Tumor necrosis factor receptor superfamily member 9 (4-1BB) signaling domain (4-1BB)

The 4-1BB (CD137) signaling domain is a critical intracellular component of second and third-generation Chimeric Antigen Receptor (CAR) T-cell therapies (Source: PubMed 25939063). Derived from the cytoplasmic portion of the Tumor Necrosis Factor Receptor Superfamily Member 9, this domain provides essential costimulatory signals upon antigen recognition by the CAR's extracellular binding domain (Source: UniProt Q07011). Unlike the CD28 costimulatory domain which promotes rapid, glycolytic-driven expansion, the 4-1BB domain favors oxidative metabolism and the formation of long-lived memory T-cells (Source: PubMed 26885861). This results in enhanced persistence of CAR-T cells in vivo, which is often correlated with sustained clinical remissions in patients with hematologic malignancies (Source: PubMed 30508708). Drugs incorporating this domain, such as Tisagenlecleucel, utilize its ability to recruit TRAF proteins and activate NF-κB and PI3K pathways to maintain anti-tumor activity while potentially reducing the severity of cytokine release syndrome compared to other costimulatory domains (Source: FDA Kymriah Label).

Other names

CD137 signaling domainTNFRSF9 signaling domain4-1BB costimulatory domain4-1BB cytoplasmic tail

The 4-1BB signaling domain functions by recruiting Tumor Necrosis Factor Receptor Associated Factors (TRAFs), specifically TRAF1, TRAF2, and TRAF3, to its cytoplasmic tail upon CAR-antigen binding. This recruitment triggers the activation of the canonical and non-canonical NF-κB pathways, as well as the MAPK/ERK and PI3K/Akt pathways, which collectively enhance T-cell survival, promote mitochondrial biogenesis, and favor the development of a central memory phenotype (Source: PubMed 26885861, PubMed 25939063).