De novo design and structure of a peptide-centric TCR mimic binding module.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40705894.
- Also identified by DOI 10.1126/science.adv3813 and PMC identifier 12313176.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
T cell receptor (TCR) mimics offer a promising platform for tumor-specific targeting of peptide-major histocompatibility complex (pMHC) in cancer immunotherapy. In this study, we designed a de novo α-helical TCR mimic (TCRm) specific for the NY-ESO-1 peptide presented by human leukocyte antigen (HLA)-A*02, achieving high on-target specificity with nanomolar affinity (dissociation constant <i>K</i><sub>d</sub> = 9.5 nM). The structure of the TCRm-pMHC complex at 2.05-Å 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 peptide selectivity and cytotoxicity as a T cell engager. These results represent a path for precision targeting of tumor antigens with peptide-focused α-helical TCR mimics.
Medical subject headings
- Antigens, Neoplasm
- HLA-A2 Antigen
- Membrane Proteins
- Peptides
- Receptors, Antigen, T-Cell
- Molecular Mimicry