ImmTAC molecules: Beyond HLA-A*02:01-the identification and isolation of dual-HLA-specific T cell receptors.

ImmTAC (Immune mobilizing monoclonal TCRs against cancer) molecules are a new class of bi-specific biologic that combine a T-cell receptor (TCR)-targeting system with an anti-CD3 effector function to activate highly potent and specific T-cell responses to cancer cells. ImmTAC molecules have the potential to overcome many of the limitations of other immuno-oncology agents; using TCRs to target intracellularly processed peptides presented by HLA allows access to a vast landscape of cancer-specific antigens that antibody-based therapies cannot currently target. Soluble agents also have a number of benefits over cellular therapies in terms of ease of manufacture and supply. At Immunocore we are constantly striving for innovation and looking for new opportunities to advance the ImmTAC platform. One limitation of TCR-targeting is HLA-restriction, which means that a single ImmTAC molecule is highly specific towards a single HLA-subtype. Lead ImmTAC molecules target HLA-A2, which has the highest coverage in the Caucasian population of approximately 55%. Our desire is to cover all patients in need; therefore, we are developing ImmTAC molecules that target peptides on other HLA alleles with an aim to increase patient access across a range of ethnic groups. In addition, the ability to target peptides presented in multiple HLA alleles would significantly increase the number of patients eligible for this treatment. HLA-A3 and HLA-A11 are part of the same superfamily and share largely overlapping peptide repertoires. We have identified peptides from gp100, a melanoma associated-antigen, which are presented by both HLA-A3 and HLA-A11. Identifying a TCR that is able to recognize a peptide in both these HLA alleles is the first step in generating our first dual-HLA-specific ImmTAC. Here we describe the generation of new TCRs suitable for ImmTAC generation, using our integrated in-house TCR discovery process. TCRs were isolated using multiple methods from HLA-A3 or HLA-A11 donors. We were able to identify antigen-specific T cells from multiple donors that recognized the gp100-peptide-HLA complex. The majority of these T cells were specific to the HLA-allele of the donor and failed to recognize the same peptide in the alternative HLA allele. However, we were able to identify TCRs that had a measurable binding affinity to the gp100 peptide presented in both HLA-A3 and HLA-A11. These data illustrate the successful isolation of wild-type TCRs suitable for affinity maturation and the first step in generating our first dual-HLA-restricted ImmTAC molecule. Citation Format: Vanessa L. Clark, Linda Hibbert, Debbie Wright, Sarah Bailey, Alice Barkell, Kathy Hale, Elizabeth Evans, Alasdair Gunn, Maria Busz, Karolina Lech, Michelle Teng, Luke Williams, Joseph Dukes, Annelise Vuidepot, Bent Jakobsen. ImmTAC molecules: Beyond HLA-A*02:01—the identification and isolation of dual-HLA-specific T cell receptors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B44.