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| Title | Targeting peptide-MHC complexes with designed T cell receptors and antibodies. |
|---|---|
| Journal, issue, pages | bioRxiv, Year 2025 |
| Publish date | Nov 20, 2025 |
 Authors | Amir Motmaen / Kevin M Jude / Nan Wang / Anastasia Minervina / David Feldman / Mauriz A Lichtenstein / Abishai Ebenezer / Colin Correnti / Paul G Thomas / K Christopher Garcia / David Baker / Philip Bradley /   |
| PubMed Abstract | Class I major histocompatibility complexes (MHCs), expressed on the surface of all nucleated cells, present peptides derived from intracellular proteins for surveillance by T cells. The precise ...Class I major histocompatibility complexes (MHCs), expressed on the surface of all nucleated cells, present peptides derived from intracellular proteins for surveillance by T cells. The precise recognition of foreign or mutated peptide-MHC (pMHC) complexes by T cell receptors (TCRs) is central to immune defense against pathogens and tumors. Although patient-derived TCRs specific for cancer-associated antigens have been used to engineer tumor-targeting therapies, their reactivity toward self- or near-self antigens may be constrained by negative selection in the thymus. Here, we introduce a structure-based deep learning framework, ADAPT (Antigen-receptor Design Against Peptide-MHC Targets), for the design of TCRs and antibodies that bind to pMHC targets of interest. We evaluate the ADAPT pipeline by designing and characterizing TCRs and antibodies against a diverse panel of pMHCs. Cryogenic electron microscopy structures of two designed antibodies bound to their respective pMHC targets demonstrate atomic-level accuracy at the recognition interface, supporting the robustness of our structure-based approach. Computationally designed TCRs and antibodies targeting pMHC complexes could enable a broad range of therapeutic applications, from cancer immunotherapy to autoimmune disease treatment, and insights gained from TCR-pMHC design should advance predictive understanding of TCR specificity with implications for basic immunology and clinical diagnostics. |
 External links | bioRxiv / PubMed:41332722 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.5 - 2.6 Å |
| Structure data | EMDB-73458, PDB-9ytd: EMDB-73460, PDB-9ytf: |
| Chemicals |  ChemComp-HOH: |
| Source |
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 Keywords | DE NOVO PROTEIN/IMMUNE SYSTEM / Fab / complex / immunology / DE NOVO PROTEIN / DE NOVO PROTEIN-IMMUNE SYSTEM complex / IMMUNE SYSTEM / HLA / TCR mimic antibody / de novo design / immune complex |
homo sapiens (human)
lama glama (llama)