A donor-unrestricted TCR-bispecific redirects T cell immunity against Mycobacterium tuberculosis via HLA-E
Authors: Rachel L. Paterson1, Dawn Howe1, Joannah R. Fergusson1, Marcin Dembek1, Magdalena Martin-Urdiroz1, David Lowne1, Nitha Charles Mulakkal1, Diana J. Garay-Baquero2, Liku Bekele Tezera2, Marco Lepore1, Paul Elkington2, Sarah Leonard1*
1 Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK.; 2 NIHR Biomedical Research Centre and Institute for Life Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
Nearly 2 billion people worldwide are infected with Mycobacterium tuberculosis (Mtb) and each year ~10 million individuals develop pulmonary tuberculosis. Resistance to standard antibiotic treatments is increasing, thus highlighting the need to develop alternative host-targeted therapeutic strategies. T cell receptor (TCR)-based immunotherapy is an attractive approach for the treatment of tuberculosis due to its ability of promoting host immune responses targeting intracellular microbial antigens presented by human leukocyte antigens (HLA) on the surface of infected cells. However, classical HLA molecules are highly polymorphic, posing a challenge for developing TCR-based therapies for a wide patient population. To overcome this challenge, we generated a novel TCR-based bispecific molecule, an ImmTAB, to target a Mycobacterium tuberculosis (Mtb) peptide presented by HLA-E, a non-classical HLA molecule with very limited polymorphism. Here, we show that ImmTAB molecules engage polyclonal T cells to eliminate HLA-E-expressing antigen positive cell lines and primary cells infected with Mtb in vitro. The HLA-E-restricted ImmTAB did not recognise other common HLA-E-presented peptides nor did it bind the Mtb peptide when presented by HLA-A2. Moreover, ImmTAB molecules failed to bind the Mtb peptide presented by Mamu-E, revealing that models of infection in macaques are unsuitable for preclinical testing of HLA-E targeting TCR-based therapeutics. Our study suggests a possible approach to enhance endogenous host T cell immunity against Mtb and provides proof-of-principle for a novel TCR-based and donor-unrestricted therapeutic strategy.