title: Albumin-deficient mouse models for studying metabolism of human albumin and pharmacokinetics of albumin-based drugs.
abstract: Serum albumin is the major determinant of blood colloidal osmotic pressure acting as a depot and distributor of compounds including drugs. In humans, serum albumin exhibits an unusually long half-life mainly due to protection from catabolism by neonatal Fc receptor (FcRn)-mediated recycling. These properties make albumin an attractive courier of therapeutically-active compounds. However, pharmaceutical research and development of albumin-based therapeutics has been hampered by the lack of appropriate preclinical animal models. To overcome this, we developed and describe the first mouse with a genetic deficiency in albumin and its incorporation into an existing humanized FcRn mouse model, B6.Cg-Fcgrt(tm1Dcr) Tg(FCGRT)32Dcr/DcrJ (Tg32). Albumin-deficient strains (Alb(-/-)) were created by TALEN-mediated disruption of the albumin (Alb) gene directly in fertilized oocytes derived from Tg32 mice and its non-transgenic background control, C57BL/6J (B6). The resulting Alb(-/-) strains are analbuminemic but healthy. Intravenous administration of human albumin to Tg32-Alb(-/-) mFcRn(-/-) hFcRn(Tg/Tg)) mice results in a remarkably extended human albumin serum half-life of ∼24 days, comparable to that found in humans, and in contrast to half-lives of 2.6-5.8 d observed in B6, B6-Alb(-/-) and Tg32 strains. This striking increase can be explained by the absence of competing endogenous mouse albumin and the presence of an active human FcRn. These novel albumin-deficient models provide unique tools for investigating the biology and pathobiology of serum albumin and are a more appropriate rodent surrogates for evaluating human serum albumin pharmacokinetics and albumin-based compounds.
authors: a The Jackson Laboratory ; Bar Harbor , ME USA.
authors: Derry C
authors: DC
authors: Roopenian
authors: Benjamin E
authors: BE
authors: Low
authors: Gregory J
authors: GJ
authors: Christianson
authors: Gabriele
authors: G
authors: Proetzel
authors: Thomas J
authors: TJ
authors: Sproule
authors: Michael V
authors: MV
authors: Wiles
mesh_terms: D000818:Animals; D006207:Half-Life; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D012709:Serum Albumin / Q000235:genetics / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D012709:Serum Albumin
keywords: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FcRn, neonatal Fc receptor; HDL, high-density lipoprotein; HSA, human serum albumin; IgG, immunoglobulin G; LDH, low-density-lipoprotein; MSA, mouse serum albumin; TALEN; TALEN, transcription activator-like effector nuclease; albumin; albumin-conjugates; analbuminemia; hFcRn, human FcRn; human serum albumin; hypoalbuminemia; mouse model; neonatal Fc receptor; pharmacokinetics; transgenic
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