| First Author | Roopenian DC | Year | 2015 |
| Journal | MAbs | Volume | 7 |
| Issue | 2 | Pages | 344-51 |
| PubMed ID | 25654695 | Mgi Jnum | J:220803 |
| Mgi Id | MGI:5636154 | Doi | 10.1080/19420862.2015.1008345 |
| Citation | Roopenian DC, et al. (2015) Albumin-deficient mouse models for studying metabolism of human albumin and pharmacokinetics of albumin-based drugs. MAbs 7(2):344-51 |
| abstractText | 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 approximately 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. |
