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Murine-human Hybrid TCR

Creative Biolabs provides services of both generation and validation of human TCR and murine-human hybrid TCR. Murine-human hybrid TCR is a promising strategy to improve cell surface TCR expression, TCR pairing and TCR/CD3ξ stability, which can enhance the anti-tumor activity of T cells.

Murine-human Hybrid TCR

Figure: Strategies addressing TCR pairing (Trends Mol Med. 2010)

The TCR (T-cell receptor)/CD3 complex is a structure to recognize antigens to active signals to lymphocytes. The association between TCR α, β chains and CD3γ/δ/ε/ζ is mediated by the transmembrane region residues that are located in the constant part of TCR chains. These charged residues interact with CD3ζ chain homodimer and CD3γ/ε-CD3δ/ε heterodimers noncovalently. There are reports that humanized murine TCRs might be less active than the native mouse receptor in human cells. However, TCRs with murine constant regions might have enhances tumor recognition and induce lymphocytes to secrete more IFN-γ, GM-CSF and other cytokines. The reason may be that the constant regions prefer to pair with themselves and decrease the mispairing with endogenous human TCR chains, increasing the stability of TCR/CD3ζ complex. Besides the functions in cytotoxic lymphocytes, the problem that the inherent CD4+ lymphocytes expressing class I MHC-restricted TCRs have low avidity can be overcome by using murine-human hybrid TCR.

For murine-human hybrid TCR generation, the human TCR which can recognize human tumor associated antigen is selected followed by the TCR-C domains (Cα and Cβ) replacement with the corresponding murine C domains. Then, a series of assays will be carried out to evaluate the expression and function of the resultant hybrid TCRs. Technically, we can use flow cytometry or other innovative strategies to test the specific antigen binding activity of TCR for assessing TCR pairing.

Our experienced scientists can design and select the appropriate and doable plan for TCR construct and optimization.

References:

  1. Andreas Hombach, et al. T cell receptor gene therapy: strategies for optimizing transgenic TCR pairing. Trends Mol Med. 2010 Feb; 16(2):77-87.
  2. Cyrille J. Cohen, et al. Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associatedwith improved pairing and TCR/CD3 stability. Cancer Res. 2006 Sep 1;66(17):8878-86.
  3. Coen Govers, et al. T cell receptor gene therapy: strategies for optimizing transgenic TCR pairing. Trends Mol Med. 2010 Feb;16(2):77-87.

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