9YTD

Designed antibody vAB66 targeting PAP-HLA A*02:01

Summary for 9YTD

• Entry DOI: 10.2210/pdb9ytd/pdb
• EMDB information: 73458
• Descriptor: HLA class I histocompatibility antigen, A alpha chain, Beta-2-microglobulin, Prostatic acid phosphatase-derived peptide, ... (7 entities in total)
• Functional Keywords: fab, complex, immunology, de novo protein, de novo protein-immune system complex, de novo protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 105791.72

Authors

Jude, K.M.,Garcia, K.C. (deposition date: 2025-10-20, release date: 2025-12-17)

Primary citation

Motmaen, A.,Jude, K.M.,Wang, N.,Minervina, A.,Feldman, D.,Lichtenstein, M.A.,Ebenezer, A.,Correnti, C.,Thomas, P.G.,Garcia, K.C.,Baker, D.,Bradley, P.
Targeting peptide-MHC complexes with designed T cell receptors and antibodies.
Biorxiv, 2025

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 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.

PubMed: 41332722
DOI: 10.1101/2025.11.19.689381

Experimental method

ELECTRON MICROSCOPY (2.5 Å)