Tumor necrosis factor receptor type 2 (TNFR2)-expressing regulatory T cells (Tregs), present in the tumor microenvironment, play an important role in tumor immune evasion. TNFR2 plays a crucial role in stimulating the activation and proliferation of Tregs, a major checkpoint of antitumor immune responses. In addition to its expression on Tregs, TNFR2 is also known to be overexpressed on some types of tumors and the survival and growth of these tumor cells is promoted by ligands of TNFR2. Therefore, antagonists of TNFR2 may act as checkpoint inhibitors that suppress Tregs but may also be cytotoxic to tumor cells whose survival is promoted by TNFR2 ligands. Targeting TNFR2 in this manner could be a feasible approach to the treatment of cancer and other immune diseases.
NCI researchers have isolated and engineered a fully human TNFR2-specific monoclonal antibody capable of inducing cell killing of Tregs. The monoclonal antibody, named E4, was isolated from a phage display scFv library. The antibody has also been produced in a defucosylated form, denoted E4F6, in an engineered CHO mutant cell. Experimental data has shown that the defucosylated antibody can specifically bind human TNFR2 on Treg cells and eliminate those cells through antibody-dependent cellular cytotoxicity (ADCC). This technology has potential uses in cancer immunotherapy to enhance antitumor responses or for targeting TNFR2-positive cancers.