Basic Information

Strain Name
C57BL/6-Cd40tm1(CD40)Bcgen/Bcgen
Stock Number
110009
Common Name
B-hCD40 Mice
Source/Investigator
Bcgen (Beijing Biocytogen Co., Ltd)
Related Genes
Cd40 (CD40 antigen)
Species
C57BL/6
Appearance
Black
Genotypes
Homozygous

Description

CD40 (cluster of differentiation 40) is a tumor necrosis factor receptor superfamily member 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. Interaction 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 antibodies have been shown to activate APC and promote anti-tumor T cell responses and to foster cytotoxic myeloid cells with the potential to control tumor growth in the absence of T-cell immunity. Thus, treatment using agonistic antibody targeting CD40 may serve as a promising cancer immunotherapy, and it is fundamentally different from antagonistic antibodies targeting negative immune checkpoints such as CTLA4 and PD-1.

Targeting Strategy

Details

Phenotype

Flow Cytometry

Splenocytes from both wild type (WT) C57BL/6 and homozygous B-hCD40 mice were analyzed by flow cytometry.
mCD40+ cells were detectable in B cells from wild type(WT) C57BL/6 mice, while hCD40+ cells were detectable in homozygous B-hCD40 mice.

Application

Human CD40 mAb efficacy evaluation (heterozygous B-hCD40 mice)

B-hCD40-Mice-details-Human-CD40-mAb-efficacy-evaluation-heterozygous-B-hCD40-mice

Murine colon cancer MC38 cells were subcutaneously implanted into heterozygous B- hCD40 mice. Mice were grouped when the tumor size was approximately 150±50 mm3 (n=5). Three human CD40 antibodies differently inhibited tumor growth, confirming that the B-hCD40 mouse model is a powerful tool for in vivo CD40 antibody pharmacological efficacy studies. (A) Tumor average volume ± SEM, (B) Mice average weight ± SEM.

Human CD40 mAb efficacy evaluation (homozygous B-hCD40 mice)

B-hCD40-Mice-details-Human-CD40-mAb-efficacy-evaluation-homozygous-B-hCD40-mice

Murine colon cancer MC38 cells were subcutaneously implanted into homozygous B-hCD40 mice. Mice were grouped when the tumor size was approximately 150±50 mm3 (n=5). Selicrelumab Analog (human CD40 antibody) significantly inhibited tumor growth, confirming that the B-hCD40 mouse model is a powerful tool for in vivo CD40 antibody pharmacological efficacy studies. (A) Tumor average volume ± SEM, (B) Mice average weight ± SEM.

Human CD40 mAb toxicity evaluation

B-hCD40-Mice-details-Human-CD40-mAb-toxicity-evaluation

Homozygous B-hCD40 mice were i.p. injected with vehicle control and different Anti-human CD40 antibodies on days indicated by red arrows (n=5). No significant difference in average body weight was detected after the treatments.

B-hCD40-Mice-details-Human-CD40-mAb-toxicity-evaluation1

B-hCD40-Mice-details-Human-CD40-mAb-toxicity-evaluation2

The blood routine examination was performed with anti-CD40 antibody on B-hCD40 mice two days after the termination of efficacy evaluation experiment.

B-hCD40-Mice-details-Human-CD40-mAb-toxicity-evaluation3

B-hCD40-Mice-details-Human-CD40-mAb-toxicity-evaluation4

The blood biochemical index was examined with anti-human CD40 antibody on B- hCD40 mice two days after the termination of efficacy evaluation experiment.

B-hCD40-Mice-details-Human-CD40-mAb-toxicity-evaluation5

Flow cytometry was performed to examine lymphocytes lineage after anti-human CD40 antibody treatment on B-hCD40 mice. The results indicated that CD40 Ab4 treatment resulted in a significant increase in the percentage of activated T cells and B cells.

B-hCD40-Mice-details-Human-CD40-mAb-toxicity-evaluation6

Concentrations of different cytokines were measured after anti-human CD40 antibody treatment on B-hCD40 mice. The results indicated that CD40 Ab4 treatment resulted in a significant increase in the production of several cytokines, such as IFN-γ, TNF-α, MCP-1 and IL27.

Activation of B lymphocyte in B-hCD40 mice

B-hCD40-Mice-details-Activation-of-B-lymphocyte-in-B-hCD40-mice

Activation of B lymphocyte in B-hCD40 mice. Homozyous B-hCD40 mice were i.p. injected with vehicle control and different anti-human CD40 antibodies. After 48h, the peritoneal cells and splenocytes were collected and analyzed for the expression of activation markers by flow cytometry.

References

1. Cancer Immunol Res. 2014 Jan;2(1):19-26. doi: 10.1158/2326-6066.CIR-13-0152.
2. Mult Scler. 2017 May;23(6):802-809. doi: 10.1177/1352458516664210. Epub 2016 Aug 8.
3. Sci Transl Med. 2018 Jan 31;10(426). pii: eaan4488. doi: 10.1126/scitranslmed.aan4488.

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