Preclinical Double-Humanized PD-1/CTLA-4 Mouse Model
Design of the hPD‑1/hCTLA-4 mouse
hPD-1 has been developed by inserting, within the mouse PD-1 locus, a chimeric PD-1 with a human extracellular domain, a murine transmembrane domain and a murine intracellular domain. The design of hCTLA-4, developed by Knockin at the mouse CTLA-4 locus, enables the expression of: a) the full-length chimeric CTLA-4 isoform (human extracellular domain and mouse intracellular domain); and b) the soluble isoform (human extracellular domain).
Both hPD-1 and hCTLA-4 expressions are regulated by endogenous mouse promoters.
Applications in immuno-oncology
The hPD-1/hCTLA-4 mouse enables the in vivo efficacy assessment and profiling of immuno-oncology agents targeting the human immune checkpoint PD-1 and/or CTLA-4 in fully immunocompetent mice.
Humanized tumor cell line MC38-hPD-L1:
Use our hPD-1/hCTLA-4 mouse model together with our cell line MC38-hPD-L1 as a syngeneic tumor model for testing the efficacy of combination therapies targeting human PD-1 and human PD-L1.
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- The PD-1 and CTLA-4 extracellular domains are entirely humanized
- Physiological regulation and expression pattern of the human PD-1 and CTLA-4
- Preservation of the target-ligand interaction
- Fully functional mouse immune system
- Lack of expression of the murine target gene, thus avoiding cross-reactivity
The model has been co-validated by partners of the precompetitive consortium of company leaders in immuno-oncology and immunotherapy.
Publication with the model by Oncology R&D, AstraZeneca in January 2021:
Simon J Dovedi, et al. Design and efficacy of a monovalent bispecific PD-1/CTLA-4 antibody that enhances CTLA-4 blockade on PD-1+ activated T cells. Cancer Discov. 2021 Jan 8
hPD-1 and hCTLA-4 expression patterns in hPD-1/hCTLA-4 mice recapitulate mPD-1 and mCTLA-4 in wild-type mice
Splenocytes from hPD-1/hCTLA-4 double homozygous mice were activated with αCD3/αCD29. Expressions of hPD-1 and mPD-1 (upper panel), and hCTLA and mCTLA-4 (lower panel) were evaluated on conventional CD4 (viable, CD3+CD4+Foxp3-) T cells at indicated time points.
hPD-1 and hCTLA-4 are expressed on TILs (tumor-infiltrating lymphocytes)
PD-1 and CTLA-4 expression on TILs from mice bearing MCA205 tumors. Mouse and human PD-1 and CTLA-4 expression were analyzed on wild-type and hPD-1/hCTLA-4 homozygous mice.
- Uncoupling Toxicity from Therapeutic Efficacy: The New Challenge of Immunotherapies
- Uncoupling Efficacy from Toxicity: A Case Study on MEDI5752
Ready to be shipped to your lab
- Cohorts available upon request
- Studies can be carried out at your site or at your favorite CRO
- SOPF certification and worldwide delivery by professional breeders
- Models provided with FTO on patent-protected technologies used for model generation
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