Proteogenomic analyses for discovery of bispecific chimeric antigen receptor targets
Mike Bogetofte Barnkob1, Christian Simon2, Lars Rønn Olsen3
1MRC Human Immunology Unit, University of Oxford; 2Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen; 3DTU Bioinformatics, Technical University of Denmark
The clinical successes of chimeric antigen receptor (CAR) T cells have been achieved by targeting single surface proteins. In order to increase treatment specificity, bispecific and inhibitory CARs are being explored. Selecting good bispecific CAR targets is essential to balance specificity and sensitivity of tumor cell targeting, ensuring both efficacy and clinical safety. Well-defined cell surface protein expression profiles are needed to facilitate target selection, and requires information about expression of a large number of surface proteins on a large number of cells at different states and differentiation stages. Vast amounts of cell-specific expression have been measured using immunohistochemistry, and flow and mass cytometry, and tissue-level transcriptomics can be used to approximate protein expression, where cell-specific measurements on protein level are missing.
Together, these data types represent a rich, but unstructured source of data. To facilitate the definition of unique surface protein profiles from these data, we have collected, processed, and organized large amounts of protein expression data on human hematopoietic cells measured by the various cytometry methods. We coupled these data with analysis of large-scale transcriptomics in order to assemble a broad data foundation for characterization of cell surface proteomes. We then developed tools for interrogating these data to define unique protein expression profiles for highly specific CAR targeting. Ongoing efforts will expand the database to contain surface protein expression for cells in additional human tissue types, as well as setting up a pipeline for experimental validation of potential CAR targets.
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