|Strain Name||C57BL/6-Tnfrsf9tm1(TNFRSF9)/Bcgen||Common Name||B-h4-1BB mice|
||TNFRSF9 (tumor necrosis factor receptor superfamily, member 9)|
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
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
High dose of urelumab therapy resulted in increased lymphocyte infiltration in liver in B-h4-1BB mice
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.
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.