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首页 模型资源 靶点人源化模型 hPD-1/hLAG3

Design of the hPD-1/hLAG3 mouse

The double-humanized PD‑1 and LAG3 (hPD-1/hLAG3) mouse model was generated by intercrossing hPD-1 and hLAG3 mice.

The PD-1 humanized model, developed by Knockin at the mouse Pd‑1 locus, expresses a chimeric PD‑1: human extracellular and mouse transmembrane and intracellular domains.

The LAG3 humanized model, developed by Knockin at the mouse Lag3 locus, expresses the full-length chimeric LAG3 isoform (human extracellular domains, and mouse transmembrane and intracellular domains).

Both hPD-1 and hLAG3 expressions are regulated by endogenous mouse promoters.

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hPD-1/hLAG3 features

  • PD-1 and LAG3 extracellular domains are entirely humanized
  • hPD-1 and hLAG3 expression driven by the respective endogenous mouse promoter
  • Fully functional mouse immune system
  • Lack of expression of the murine target gene, thus avoiding cross-reactivity

  • hPD-1 is expressed on hPD-1/hLAG3 lymphocytes

    Splenocytes from hPD-1/hLAG3 double homozygous mice and wild-type mice were activated with αCD3/αCD28 and cultured in presence of recombinant mIL-2. mPD-1 and hPD-1 expression was evaluated at day 3 on conventional CD4 T cells (viable, CD3+CD4+Foxp3-), Treg cells (viable, CD3+CD4+CD25+Foxp3+) and CD8 T cells (viable, CD3+CD8+).

     

  • LAG3 is expressed on hPD-1/hLAG3 lymphocytes

    Splenocytes from hPD-1/LAG3 double homozygous mice and wild-type mice were activated with αCD3/αCD28 and cultured in presence of recombinant mIL-2. mLAG3 and hLAG3 expression was evaluated at day 3 on conventional CD4 T cells (viable, CD3+CD4+Foxp3-), Treg cells (viable, CD3+CD4+CD25+Foxp3+) and CD8 T cells (viable, CD3+CD8+).

     

  • In vivo anti-tumor activity in response to combination of anti-human PD-1 and anti-human LAG3 in hPD-1/hLAG3 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. An anti-PD-1–GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy 
  2. Human PD-1 agonist treatment alleviates neutrophilic asthma by reprogramming T cells
  3. Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment
  4. Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+Activated T Cells