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T cells play a crucial role in the immune system, orchestrating the body's defense against pathogens and tumor cells. To identify and study these essential immune cells, researchers rely on specific markers that can reliably identify T cells. One such marker is CD3 antigen, a transmembrane protein complex that is expressed on the surface of mature T cells.
T cell receptors (TCRs) are unable to bind to free antigens, they need to bind to fragments of larger polypeptides associated with major histocompatibility complexes (MHC) or human leukocyte antigens (HLA) in humans. The binding occurs at the immunological synapse. MHC class I molecules, which are present in all nucleated cells, present antigens to CD8, a protein mainly found on cytotoxic T cells, leading to the destruction of infected cells. MHC class II molecules are found in certain immune cells where they present antigens to helper T cells with the help of CD4, leading to an antibody response. Other molecules like CD45, CD28, and CD2 help with T-cell activation and the formation of the TCR signalosome, a complex responsible for signaling within the cell.
Fig. 1 The T cell receptor (TCR) structure and TCR-T cell components. (Sun Y, etal., 2021)
The CD3 antigen is a multimeric protein complex consisting of four distinct chains: γ, δ, ε, and ζ. Among them, two pairs of heterodimers (CD3δ/CD3ε, CD3γ/CD3ε) can form TCR/CD3 complexes with T cell receptors, and participate in the regulation of T cell antigen recognition, signal transduction, and T cell development. The intracellular region of the TCR is very short and cannot complete signal transduction independently, as in the form of chimeric antigen receptor CAR-T cell therapy. Compared with CAR-T, bispecific antibodies can be dose-controlled to reduce toxicity. Therefore, CD3 is a promising target for tumor therapy in the field of bispecific antibodies.
Upon antigen stimulation, changes occur in the CD3 polypeptides within the cytoplasm, brought on by the Src family protein tyrosine kinases (PTKs). The PTKs phosphorylate the CD3 complex, creating a docking site for proteins such as ZAP-70, a member of the syk kinase family. Recruited ZAP-70 binds to CD3-ζ and then phosphorylates the transmembrane adapter protein LAT, allowing SLP-76 to bind to it and form a signalosome complex. This complex activates multiple downstream molecules required for T-cell activation.
Phosphorylated LAT binds to multiple proteins, including PLCγ1, the p85 subunit of phosphoinositide 3 kinases, growth factor receptor-bound protein 2 (GRB2), and GRAP2. SLP-76 is recruited to phosphorylated LAT by Gads and interacts with various proteins, such as PLC γ 1, Vav1, and Nck. The formation of this signaling complex leads to the activation of several signaling pathways crucial for cytoskeletal rearrangements and cell interactions. Co-stimulatory molecule ligation, such as with CD28, enhances these pathways, but hematopoietic progenitor kinase-1 (HPK1), which binds with SLP-76, negatively regulates T cell activation.
TCR-T therapy is a type of T cell therapy that is genetically engineered by cell receptors. Through cell genetic engineering, these TCR-T cells have stronger "affinity" and "combat power" than T cells. They can identify cancer cells more accurately and efficiently and can induce more powerful anti-tumor effects. Compared with CAR-T therapy, TCR-T therapy can not only recognize tumor-specific or tumor-associated antigens located on the cell surface but also recognize intracellular antigen fragments presented by MHC molecules. This means that TCR-T therapy has a wider range of targets and has more potential to break through the solid defense line of solid tumors.
Currently, nearly half of the bispecific antibodies used in the clinical stage for tumor therapy target the CD3 antigen. CD3-related bispecific antibodies have two antigen-binding regions. One recognizes and binds CD3, while the other binds the target antigen on the cancer cell, inducing T cells to target the cancer cell. Cancer cells stimulate the TCR/CD3 complex to activate downstream signaling pathways, leading to the expression and release of granzymes, which in turn lead to perforation of the tumor cell membrane, resulting in the latter's lysis and apoptosis.
Most bispecific antibodies developed to target CD3 are mainly directed at the CD3ε chain. When designing bispecific antibodies, the interaction between the antibody and other parts of the antigen needs to be considered. In addition, due to the flexibility of the CD3ε chain, its spatial structure may change when it exists in a monovalent state and interacts with other proteins. Therefore, studying the structure and physiological function of CD3 peptide chain proteins is very important for the development of CD3-related antibodies.
Fig. 2 Mechanism of action of CD3+ bispecific T-cell redirection in cancer. (Sun Y, et al., 2021)
Creative Diagnostics has optimized and developed highly uniform and highly active CD3 series products, which have demonstrated excellent performance on different application technology platforms, such as development and screening of antibody drugs, characterization and QC of antibody drugs, and clinical blood concentration analysis. By utilizing our expertise and reliable products, researchers can gain a deeper understanding of T-cell biology and contribute to the advancement of immunology and disease research.
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