CD226 Immune Checkpoint Molecule for Drug Development

Overview of CD226

CD226 (also known as DNAM-1, TLiSA1, PTA-1) is a costimulatory receptor expressed on NK cells, T lymphocytes, monocytes, and B cells. CD226 is a transmembrane glycoprotein containing two immunoglobulin V-like domains (D1 and D2), an intracellular domain, and a type I transmembrane domain. The extracellular part of CD226 contains two Ig-like domains, and its cytoplasmic tail contains three tyrosine residues. CD226 ligands are identified as PVR (CD155) and Nectin-2 (CD112). Studies on the expression of CD226 in NK cells indicate that its interaction with ligands on tumor cells plays an important role against different types of cancer.

Structure of CD226

Structural analysis shows that the extracellular D1 domain of CD226 binds to PVR through a conserved docking mode. Whether the D2 domain of CD226 is essential for its binding to PVR needs further investigation. The solution binding affinity measured between human PVR-Fc and CD226-Fc is similar to that between nectin-2-Fc and CD226-Fc. However, compared with PVR expressing cells, the binding efficiency of CD226-Fc to nectin-2 is lower, which indicates that the homologous interaction of actin-2 might hinder the binding of CD226 to nectin-2.

CD226 in Tumor Immunity

The importance of the CD226-PVR (TIGIT/CD155) axis in regulating tumor immunity has been confirmed in preclinical mouse models in vitro and in vivo. CD8⁺ T cells or DX5⁺ (CD49b) NK cells isolated from CD226-deficient mice are less cytotoxic to PVR-expressing tumor cells and less cytotoxic to PVR-negative tumor cells. Consistent with the in vitro results, CD226-deficient mice also show a more significant tumor burden on various tumors than wild-type (WT) mice. In lung metastasis mouse models, CD226 deletion leads to impaired NK-cell-mediated tumor growth inhibition. The anti-CD226 blocking monoclonal antibody can be used to study the inhibiting effect of the CD226-PVR axis on the anti-tumor immune response.

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