7RE7

TCR mimic antibody (Fab fragment) in complex with AFP/HLA-A*02

Summary for 7RE7

• Entry DOI: 10.2210/pdb7re7/pdb
• Descriptor: Fab heavy chain, TRIETHYLENE GLYCOL, PENTAETHYLENE GLYCOL, ... (13 entities in total)
• Functional Keywords: tcr mimic antibody (fab fragment), class i major histocompatibility complex (hla-a*02), alpha fetoprotein peptide., immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 190966.27

Authors

Dasgupta, M.,Baker, B.M. (deposition date: 2021-07-12, release date: 2022-07-27, Last modification date: 2024-10-23)

Primary citation

Liu, C.,Liu, H.,Dasgupta, M.,Hellman, L.M.,Zhang, X.,Qu, K.,Xue, H.,Wang, Y.,Fan, F.,Chang, Q.,Yu, D.,Ge, L.,Zhang, Y.,Cui, Z.,Zhang, P.,Heller, B.,Zhang, H.,Shi, B.,Baker, B.M.,Liu, C.
Validation and promise of a TCR mimic antibody for cancer immunotherapy of hepatocellular carcinoma.
Sci Rep, 12:12068-12068, 2022

PubMed Abstract: Monoclonal antibodies are at the vanguard of the most promising cancer treatments. Whereas traditional therapeutic antibodies have been limited to extracellular antigens, T cell receptor mimic (TCRm) antibodies can target intracellular antigens presented by cell surface major histocompatibility complex (MHC) proteins. TCRm antibodies can therefore target a repertoire of otherwise undruggable cancer antigens. However, the consequences of off-target peptide/MHC recognition with engineered T cell therapies are severe, and thus there are significant safety concerns with TCRm antibodies. Here we explored the specificity and safety profile of a new TCRm-based T cell therapy for hepatocellular carcinoma (HCC), a solid tumor for which no effective treatment exists. We targeted an alpha-fetoprotein peptide presented by HLA-A*02 with a highly specific TCRm, which crystallographic structural analysis showed binds directly over the HLA protein and interfaces with the full length of the peptide. We fused the TCRm to the γ and δ subunits of a TCR, producing a signaling AbTCR construct. This was combined with an scFv/CD28 co-stimulatory molecule targeting glypican-3 for increased efficacy towards tumor cells. This AbTCR + co-stimulatory T cell therapy showed potent activity against AFP-positive cancer cell lines in vitro and an in an in vivo model and undetectable activity against AFP-negative cells. In an in-human safety assessment, no significant adverse events or cytokine release syndrome were observed and evidence of efficacy was seen. Remarkably, one patient with metastatic HCC achieved a complete remission after nine months and ultimately qualified for a liver transplant.

PubMed: 35840635
DOI: 10.1038/s41598-022-15946-5

Experimental method

X-RAY DIFFRACTION (2.547 Å)