The Omics Brief | Proteomics at the Edge: Mapping the Cell Surface for Target Discovery

The cell surface and its proteins represent a significant untapped space for drug discovery. Tumor-associated antigens (TAAs) play key roles in immune modulation, tumor growth and metastasis, and drug response, all of which are central to oncologic therapeutics.

Traditionally there have been a number of challenges that have prevented us from being able perform comprehensive TAA profiling to measure the cell surface proteome. The complex topology of the cell surface, for one, can affect druggability. TAAs are also often lower abundance compared to other intercellular, high-abundance proteins, and analytical limitations both with sensitivity and reproducibility, as well as importantly the capture of protein isoforms and post-translational modifications (PTMs), have limited the ability to broadly map the cell surface proteome as a means for target identification in drug development.

In this Omics Brief, we take a closer look at the evolving innovations – from new drug modalities that can now reach previously difficult-to-drug TAAs, to next-generation mass spectrometry that provides the sensitivity needed for deep TAA profiling across the breadth of the cell surface proteome, to AI workflows that enable identification of differentially expressed, disease-modifying, tractable cell surface TAAs – enabling greater discovery of novel targets for radioligands, ADCs, and T-cell engagers.