Novel ImmTAVTM and ImmTABTM molecules for the treatment of infectious diseases

Immunotherapeutic strategies harness the body’s own immune system to eradicate cancer cells and pathogens, such as bacteria or viruses. T cells play a critical role in these strategies, directing potent and antigen-specific immune responses. T cell receptors (TCRs) recognise foreign antigenic peptides presented by human leukocyte antigens (HLAs) on the cell surface and upon recognition, cytotoxic T cell responses are activated to eliminate the target cells. However, natural antigen-specific TCRs exhibit moderate binding affinities (µM to nM range) and may not effectively bind to target-specific antigens. At Immunocore, we have overcome this limitation by developing a novel class of soluble bispecific molecules that combines an affinity-enhanced TCR (pM affinity) with an anti-CD3 effector function called ImmTAC (Immune mobilising monoclonal TCRs Against Cancer). Our most advanced ImmTAC, IMCgp100, is currently in pivotal trials and has demonstrated encouraging preliminary anti-tumour activity against metastatic uveal melanoma. We have expanded our platform to address the unmet need in infectious diseases, such as hepatitis B virus (HBV) and tuberculosis (TB). These diseases constitute a global burden of 240-350 million people chronically infected with HBV and 10 million people affected by TB. Furthermore, chronic HBV patients exhibit defective T cell responses, producing liver cirrhosis and/or hepatocellular carcinoma in 10-30% of the cases. Our pipeline involves isolating antigenic-specific TCRs from either from PBMCs or naïve libraries. Isolated TCRs are expressed in E. coli and their binding affinities assessed by surface plasmon resonance (SPR). The affinity of antigen-specific TCRs is enhanced through directed evolution by phage display and specificity and potency tested by assessing in vitro killing capacity towards antigen-positive target cell lines. Here, we describe the process of developing ImmTAV/B molecules (Immune mobilising monoclonal TCRs Against Viruses/Bacteria) targeting HBV and TB.