Tumor necrosis factor receptor superfamily member 9 and V-set domain-containing T-cell activation inhibitor 1 (4-1BB and B7-H4)

4-1BB (CD137) and B7-H4 (VTCN1) are dual therapeutic targets often addressed by bispecific antibodies designed to modulate the tumor microenvironment. 4-1BB is a costimulatory member of the tumor necrosis factor receptor superfamily that enhances T-cell survival and effector function, while B7-H4 is an inhibitory ligand in the B7 family that is frequently overexpressed in solid tumors like breast and ovarian cancers to facilitate immune evasion [1, 2, 5]. Bispecific antibodies targeting both molecules aim to simultaneously block the immunosuppressive B7-H4 pathway and provide a localized agonistic signal to 4-1BB-expressing immune cells [8, 10]. A critical design feature of these therapies is conditional 4-1BB activation, which occurs only when the antibody is cross-linked by binding to B7-H4 on the tumor surface, thereby restricting immune stimulation to the tumor site and reducing the risk of systemic toxicities such as hepatotoxicity [11, 12]. This dual-action approach is currently being evaluated in clinical trials to treat advanced or metastatic solid tumors that are resistant to standard checkpoint inhibitors [9, 17].

Other names

CD137TNFRSF9ILAVTCN1B7S1B7xB7-H44-1BB

B7-H4-dependent 4-1BB agonism and B7-H4 checkpoint blockade