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B-h4-1BB mice
Strain Name  C57BL/6-Tnfrsf9tm1(TNFRSF9)/Bcgen Common Name  B-h4-1BB mice
Background C57BL/6 Catalog number  110004
Related Genes 
TNFRSF9 (tumor necrosis factor receptor superfamily, member 9)

Gene description


TNFRSF9 (Tumor necrosis factor receptor super family, member 9), 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. Fortunately, new therapeutic modalities using 4-1BB targeting aptamers as well as therapeutic combinations with other immuno-modulatory and traditional anti-cancer treatments have revived excitement for the use of 4-1BB agonists in the clinical.


Protein expression analysis


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Strain specific 4-1BB protein expression analysis in wild-type (+/+) or homozygous B-h4-1BB (H/H) mice by flow cytometry. Splenocytes were collected from +/+ and homozygous mice stimulated with anti-CD3ε in vivo, and analyzed by flow cytometry with species-specific anti-4-1BB antibodies. Mouse 4-1BB was detectable in +/+ mice, while human 4-1BB was exclusively detectable in B-h4-1BB H/H mice.


High dose of urelumab resulted in liver toxicity in B-h4-1BB mice


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Hepatotoxicity of anti-h4-1BB antibody (in house) was analyzed by blood biochemical test. A. ALT and AST concentrations in serum. Results showed that the concentration of ALT was significantly increased after being treated with a high dose of urelumab(G2) compared to the control group G1. But there was no significant difference between group G1 and low dose group G3, and both G2 and G3 have no change in AST. The results showed high dose of urelumab resulted in liver toxicity in B-h4-1BB mice. B. Body weight. There were no significant differences in body weight among the groups.


High dose of urelumab therapy resulted in increased lymphocyte infiltration in liver in B-h4-1BB mice


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Pathological analysis of liver toxicity. Chronic inflammation (arrow) was observed in the liver of B-h4-1BB mice which were treated with high dose (20mg/kg) of urelumab (in house) for 21 days. While there were no microscopic changes in groups G1 and G3 which respectively treated with low dose (1mg/kg) of urelumab (in house) and high dose (20mg/kg) of Isotype.


In vivo efficacy of anti-human 4-1BB antibody

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Antitumor activity of anti-human 4-1BB antibodies in B-h4-1BB mice. (A) Anti-human 4-1BB antibodies inhibited MC38 tumor growth in B-h4-1BB mice. Murine colon cancer MC38 cells were subcutaneously implanted into homozygous B-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 anti-human 4-1BB antibody urelumab (in house)  with doses and schedules indicated in panel. (B) Body weight changes during treatment. As shown in panel A, anti-human 4-1BB antibodies were efficacious in controlling tumor growth in B-h4-1BB mice, demonstrating that the B-h4-1BB mice provide a powerful preclinical model for in vivo evaluation of anti-human 4-1BB antibodies. Values are expressed as mean ± SEM.