7TR4

MA2-MART1-HLAA0201

Summary for 7TR4

• Entry DOI: 10.2210/pdb7tr4/pdb
• Descriptor: HLA-A*02:01, Beta-2-microglobulin, Light chain, ... (7 entities in total)
• Functional Keywords: tcrm antibody mart1 hla-a2, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 90845.76

Authors

Yang, X.,Jude, K.M.,Garcia, K.C. (deposition date: 2022-01-27, release date: 2022-11-23, Last modification date: 2024-10-23)

Primary citation

Yang, X.,Nishimiya, D.,Lochte, S.,Jude, K.M.,Borowska, M.,Savvides, C.S.,Dougan, M.,Su, L.,Zhao, X.,Piehler, J.,Garcia, K.C.
Facile repurposing of peptide-MHC-restricted antibodies for cancer immunotherapy.
Nat.Biotechnol., 41:932-943, 2023

PubMed Abstract: Monoclonal antibodies (Abs) that recognize major histocompatability complex (MHC)-presented tumor antigens in a manner similar to T cell receptors (TCRs) have great potential as cancer immunotherapeutics. However, isolation of 'TCR-mimic' (TCRm) Abs is laborious because Abs have not evolved the structurally nuanced peptide-MHC restriction of αβ-TCRs. Here, we present a strategy for rapid isolation of highly peptide-specific and 'MHC-restricted' Abs by re-engineering preselected Abs that engage peptide-MHC in a manner structurally similar to that of conventional αβ-TCRs. We created structure-based libraries focused on the peptide-interacting residues of TCRm Ab complementarity-determining region (CDR) loops, and rapidly generated MHC-restricted Abs to both mouse and human tumor antigens that specifically killed target cells when formatted as IgG, bispecific T cell engager (BiTE) and chimeric antigen receptor-T (CAR-T). Crystallographic analysis of one selected pMHC-restricted Ab revealed highly peptide-specific recognition, validating the engineering strategy. This approach can yield tumor antigen-specific antibodies in several weeks, potentially enabling rapid clinical translation.

PubMed: 36593402
DOI: 10.1038/s41587-022-01567-w

Experimental method

X-RAY DIFFRACTION (2.3 Å)