Engineering ImmTAC molecules- crossreactivity in a MAGE A3 specific TCR
Harper SA, Raman MC, Rizkallah PJ, Simmons R, Donnellan Z, Dukes J, Bossi G, Le Provost GS, Todorov P, Baston E, Hickman E, Mahon T, Hassan N, Vuidepot A, Sami M, Cole DK, Jakobsen BK.
ImmTAC molecules are bispecific therapeutics that enable the immune system to recognise and kill cancer cells. Recognition occurs via a soluble T cell receptor (TCR) that binds to peptides derived from intracellular cancer targets. Killing is mediated by an anti-CD3 specific scFv that re-directs a potent T cell response.
A TCR can recognize its target peptide only in the context of a cell surface receptor. Affinity for the peptide-receptor complex (pHLA) is typically weak, >µM, allowing them to be highly promiscuous. By contrast it is necessary for ImmTAC molecules to be highly specific. Affinity enhancement whilst engineering specificity is primarily achieved through phage display, targeting mutations in the CDR loops.
Here we present an example of structure led engineering in a TCR that in the context of HLA-A*01 recognises a peptide from the cancer testis antigen Mage A3. This TCR was described in a recent clinical report from another company, where fatal cardiac toxicity followed administration of TCR-engineered T cells. Mutants were designed to reduce off-target cross-reactivity to a structurally related peptide derived from titin a protein expressed in cardiac tissue.