|Strain Name||C57BL/6-Ctla4tm1(CTLA4)Tnfrsf18tm1(TNFRSF18)/Bcgen||Common Name||B-hCTLA4/hGITR mice|
CTLA4 (cytotoxic T-lymphocyte-associated protein 4)
TNFRSF18 (tumor necrosis factor receptor superfamily, member 18)
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.
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
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.