Humanized Neonatal Fc Receptor (FcRn) / Albumin Mouse Model for Pharmacokinetic Studies

Applications: All therapeutic areas and ADME studies

This new double humanized neonatal Fc receptor (FcRn)/albumin mouse model maintains an autologous receptor-ligand interaction and mimics the physiological drug clearance in humans, and therefore represents a unique and reliable tool to:

  • Measure and optimize albumin-linked small molecules and conventional drug pharmacokinetics
  • Study and predict the half-life of circulating biologics and biosimilar drugs

Model features:

  • Expression level of HSA in physiological range of 30-50 mg/ml, corresponding to a concentration observed in humans (Fig. 1)
  • No expression of murine serum albumin
  • No physiological deregulation reported; blood chemistry parameters are in normal range (Fig. 2)
  • Humanized FcRn secures physiological binding affinities of biologics (Fig. 3), and human albumin-linked NCEs (Fig. 4)

References:

Original reference:
Viuff D, Antunes F, Evans L, Cameron J, Dyrnesli H, Thue Ravn B, Stougaard M, Thiam K, Andersen B, Kjærulff S, Howard KA. 2016. Generation of a double transgenic humanized neonatal Fc receptor (FcRn)/albumin mouse to study the pharmacokinetics of albumin-linked drugs. J Control Release. [PubMed]

Model validation

Our biopharmaceutical partners have assessed proprietary xenobiotics exhibiting strong interspecies specifications (mouse versus human) using our human FcRn/human serum albumin (hFcRn/HSA) mouse model. Their results revealed that the pharmacokinetics of HSA-binding drugs in hFcRn/HSA humanized mice are similar to that in humans:

  • Compound 1 has a half-life of 2 hours in wild-type (WT) mice versus 24 hours in humans. When tested in hFcRn/HSA humanized mice, the half-life of this compound was, as in humans, 24 hours.
  • Compound 2 has a half-life of 26 hours in WT mice versus 48 hours in humans. When tested in hFcRn/HSA humanized mice, the half-life of this compound was 46 hours.

The hFcRn/HSA humanized mouse provides more predictable "human-like" pharmacokinetic results than WT mice. This model is well suited for in vivo assessment of HSA-binding drugs' pharmacokinetic, distribution and toxicity.

 

Human Serum Albumin detection in HSA Knockin miceFig. 1)

Circulating Human Serum Albumin is detected in humanized mice.

HSA titer was determined from blood samples of (WT), heterozygous and homozygous humanized mice.

HSA levels in homozygous mice are similar to serum albumin concentration in humans (35-50 mg/ml).  

Fig. 2)

Blood chemistry analysis performed on human FcRn/HSA homozygous mice showed that all parameters analyzed are within normal range when compared to (WT) mice.
(Viuff et al. Journal of Control Release, 2016)

Fig. 3)

The human IgG displays a 150 times higher affinity toward the mouse FcRn versus the human FcRn creating a bias in the study of humanized therapeutic antibodies or human Fc-coupled biologics in vivo half-life by overestimating the PK properties.
(Viuff et al. Journal of Control Release, 2016)


1Values correspond to low-affinity IgG-binding.

Fig. 4)

The reported weak interaction of HSA for murine FcRn and the illustrated higher affinity of the human FcRn for MSA have made the single humanized mouse (HSA or human FcRn) useless for studying the PK of HSA-based drugs.
(Viuff et al. Journal of Control Release, 2016)

Conclusion

These data demonstrate that only the double transgenic mouse model bearing both human FcRn and HSA can reliably mimic the metabolic turnover and in vivo half-life, making it a reference tool in the optimization of albumin-linked drugs or conventional drugs.

 

Ready to be shipped to your lab

  • Available onto C57BL/6N genetic background
  • Health-certified prior to delivery: SOPF/VAF Elite (Specific and Opportunistic Pathogen-Free/Virus- and Antibody-Free)
  • Worldwide delivery using logistic networks of renowned professional breeders

Access conditions

  • Freedom to operate for basic and pharmaceutical research
  • Generated data are the exclusive property of the customer and royalty-free
  • The model is available through in-licensing (flat annual fee, depending on company size)
  • On-demand production of cohorts by contract breeding