Generation of ImmTACTM molecules: Engineering high-affinity soluble T-cell receptors for the treatment of cancer

Immunotherapeutic strategies are centered on harnessing the human immune system to recognise and destroy cancer cells. At Immunocore, we have developed bi-specific Immune-mobilising monoclonal TCRs Against Cancer (ImmTAC) molecules comprising a soluble TCR fused to an anti-CD3 effector function that redirect T-cells to destroy cancer cells. The TCR-targeting domain overcomes a key limitation of traditional antibody-based therapies by targeting short peptide fragments derived from intracellularly processed proteins presented on the cell surface by human leukocyte antigens (HLAs), offering up to nine-fold more potential targets than are accessible to antibodies. To mediate efficient T-cell-mediated tumor clearance, ImmTAC molecules are engineered to overcome the weak affinities of natural TCRs imposed by thymic selection through a complex multistep engineering process described herein.T-cell clones recognising in-house validated cancer-specific peptides are isolated and affinity-enhanced up to a million fold by introducing mutations to the complementarity determining regions, resulting in picomolar affinity TCRs capable of recognizing exceptionally low numbers of target on the cancer cell surface. The TCR is fused to an anti-CD3 scFv to generate an ImmTAC molecule and is made soluble through the inclusion of a non-native disulphide bond. The efficacy and specificity of the ImmTAC molecule is scrutinized using a range of cellular and molecular assays. The potential application of the ImmTAC platform is exemplified by the expanding portfolio of ImmTAC molecules targeting diverse disease indications. Our lead candidate, IMCgp100, recognizes the melanoma-associated gp100 peptide and is in pivotal trials for the treatment of patients with metastatic uveal melanoma. Citation Format: Izabela Bombik, Alessio Bortoluzzi, Nicole Mai, Andrew Preston, Annelise Vuidepot, Bent K. Jakobsen, Nathaniel Liddy. Generation of ImmTACTM molecules: Engineering high-affinity soluble T-cell receptors for the treatment of cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B001.