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B-hPD-1/hPD-L1/h4-1BB mice​
Strain Name C57BL/6-Pdcd1tm1(PDCD1) Cd274tm1(CD274)Tnfrsf9tm1(TNFRSF9)/Bcgen Common Name  B-hPD-1/hPD-L1/h4-1BB mice
Background C57BL/6 Catalog number  130569
Related Genes 

PD-1(Programmed death-1) 

NFRSF9(TNF receptor superfamily member 9, also known as 4-1BB)

Gene description

TNFRSF9 also called CD137 and 4-1BB, is a co-stimulatory molecule and is mainly expressed on the surface of T, B, NK and mononuclear cells. CD137 is activated by its ligand CD137L or activating anti-CD137 antibodies enhance tumor rejection because it is upregulated on T cells following activation and its engagement increases T cell proliferation and pro-inflammatory cytokine production. The clinical development of 4-1BB targeting therapy was slow due to the toxicity associated with overt immune activation.New therapeutic combinations with other immuno-modulatory and traditional anti-cancer treatments have revived excitement for the use of 4-1BB agonists in the clinical. PD-L1 (Programmed cell death ligand-1), also known as B7-H1 and CD274, is mainly expressed in antigen-presenting cells (APCs) and activated T cells. and highly expressed in a variety of solid tumors. PD-1 and PD-L1 interactions can reduce T Cell activation and promote tumor immune escape. The PD-1/PD-L1 signaling pathway can be blocked and antitumor immune response can be restored by using by anti-PD-1 or anti-PD-L1 antibodies to block the binding of PD1 to PD-L1. 

Targeting strategy

Gene targeting strategy for B-hPD-1/hPD-L1/h4-1BB mice. 

The exon 2 of mouse PD-1 gene that encode the IgV domain were replaced by human PD-1 exon 2 in B-hPD-1/hPD-L1/h4-1BB mice. The exon 3 of mouse Pd-l1 gene that encode the IgV domain were replaced by human PD-L1 exon 3 in B-hPD-L1/hPD-L1/h4-1BB mice. The exons 2-7 of mouse 4-1bb gene that encode the extracellular domain were replaced by human 4-1BB exons 2-7 in B-hPD-1/hPD-L1/h4-1BBmice.

Protein expression analysis

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Strain specific PD-1 expression analysis in homozygous B-hPD-1/hPD-L1/h4-1BB mice by flow cytometry. 

Splenocytes were collected from WT and homozygous B-hPD-1/hPD-L1/h4-1BB (H/H) mice stimulated with anti-CD3ε in vivo, and analyzed by flow cytometry with species-specific anti-hPD-1, anti-PD-L1 and anti-4-1BB antibody. Mouse PD-1, PD-L1 and 4-1BB were detectable in WT mice but not in homozygous B-hPD-1/hPD-L1/h4-1BB mice. Human PD-1, PD-L1 and 4-1BB were exclusively detectable in homozygous B-hPD-1/hPD-L1/h4-1BB mice but not WT mice.

Combination therapy of anti-human PD-L1 antibody and anti-human 4-1BB antibody

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Antitumor activity of anti-human PD-L1 antibody combined with anti-human 4-1BB antibody in B-hPD-1/hPD-L1/h4-1BB mice. 

(A) Anti-human PD-L1 antibody (in house) combined with anti-human 4-1BB antibody (in house) inhibited MC38 tumor growth in B-hPD-1/hPD-L1/h4-1BB mice. Murine colon cancer MC38-hPD-L1 cells were subcutaneously implanted into homozygous B-hPD-1/hPD-L1/h4-1BB mice (female, 6-7 week-old, n=6). Mice were grouped when tumor volume reached approximately 100 mm3, at which time they were treated with human PD-L1 and human 4-1BB antibodies in panel A. (B) Body weight changes during treatment. Values are expressed as mean ± SEM.