AACR 2020: Evaluating anti-PD-1/4-1BB combination therapy: In vivo efficacy with humanized double knock-in mice
The transmembrane protein receptor 4-1BB is a member of the tumor necrosis factor (TNF) receptor super family and is involved in the co-stimulation of immune cells. 4-1BB is expressed in activated CD4 helper T cells, B cells, natural killer cells, natural killer T cells, dendritic cells, and activated endothelium. Most regulatory T cells (Tregs) also express 4-1BB, but it remains unclear that whether agonistic antibody treatment exerts pro- or anti-suppressive effect on these cells. 4-1BB enhances tumor rejection because it is upregulated on T cells following activation as its engagement increases T cell proliferation and pro-inflammatory cytokine production. Despite of the toxicity of 4-1BB-targeting drugs associated with overt immune activation, new therapeutic modalities using 4-1BB targeting aptamers, as well as combination therapies with other immuno-modulatory and traditional anti-cancer treatments, have revived excitement for the use of 4-1BB agonists in the clinic.
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. In such model, mouse PD-1 gene exon 2, and 4-1BB gene exons 2-7 were replaced with their human counterparts. Murine colon cancer MC38 cells, humanized PD-L1 in MC38 cells, humanized PD-L1 in murine melanoma B16F10 cells, and murine lymphoma EL4 cells were subcutaneously implanted into homozygous B-hPD-1/h4-1BB mice. Combination treatment of Urelumab (anti-4-1BB) and Pembrolizumab (anti-PD-1) has shown enhanced inhibitory effects compared to single antibody treatments using the B-hPD-1/h4-1BB mice models. Based on these findings, it could be concluded that the B-hPD-1/h4-1BB double-humanized mouse model is a validated tool for in vivo evaluation of hPD-1 and h4-1BB antibody combination therapy.