请输入关键字
请输入关键字
订购
*国家
中国
美国
*省份
*城市
*姓名
*电话
*单位
*职位
*邮箱
*请输入验证码
*验证码
B-hCTLA4/hGITR mice
Strain Name C57BL/6-Ctla4tm1(CTLA4)Tnfrsf18tm1(TNFRSF18)/Bcgen Common Name  B-hCTLA4/hGITR mice
Background C57BL/6 Catalog number  120962
Related Genes 
CTLA4 (cytotoxic T-lymphocyte-associated protein 4)
TNFRSF18
(tumor necrosis factor receptor superfamily, member 18)
Gene description


CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152, competitively binds to B7-1 (CD80) and B7-2 (CD86) on Antigen-Presenting Cells (APCs) to block the T cell activating signal by B7 and CD28 (on T cells) interaction. The inhibition of CTLA4 by its inhibitory antibodies enhances T cell activity. The CTLA4 antibody is the first FDA-approved antibody to treat advanced melanoma. 
TNFRSF18 (GITR) is a type 1 transmembrane protein that can act as a co-stimulatory receptor, expressed increases rapidly on both Tregs and effector T-cells, reaching the highest level on activated Tregs, and also expressed on NK, B, macrophages and dendritic cells. GITR activation can promote effective T-cell function and inhibit Treg function. Preclinical data on GITR-agonist monoclonal antibodies (mAbs) demonstrated antitumour activity and enhancing CD8+ and CD4+ effector T-cell activity and depleting tumour-infiltrating Tregs. 
CTLA-4 and GITR are potential targets for immune modulation through anti-CTLA-4 blocking antibodies and anti-GITR agonistic antibodies.Thus representing a potential target to enhance immunotherapy.


Targeting Strategy


Gene targeting strategy for B-hCTLA4/hGITR mice. The exon 2 of mouse Ctla4 gene that  encode the extracellular domain was replaced by human CTLA4 exon 2 in B-hCTLA/hGITR mice. The exons 1-4 of mouse Tnfrsf18 gene that  encode the extracellular domain were replaced by human TNFRSF18 exons 1-4 in B-hCTLA4/hGITR mice. 


Protein expression analysis

from clipboard



Strain specific CTLA4 and GITR expression analysis in homozygous B-hCTLA4/hGITR mice by flow cytometry. 

Splenocytes were collected from WT and homozygous B-hCTLA4/hGITR (H/H) mice stimulated with anti-CD3ε in vivo (7.5 μg/mice),  and analyzed by flow cytometry with species-specific anti-CTLA4 antibody or anti-GITR antibody. Mouse CTLA4 and GITR were exclusively detectable in WT mice. Human CTLA4 and GITR  were exclusively detectable in homozygous B-hCTLA4/hGITR  but not WT mice.


Combination therapy of anti-human CTLA4 antibody and anti-human GITR antibody


from clipboard


Antitumor activity of anti-human CTLA4 antibody combined with anti-human GITR antibody in B-hCTLA4/hGITR mice. 

(A) Anti-human CTLA4 antibody combined with anti-human GITR antibody inhibited MC38-hPD-L1 tumor growth in B-hCTLA4/hGITR mice. Murine colon cancer MC38-hPD-L1 cells were subcutaneously implanted into homozygous B-hCTLA4/hGITR 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 BMS986156 (in house) and Yervoy (in house) with doses and schedules indicated in panel A. (B) Body weight changes during treatment. As shown in panel A, combination of BMS986156 and Yervoy shows more inhibitory effects than BMS986156 individual group but not obviously in Yervoy individual group, maybe the doses and schedules should be optimization. The B-hCTLA4/hGITR mice provide a preclinical model for in vivo evaluating combination therapy efficacy of hCTLA4 antibodies and hGITR antibodies. Values are expressed as mean ± SEM.