5BS0

MAGE-A3 Reactive TCR in complex with Titin Epitope in HLA-A1

Summary for 5BS0

• Entry DOI: 10.2210/pdb5bs0/pdb
• Related: 5brz
• Descriptor: HLA class I histocompatibility antigen, A-1 alpha chain, Beta-2-microglobulin, Titin, ... (8 entities in total)
• Functional Keywords: immuno pmhc tcr titin, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P30443; Secreted : P61769; Cytoplasm : Q8WZ42; Membrane ; Single-pass membrane protein : P01848
• Total number of polymer chains: 5
• Total formula weight: 94367.25

Authors

Raman, M.C.C.,Rizkallah, P.J.,Simmons, R.,Donellan, Z.,Dukes, J.,Bossi, G.,LeProvost, G.,Mahon, T.,Hickman, E.,Lomax, M.,Oates, J.,Hassan, N.,Vuidepot, A.,Sami, M.,Cole, D.K.,Jakobsen, B.K. (deposition date: 2015-06-01, release date: 2016-03-02, Last modification date: 2024-11-06)

Primary citation

Raman, M.C.,Rizkallah, P.J.,Simmons, R.,Donnellan, Z.,Dukes, J.,Bossi, G.,Le Provost, G.S.,Todorov, P.,Baston, E.,Hickman, E.,Mahon, T.,Hassan, N.,Vuidepot, A.,Sami, M.,Cole, D.K.,Jakobsen, B.K.
Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy.
Sci Rep, 6:18851-18851, 2016

PubMed Abstract: Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self-antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics.

PubMed: 26758806
DOI: 10.1038/srep18851

Experimental method

X-RAY DIFFRACTION (2.4 Å)