Characterization of an Antagonistic Antibody reactive to human and mouse TNFR2 with Anti-tumor Capacity
Accumulating evidence indicate that tumor necrosis factor receptor type II (TNFR2) is a promising target for cancer immunotherapy, but the species-restricted reactivity of anti-human TNFR2 antibodies limits their mechanistic study in mouse tumor models. To overcome this limitation, we developed a novel humanized antibody, designated as UM-h101, which could bind to both human and mouse TNFR2. UM-h101 inhibited TNFR2-dependent NF-kB activation and TNF-induced proliferative expansion of human and mouse regulatory T cells (Tregs), demonstrating its antagonistic property. In immunocompetent mouse tumor models, UM-h101 markedly inhibited the growth of tumors, accompanied by the reduction of Tregs and increase in the activated CD8 CTLs in tumor. Single-cell RNA sequencing revealed that UM-h101 altered the tumor microenvironment to enhance its inflammatory response against the tumor. Furthermore, CD8 CTLs from UM-h101-treated tumors displayed enhanced oxidative phosphorylation and improved mitochondrial fitness. Further mechanistic analyses showed that UM-h101 downregulated expression levels of arginase-2 (ARG2), increased availability of intracellular arginine, and thereby restored mitochondrial fitness and sustained effector function in CD8 CTLs. This study collectively identified UM-h101 as a TNFR2 antagonist that is reactive across species, which may be valuable for therapeutic development and for exploring the mechanisms of TNFR2-targeted cancer immunotherapy.