hPD-1 Mice

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Catalog Number: C001524

Strain Name: C57BL/6JCya-Pdcd1em1(hPDCD1)/Cya

Genetic Background: C57BL/6JCya

Reproduction: Homozygote x Homozygote


Strain Description

Programmed cell death protein 1 (PDCD1/PD-1) is a member of the B7-CD28 costimulatory receptor family. It is an inhibitory receptor expressed on activated T cells and plays a role in regulating the function of effector T cells, including CD8+ T cells, and promoting the differentiation of CD4+ T cells into regulatory T cells. PD-1 is expressed in a variety of tumors and plays an important role in antitumor immunity. In addition, PD-1 is involved in the defense against autoimmune diseases and has inhibitory effects on antitumor and antimicrobial immunity [1]. PD-1 binds to programmed death ligands 1 and 2 (PD-L1 and PD-L2) to inhibit T cell activation, reduce the production of corresponding cytokines, and regulate T cell survival [2]. Drugs targeting this pathway can reactivate T cells to activate antitumor immune responses [3].

This strain is a genetically modified mouse model in which the gene encoding the mouse PD-1 protein is humanized, resulting in the expression of human PD-1 protein in mice. This model can be used for research in drug development, efficacy and safety evaluation, tumor immunotherapy evaluation, and immune system mechanisms related to PD-1.

The mouse Pdcd1 gene was edited using gene editing technology to replace the sequence encoding the extracellular domain of mouse PD-1 protein (aa.25~169) with the sequence from the human PD1 gene encoding the human PD-1 protein extracellular domain (aa.24~170) while retaining the mouse signal peptide.

Figure 1. Schematic representation of the gene editing strategy for generating hPD-1 mice.

● Development and screening of PD-1-targeted drugs;
● Efficacy and safety evaluation of PD-1-targeted drugs;
● Evaluation of tumor immunotherapy;
● Research on the immune system and tumor immune escape mechanisms.

1. Detection of Human PD1 Protein Expression in the Spleen

Figure 2. Detection of human PD1 (hCD279) expression after ex vivo activation of splenic cells. The results show that there is significant expression of human PD1 protein in the splenic cells of hPD1 mice 72 hours post-activation.

 

2. In vivo efficacy of anti-human PD-1 antibody

Figure 3. Evaluation of the Antitumor Activity of the Anti-human PD-1 Antibody in hPD-1 Mice. The colon adenocarcinoma model was established in female hPD1 mice (6 weeks old, n=5) via subcutaneous injection of the MC38 cells. Mice in the treatment group received the anti-human PD-1 antibody, Pembrolizumab, biweekly (BIW) [4]. During the experimental period, measurements of tumor volume and mouse weight were taken twice weekly, and at the end of the experiment, the mouse tumor tissue was removed for tumor weight measurement. The results showed that MC38 cells can form tumors in hPD-1 mice, and Pembrolizumab treatment can effectively inhibit tumor growth (Figure 3.a-b). While all mice exhibited a progressive increase in weight, a notable weight discrepancy was observed between the treatment and non-treatment groups (Figure 3.c).

References

[1] National Center for Biotechnology Information. "Gene: PDCD1." NCBI, U.S. National Library of Medicine, 2023, www.ncbi.nlm.nih.gov/gene/5133
[2] Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007 Jul;19(7):813-24.
[3] Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018 Mar;18(3):153-167.
[4] Kwok G, Yau TC, Chiu JW, Tse E, Kwong YL. Pembrolizumab (Keytruda). Hum Vaccin Immunother. 2016 Nov;12(11):2777-2789.