CD3ε-Based CAR Design & Construction

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In the field of tumor immunotherapy, adoptive cell transfer (ACT) therapy, especially T cell-based cell therapy strategies, has shown sustained clinical efficacy. Two genetically modified T cells (CAR-T cells and TCR engineered T cells) have been developed for adoptive transfer, and substantial progress has been made in the treatment of malignant tumors. Therefore, the in-depth exploration of the structure and function of these TCRs plays an important role in the further development of T cell therapy strategies, especially CAR-T therapy.

At present, traditional CARs modular design consists of four main components, which are antigen binding domain, hinge (hinge), transmembrane domain, and intracellular signal domain. Among them, the signal transduction domain is usually the T-cell receptor TCR/CD3ζ chain, which contains an immunoreceptor tyrosine activation motif (based on the immunoreceptor tyrosine activation motif, ITAM), so most CARs pass CD3ζ-derived tyrosine-based immune receptors activate CAR-T cells.

Recently, a study has revealed the phosphorylation characteristics of ITAM domains in different CD3 chains of TCR, and found that one of the CD3ε subgroups of ITAM has a new function of monophosphorylation, which is expected to help design new CAR-T therapies and improve its anti-tumor activity and durability, and reduce the cytokine side effects of CAR-T treatment. As a professional supplier in the field of cell therapy, Creative Biolabs always pays attention to the most cutting-edge research results and is committed to supporting researchers around the world. Keeping pace with the everyday advances in cell therapy, we provide customers with this novel CAR construct - CD3ε intracellular signal domain-based CAR, as this description is about to become the focus.

Highlight Functions of CD3ε- Based CAR

TCR mediates antigen-induced signal transduction through its related CD3ε, δ, γ, and ζ, but the specific role of different CD3 chains remains to be explored. In this study, the research team found that under different stimulation conditions of TCR, the ITAM of each subunit of CD3 mainly showed a double phosphorylation modification mode; however, due to the selectivity of Lck kinase, only one CD3ε ITAM subgroup has monophosphate It can also specifically recruit inhibitory Csk kinases to inhibit TCR signal transduction, which indicates that TCR is a self-controlling signal transduction mechanism that contains both activation and inhibitory motifs.

In addition, the researchers further integrated the CD3ε cytoplasmic domain into the second-generation CAR and found that it can improve the anti-tumor activity of CAR-T cells. Specifically, the ITAM domain of CD3ε can reduce the production of CAR-T cytokines by recruiting Csk, and the BRS (basic residue rich sequence) sequence of CD3ε promotes the persistence of CAR-T cells by recruiting p85.

In general, CD3ε is a built-in multifunctional signal conditioner, and the ever-increasing diversity of CD3 is expected to continue to promote the design strategy of the next generation of CAR.

Highlights

The four types of CD3 signaling chains of TCR have functional diversity
CD3ε recruits Csk and p85 via its mono-phosphorylated ITAM and BRS motif respectively
Incorporation of CD3ε into 28Z CAR alters signaling to promote antitumor function
CD3ε-based CAR-T cells have reduced cytokine production but enhanced persistence

One-stop CD3ε-Based CAR Development Services

With state-of-art Smart™ CAR development platform, Creative Biolabs is capable of offering CAR-T-cell development service. For the regular or custom CAR backbone construction, please refer to our related services: CAR Design & Construction. To further assess CAR biological efficacy (e.g., cytokine production, tumor killing, and CAR-T cell proliferation), our scientists can also provide comprehensive downstream services to complete your whole research. Please click: CAR Cell In Vitro Assay Service, CAR-T Preclinical In Vivo Assay for more details.

Chemically Programmed Switch CAR Construction Service

For more detailed information, please feel free to contact us or directly sent us an inquiry.

Reference

Wu, W., et al. (2020). Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy. Cell.