|Strain Name||C57BL/6-Pdcd1tm1(PDCD1)Tnfrsf9tm1(TNFRSF9)/Bcgen||Common Name||B-hPD-1/h4-1BB mice|
PD-1 (Programmed death-1) ；
TNFRSF9 (TNF receptor superfamily member 9, also known as 4-1BB)
TNFRSF9 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.New therapeutic combinations with other immuno-modulatory and traditional anti-cancer treatments have revived excitement for the use of 4-1BB agonists in the clinical.
Biocytogen has developed a double humanized B-hPD-1/h4-1BB mouse model to unlock the tremendous potential of combination therapy involving 4-1BB agonists and anti-PD-1 antibodies.
Protein expression analysis
Strain specific PD-1 expression analysis in homozygous B-hPD-1/h4-1BB mice by flow cytometry. Splenocytes were collected from WT and homozygous B-hPD-1/h4-1BB (H/H) mice stimulated with anti-CD3ε in vivo, and analyzed by flow cytometry with species-specific anti-PD-1 antibody and anti-4-1BB antibody. Mouse PD-1 and 4-1BB were detectable in WT mice. Human PD-1 and 4-1BB were exclusively detectable in homozygous B-hPD-1/h4-1BB but not WT mice.
In vivo efficacy of combination of anti-human PD-1 antibody and anti-human 4-1BB antibody
Antitumor activity of combination of anti-human PD-1 antibody and anti-human 4-1BB in B-hPD-1/h4-1BB mice. (A) combination of anti-human PD-1 antibody and anti-human 4-1BB antibody inhibited MC38 tumor growth in B-hPD-1/h4-1BB mice. Murine colon cancer MC38 cells were subcutaneously implanted into homozygous B-hPD-1/h4-1BB mice (female, 6-week-old, n=8). Mice were grouped when tumor volume reached approximately 100 mm3, at which time they were treated with anti-human PD-1 antibody and anti-human 4-1BB antibody with doses and schedules indicated in panel. (B) Body weight changes during treatment. As shown in panel A, combination of anti-human PD-1 antibody and anti-human 4-1BB antibody were efficacious in controlling tumor growth in B-hPD-1/h4-1BB mice, demonstrating that the B-hPD-1/h4-1BB mice provide a powerful preclinical model for in vivo evaluation of combination of anti-human PD-1 antibody and anti-human 4-1BB antibody. Values are expressed as mean ± SEM.