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首页 模型资源 靶点人源化模型 hPD-1/hCTLA-4

Design of the hPD‑1/hCTLA-4 mouse

The double-humanized PD-1 and CTLA-4 mouse model (hPD-1/hCTLA-4) was generated by intercrossing hPD-1 and hCTLA-4 mice.

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.

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hPD-1/hCTLA-4 features

  • 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

  • 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.

Case studies

  1. Uncoupling efficacy from toxicity: a case study on MEDI5752

Commentaries

  1. VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
  2. CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity
  3. A new promising family of small molecules regulating the PD-L1/PD-1 signaling pathway
  4. An alternative approach to immunotherapy: A bispecific agonist 
     

Scientific articles

  1. Human PD-1 agonist treatment alleviates neutrophilic asthma by reprogramming T cells
  2. Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment
  3. An anti-PD-1–GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy
  4. Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+Activated T Cells