TNFR2-targeting biologics: Molecular mode of action, possible applications, and future developments

Tumor necrosis factor α (TNF) and its receptors have emerged as key players in autoimmunity but also influence tumor development and the tumor microenvironment in many ways. TNF-inhibiting biologics are used very successfully in the clinic to treat autoimmune diseases. However, in some TNF-mediated diseases, TNF blockers are either ineffective or even worsen the disease course. One possible explanation for this treatment failure is that TNF blockers inhibit not only the typically TNF receptor 1 (TNFR1)-mediated TNF pathology, but also the immunosuppressive activities of TNFR2. Therefore, there is great interest in testing TNFR1- and TNFR2-specific biologics in autoimmune diseases and tumor therapy. In this review, we focus on the development of TNFR2-selective biologics. After a brief introduction to the biology and pathobiology of TNFR2, we discuss in detail the current concepts of how TNFR2 becomes activated by its natural ligands but also by genetically engineered biologics. This serves as a rational basis for discussing the aspects that must be considered in the development of both inhibitors and engagers of TNFR2. In particular, we provide a comprehensive overview on the structure and molecular mode of action of the plethora of published TNFR2-targeting biologics, paying particular attention to common principles and mechanisms but also to the limitations and challenges of some of these biologics.