T-cell surface glycoprotein CD3 zeta chain (1XX variant) (CD3z-1XX)

The 1XX intracellular signaling domain is a proprietary, engineered version of the T-cell surface glycoprotein CD3 zeta chain (CD3ζ) used in next-generation chimeric antigen receptor (CAR) T-cell therapies, such as ATA2271 (Atara Biotherapeutics, 2021). Developed to address the limitations of conventional CARs, the 1XX technology involves the functional inactivation of two of the three immunoreceptor tyrosine-based activation motifs (ITAMs) within the CD3ζ cytoplasmic tail (Feucht et al., 2019). By restricting signaling to a single functional ITAM, the 1XX domain provides a calibrated activation signal that prevents the over-stimulation and metabolic exhaustion typically associated with wild-type CD3ζ signaling (Nature Medicine, 2019). This calibration favors the development of T cells with a memory-like phenotype, which exhibit superior persistence and sustained effector function within the tumor microenvironment. In clinical applications like ATA2271, which targets mesothelin-expressing solid tumors, the 1XX domain is a critical component for improving the durability of the immune response (ClinicalTrials.gov NCT04481399). Consequently, it represents a significant advancement in synthetic immunology aimed at overcoming the barriers to treating solid malignancies.

Other names

CD247CD3z1XX signaling domainModified CD3-zeta chainCD3-zeta 1XX

The 1XX signaling domain provides calibrated T-cell activation by utilizing only one functional immunoreceptor tyrosine-based activation motif (ITAM), which reduces signal strength to prevent T-cell exhaustion and promote long-term persistence (Feucht et al., 2019).