Humanized Cell Membrane Receptors
Model for Compound Testing
Cell membrane receptors such as GPCR, cytokine receptors, Ig Receptors (FcR) ligand-gated anion channels, voltage-gated sodium channels, etc. are important drug targets. Substituting the mouse protein by a human homolog enables efficacy and allows affinity studies to be run with increased predictability and accuracy.
genOway has an extensive experience in humanizing receptors (more than 100 models successfully created) to insure that the transcription, translation and expression is efficient and mimics the human situation.
Humanized mouse models for cell membrane receptors have demonstrated the value they provide to drug development programs and the "Humanization & Knockin Technology" is a key technology to achieve that goal.
Case study: Humanization of the cell membrane receptor CCR2 (also called CD192) for in vivo testing of small molecule specificity and efficacy.
Adapted from Prosser et al, DDR 2002, Targeted Replacement of Rodent CCR2 With the Human Orthologue CCR2B: A Mouse Model for In Vivo Analysis of Human Target-Selective Small Molecule MCP-1 Receptor Antagonists.
Human CCR2 is Functional
The human CCR2 gene is expressed and functional in humanized animals, substituting the inactivated murine CCR2.
Expression studies are done on mRNA (data not shown).
Humanized CCR2 Model is a Highly Valuable Screening Tool
Activity of a human selective CCR2 antagonist is better predicted and mimicked in humanized CCR2 models than in wild type models.
The potency of SB-399721 at inhibiting JE-stimulated chemotaxis of peritoneal cells from CCR2 Knockin mice (IC50 = 820 ± 83 nM) was approximately 7-fold greater than that at peritoneal cells from wild type littermates (IC50 5,500 ± 900 nM).