8FJA

CryoEM structure of HLA-A2 MAGEA4 (230-239) in complex with REGN6972 Fab

Summary for 8FJA

• Entry DOI: 10.2210/pdb8fja/pdb
• EMDB information: 29220
• Descriptor: REGN6972 Fab light chain, REGN6972 Fab heavy chain, MHC class I antigen, ... (5 entities in total)
• Functional Keywords: hla, mhc, immune system, antibody
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 93789.33

Authors

Saotome, K.,Franklin, M.C. (deposition date: 2022-12-19, release date: 2023-12-20, Last modification date: 2025-05-21)

Primary citation

Salzler, R.,DiLillo, D.J.,Saotome, K.,Bray, K.,Mohrs, K.,Hwang, H.,Cygan, K.J.,Shah, D.,Rye-Weller, A.,Kundu, K.,Badithe, A.,Zhang, X.,Garnova, E.,Torres, M.,Dhanik, A.,Babb, R.,Delfino, F.J.,Thwaites, C.,Dudgeon, D.,Moore, M.J.,Meagher, T.C.,Decker, C.E.,Owczarek, T.,Gleason, J.A.,Yang, X.,Suh, D.,Lee, W.Y.,Welsh, R.,MacDonald, D.,Hansen, J.,Guo, C.,Kirshner, J.R.,Thurston, G.,Huang, T.,Franklin, M.C.,Yancopoulos, G.D.,Lin, J.C.,Macdonald, L.E.,Murphy, A.J.,Chen, G.,Olsen, O.,Olson, W.C.
CAR T cells based on fully human T cell receptor-mimetic antibodies exhibit potent antitumor activity in vivo.
Sci Transl Med, 17:eado9371-eado9371, 2025

PubMed Abstract: Monoclonal antibody therapies have transformed the lives of patients across a diverse range of diseases. However, antibodies can usually only access extracellular proteins, including the extracellular portions of membrane proteins that are expressed on the cell surface. In contrast, T cell receptors (TCRs) survey the entire cellular proteome when processed and presented as peptides in association with human leukocyte antigen (pHLA complexes). Antibodies that mimic TCRs by recognizing pHLA complexes have the potential to extend the reach of antibodies to this larger pool of targets and provide increased binding affinity and specificity. A major challenge in developing TCR mimetic (TCRm) antibodies is the limited sequence differences between the target pHLA complex relative to the large global repertoire of pHLA complexes. Here, we provide a comprehensive strategy for generating fully human TCRm antibodies across multiple HLA alleles, beginning with pHLA target discovery and validation and culminating in the engineering of TCRm-based chimeric antigen receptor T cells with potent antitumor activity. By incorporating mass spectrometry, bioinformatic predictions, HLA-humanized mice, antibody screening, and cryo-electron microscopy, we have established a pipeline to identify additional pHLA complex-specific antibodies with therapeutic potential.

PubMed: 40138458
DOI: 10.1126/scitranslmed.ado9371

Experimental method

ELECTRON MICROSCOPY (3 Å)