T cells have the capacity to detect an extremely large variety of antigens and mount robust inflammatory and cytotoxic responses against transformed or infected cells. Because of these unique properties, T cells are subjects of intense translational research activity, which aim to develop effective immunotherapy approaches to treat cancer and infections. These studies focus on “classical” MHC- restricted T cells recognizing peptide presented by cancer or infected cells.

In addition to peptides, T cells also recognize other classes of antigens, including lipids and metabolites displayed by non-polymorphic antigen presenting molecules such as CD1, MR1 and BTN3A1. These T cells, defined as “unconventional”, comprise heterogeneous populations with diverse roles in cancer, infections and autoimmunity, and therefore display a broad immunotherapeutic potential, as suggested by a number of recent proof-of principle studies.

At Immunocore, we developed a novel class of soluble bi-specific biologics, ImmTAC^TM/V, consisting of affinity-enhanced TCRs recognizing selected tumor or microbial antigens presented by specific HLAs, fused to an anti-CD3 effector domain. The TCR domain strongly binds cells expressing both the target antigen and the specific HLA type, while the anti-CD3 domain induces activation of the patient’s T cells, thus redirecting their response toward malignant or infected cells.  

We aim to apply our ImmTAC/V technology to also target disease-associated non-peptide molecules recognized by unconventional T cells. As lipid and metabolite antigens are subjected to a low-mutation rate and are presented by non-polymorphic proteins, this approach may overcome the therapeutic limitations imposed by the occurrence of immune-escape variants and the high polymorphism of HLAs.