CellRapeutics™ Framework Engineering Service to Enhance T Cell Receptor Specificity

T cell receptors (TCRs) play a role in cellular immunity by identifying short peptide antigens that are attached to major histocompatibility complex (MHC) proteins. Creative Biolabs' framework engineering service leverages advanced technology and rich experience to increase the specificity of TCR to meet the special needs of our customers.

TCR Loop Motion

The loop motion refers to the dynamic movements and conformational changes that occur in the complementarity-determining region (CDR) loops of the TCR structure. When TCR binds to peptide-MHC complexes, the CDR loops undergo structural adjustments and movements to accommodate the specific antigenic peptide. These changes are important for the TCR to form stable interactions with the peptide-MHC complexes and initiate downstream signaling cascades in T cells.

Fig. 1 The same TCR binds to different pMHC ligands at different positions of the CDR loop.¹

The dynamic nature of loop motion enables the TCR to sample different conformations and optimize its binding affinity and specificity for various antigens. Understanding the TCR loop motion is essential for elucidating the mechanisms of antigen recognition, T cell activation, and immune responses.

TCR Framework Engineering

The role of TCR specificity is important in the immune response. TCR specificity involves antigen recognition, initiation of immune response, and avoidance of autoimmunity. Also, it enables T cells to continuously adapt and recognize new antigens, promoting adaptive immune responses against infections, tumors, and other diseases.

Framework engineering can enhance TCR specificity by controlling the loop motions through mutations in the framework regions. By reducing loop flexibility, the framework mutation improves the specificity of TCRs by restricting their ability to adjust to various ligands and peptides.

The specificity of 868 TCR for HIV SL9 presented by HLA-A2 was studied in a study. A G to P (glycine to proline) mutation has been identified above the CDR3β loop through deep mutational scanning. While the mutation had no significant effect on binding affinity and functional avidity for the SL9 epitope, it weakened recognition of SL9 escape variants, indicating a more focused response.

Key features

1. Increase binding specificity without changing the chemical composition of the binding site.
2. Avoid introducing any new reactivities.
3. Avoid affecting the binding affinity.

The framework region of the TCR can be exploited to improve TCR specificity and reduce the risk of off-target recognition when used with TCR-based therapies. Creative Biolabs is committed to developing TCR framework engineering to optimize your TCR products. We would be glad to provide you with further details upon request, please don't hesitate to contact us.

References

1. Holland, C. J., et al. "Minimal conformational plasticity enables TCR cross-reactivity to different MHC class II heterodimers." Scientific reports. 2 (2012): 629.
2. Rosenberg, A. M., et al. "Enhanced T cell receptor specificity through framework engineering." Frontiers in immunology. 15 (2024): 1345368.