Sodium-dependent phosphate transport protein 2B (NaPi2b) and Tumor necrosis factor receptor superfamily member 9 (4-1BB) (NaPi2b and 4-1BB)

Sodium-dependent phosphate transport protein 2B (NaPi2b), encoded by the SLC34A2 gene, is a multi-pass membrane protein that facilitates the transport of inorganic phosphate into cells (1, 17). It is highly overexpressed in various malignancies, including ovarian cancer, non-small cell lung cancer (NSCLC), and thyroid cancer, while its expression in healthy tissues is largely restricted to the lungs and small intestine (6, 7). Tumor necrosis factor receptor superfamily member 9 (4-1BB or CD137) is a potent costimulatory receptor found on activated T cells, natural killer (NK) cells, and other immune populations (5, 16). Activation of 4-1BB provides critical survival signals and enhances the effector functions of cytotoxic T lymphocytes (10, 16). The therapeutic strategy of dual-targeting NaPi2b and 4-1BB involves the use of bispecific antibodies or fusion proteins, such as LM-2417, to bridge tumor cells and immune cells (20, 21). By binding to NaPi2b on the tumor surface, these agents facilitate the clustering and activation of 4-1BB on adjacent T cells specifically within the tumor microenvironment (20, 22). This conditional activation is intended to focus the immune response against the cancer while avoiding the systemic toxicities, such as severe hepatotoxicity, that have hindered the development of traditional monospecific 4-1BB agonists (20, 25). This approach represents a promising method for enhancing the therapeutic window of immune-stimulating therapies in solid tumors (20, 32).

Other names

SLC34A2TNFRSF9CD137Sodium/phosphate cotransporter 2BNAPI-3BNAPI-IIbNPTIIbILAT-cell antigen 4-1BB homolog

Bispecific engagement of NaPi2b on tumor cells and 4-1BB on immune cells, leading to tumor-localized 4-1BB agonism and T-cell activation (20, 22).