AACR 2020: Novel TNFR2 humanized mouse model for human TNFR2 antibody evaluation
In recent years, immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), is a transmembrane receptor that has been linked into immune modulation and tissue regeneration. TNFR2 is mainly expressed on the surface of a subset of potent regulatory T cells (Tregs) and promote the proliferation of Tregs through nuclear factor kappa B (NF-κB). Anti-TNFR2 antibodies have been developed to inhibit NF-κB driven growth and have revived excitement for the use of anti-TNFR2 antibodies in the clinic.
To investigate the role of TNFR2, Biocytogen generated TNFR2 humanized mouse for both in vitro function validation of signaling pathway and in vivo efficacy evaluation of TNFR2 antibodies. In this model, the exon 2~6 of mouse Tnfr2 gene which encode the extracellular was replaced by human TNFR2 counterparts. Human TNFR2 is detectable on the Tregs in spleen and the TNFR2 antibodies bind well to the splenocytes of the TNFR2 humanized mice. Basal leukocyte subpopulations of TNFR2 humanized mice are comparable to that of wild-type mice, including T/B cells, NK cells, DC, granulocytes and monocytes/macrophages. Anti-human TNFR2 antibodies can repress the growth of colon cancer cells engrafted on TNFR2 humanized mice. The TNFα/TNFR2 signaling pathway is under validation on TNFR2 humanized mice and TNFα/TNFR2 double humanized mice due to the uncertain cross-reactivity between mouse and human TNFα/TNFR2.
Taken together, TNFR2 humanized mice is a useful tool for in vivo efficacy evaluation of human TNFR2 antibodies that can be advanced to human clinical trials.