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bioRxiv · 10.1101/2024.12.16.628822

De novo design and structure of a peptide-centric TCR mimic binding module

Householder, K. D.·Xiang, X.·Jude, K. M.·Deng, A.·Obenaus, M.·Wilson, S. C.·Chen, X.·Wang, N.·Garcia, K. C.
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Abstract

T cell receptor (TCR) mimics offer a promising platform for tumor-specific targeting of peptide-MHC in cancer immunotherapy. Here, we designed a de novo -helical TCR mimic (TCRm) specific for the NY-ESO-1 peptide presented by HLA-A*02, achieving high on-target specificity with nanomolar affinity (Kd = 9.5 nM). The structure of the TCRm/pMHC complex at 2.05 [A] resolution revealed a rigid TCR-like docking mode with an unusual degree of focus on the up-facing NY-ESO-1 side chains, suggesting the potential for reduced off-target reactivity. Indeed, a structure-informed in silico screen of 14,363 HLA-A*02 peptides correctly predicted two off-target peptides, yet our TCRm maintained a wide therapeutic window as a T cell engager. These results represent a path for precision targeting of tumor antigens with peptide-focused -helical TCR mimics.

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Householder, K. D., Xiang, X., Jude, K. M., Deng, A., Obenaus, M., Wilson, S. C., Chen, X., Wang, N., Garcia, K. C.. 2024-12-20. De novo design and structure of a peptide-centric TCR mimic binding module. https://doi.org/10.1101/2024.12.16.628822

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