TNFRSF9. also known as CD137 or 4-1BB, is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and plays a critical role in modulating immune responses. Expressed primarily on activated T cells, natural killer (NK) cells, and antigen-presenting cells (APCs), it functions as a co-stimulatory receptor. Upon binding to its ligand (CD137L), TNFRSF9 triggers signaling cascades that enhance T-cell proliferation, survival, and cytokine production, making it a key player in adaptive immunity and immune surveillance.
Antibodies targeting TNFRSF9 are broadly categorized as agonist or antagonist based on their functional effects. Agonist antibodies (e.g., utomilumab, urelumab) mimic CD137L activity, amplifying anti-tumor immune responses by boosting T-cell and NK-cell activation. These have shown promise in cancer immunotherapy, particularly in combination with PD-1/PD-L1 inhibitors. Conversely, antagonist antibodies aim to suppress excessive immune activation, potentially treating autoimmune or inflammatory disorders by blocking CD137-CD137L interactions.
Despite their therapeutic potential, clinical development faces challenges. Early trials with CD137 agonists revealed dose-limiting toxicities, such as hepatotoxicity, linked to excessive immune activation. Structural studies highlight that TNFRSF9 antibodies engage specific epitopes to modulate receptor clustering and downstream NF-κB/MAPK signaling pathways. Ongoing research focuses on optimizing antibody design (e.g., affinity, Fc engineering) to balance efficacy and safety, while exploring biomarkers to predict patient responses. Overall, TNFRSF9 antibodies represent a dynamic tool for immune modulation, with applications spanning oncology and autoimmunity.