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Humanized mice (target-specific)
Preclinical humanized TFRC mouse model
The hTFRC mouse model enables in vivo efficacy assessment and profiling of compounds targeting the human cell shuttle TFRC in fully immunocompetent mice.
Design of the hTFRC mouse
The humanized TFRC mouse model is developed by Knockin at the mouse TFRC locus, and expresses a chimeric protein with a human extracellular domain (ECD) and a murine transmembrane and intracellular domain.
The humanized TFRC mouse model was intercrossed with the hSA/FcRn double humanized mouse model (reference link) to enable translatable PK and biodistribution of compounds targeting TFRC.
hTFRC features
- Entirely humanized TFRC extracellular domain
- Physiological regulation and expression pattern of human TFRC
- Fully functional mouse immune system
- High expression along BBB to allow combined therapies targeting CNS
- Versatility of applications: oncology and neurology
- Available on C57Bl/6N genetic background
Validation
Human TFRC expression mirrors expression of mouse TFRC on different cell types
Expression of TFRC (anti-mouse TFRC clone C2, anti-human TFRC clone OKT-9) on TER-119+ cells from freshly isolated bone marrow cells (A), blood (B), and splenocytes (C), gated on single viable cells.
Human transferrin internalization is efficient in cells from hTFRC mice
Splenocytes of hTFRC mice were incubated with human conjugate pHrodo red transferrin for 2 hours at 37°C. Internalization of human transferrin (Tf) was confirmed by the increase of the MFI values of pHrodo Tf.
Specific activity of hTFRC: pre-incubation of splenocytes with pHrodo competitor, rh-transferrin, reduced the level of pHrodo internalization.
Targeting human TFRC improves shuttling to the brain of the anti-BACE1 antibody
Combination of anti-hTFRC/anti-BACE1, but not anti-BACE1 alone, enables the biodistribution of IgG in the brain and the reduction of amyloid-β.
Rational: anti-BACE1 inhibits amyloid-b(Ab) production in vivo (Atwal et al.,2011)
hTFRC mice were treated with different anti-BACE1/anti-TFRC antibodies for 24h. Concentrations of hIgG and Ab were quantified by ELISA-based assay in plasma and brain homogenates.
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Preclinical humanized TFRC mouse model
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