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B-h4-1BB/hCD40 mice
Strain Name C57BL/6-Tnfrsf9tm1(TNFRSF9)Cd40tm1(CD40)/Bcgen Common Name  B-h4-1BB/hCD40 mice
Background C57BL/6 Catalog number  121212
Related Genes 
4-1BB; CD137; 
Bp50, CDW40, TNFRSF5, p50

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. 
CD40 (CD40 molecule) also is a member of the tumor necrosis factor receptor superfamily expressed on APC such as dendritic cells (DC), B cells, and monocytes as well as many non-immune cells and a wide range of tumors. Engagement with its trimeric ligand CD154 on activated T helper cells results in APC activation, which has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Agonistic CD40 monoclonal antibodies (mAbs) have been shown to activate APC and promote anti-tumor T cell responses. Thus, agonistic anti-CD40 mAb may serve as a new class of antitumor  therapeutics that potentiate immunity via a different mechanism than the blocking immune checkpoint inhibitors such as anti-CTLA4 or anti-PD-1.


Protein expression analysis


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Strain specific CD40 and 4-1BB expression analysis in homozygous B-h4-1BB/hCD40 mice by flow cytometry. Splenocytes were collected from wild-type mice (+/+) and homozygous B-h4-1BB/hCD40 mice (H/H) stimulated with anti-CD3ε in vivo (7.5 μg/mice for 24 hours, i.p.), and analyzed by flow cytometry with species-specific anti-CD40 antibody and species-specific anti-4-1BB antibody . Mouse CD40 and 4-1BB were detectable in wild-type mice. Human CD40 and 4-1BB were exclusively detectable in homozygous B-h4-1BB/hCD40 mice (H/H) but not in wild-type mice.


Combination therapy of anti-human 4-1BB antibody and anti-human CD40 antibody


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Antitumor activity of anti-human 4-1BB antibody combined with anti-human CD40 antibody in B-h4-1BB/hCD40 mice. (A) Anti-human 4-1BB antibody (in house) combined with anti-human CD40 antibody (in house) inhibited MC38 tumor growth in B-h4-1BB/hCD40 mice. Murine colon cancer MC38 cells were subcutaneously implanted into homozygous B-h4-1BB/hCD40 mice (female, 6-8 week-old, n=5). Mice were grouped when tumor volume reached approximately 400 mm3, at which time they were treated with h4-1BB and hCD40 antibodies. (B) Body weight changes during treatment. As shown in panel A, combination of h4-1BB and hCD40 antibodies were more efficacious in controlling tumor growth in B-h4-1BB/hCD40 mice. B-h4-1BB/hCD40 mice provide a powerful preclinical model for in vivo evaluation of anti-human 4-1BB and CD40 antibodies. Values are expressed as mean ± SEM.