal Fc receptor
- HSA:
-
Human serum albumin
- kDa:
-
Kilodalton
- MSA:
-
Mouse serum albumin
- TALEN:
-
Transcription activator-like effector nuclease
- Tg32:
-
B6.Cg-Fcgrt tm1Dcr Tg(FCGRT)32Dcr/DcrJ
- Tg32-Alb−/− :
-
B6.Cg-Alb em12Mvw Fcgrt tm1Dcr Tg(FCGRT)32Dcr/MvwJ
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Acknowledgements
This work was done with help and excellent assistance of Cindy Avery and Deb Woodworth for genotyping and animal maintenance, plus discussions with Gregory J Christianson, Thomas J Sproule, plus Dr’s Gabriele Proetzel, Derry C Roopenian, and Vishnu Hosur. This work was supported by National Institutes of Health Grant OD011190 (M.V.W.) and The Jackson Laboratory.
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Low, B.E., Wiles, M.V. (2016). A Humanized Mouse Model to Study Human Albumin and Albumin Conjugates Pharmacokinetics. In: Proetzel, G., Wiles, M. (eds) Mouse Models for Drug Discovery. Methods in Molecular Biology, vol 1438. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3661-8_7
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DOI: https://doi.org/10.1007/978-1-4939-3661-8_7
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