ESMO Immuno-Oncology Congress 2023

Abstract 140P

Background

The cell membrane of the trypanosomiasis-causing parasite Trypanosoma brucei is densely coated with 10 million copies of Variant Surface Glycoproteins (VSGs). VSG is highly immunogenic and can elicit a robust and long-lasting humoral immune response from the host organism.

Methods

Our laboratory has adapted the T. brucei coat into a uniquely powerful immunization platform (VSG-immunogen Array by Sortase Tagging) that has the capacity to elicit antibody responses against previously untargetable antigen classes. The antigens of interest are covalently coupled to the VSG proteins on the membrane by a sortase reaction. Sortase is a bacterial enzyme that can covalently link any polypeptides to each other, provided that they contain the sortase recognition peptides. We have engineered trypanosomes whose VSGs bear the N-terminal sortase recognition motif, and we generate antigens that display the cognate C-terminal motif. This platform has elicited high-affinity monoclonal antibodies against several immunogens of interest, including small molecules and peptides.

Results

A current obstacle in the treatment of many diseases is the difficulty of targeting proteins within the target cells. TCR-like monoclonal antibodies (TCR-like-mAbs) present a unique solution by targeting MHC receptors presenting such intracellular proteins. Currently, we are developing antibodies against intracellular protein targets that are presented on MHC after processing by the proteasome machinery, for example the MART-1 peptide. MART-1 is a protein expressed in metastatic melanoma cells. The protein is further processed by proteasome machinery, leading to a stretch of peptide from amino acids 27-35 (EAAGIGILTV) being presented on the cell surface via MHC class I.

Conclusions

To target peptides such as MART-1, we are using the VAST platform to elicit high-affinity TCR-like antibodies that can recognize peptides within the context of MHC, but in an MHC agnostic manner.