Cross-Linking MS for Rapid TCR Binding Mode Analysis
Streamlining TCR structural mapping for therapeutic design
About This Webinar
Determining how TCR-based therapeutics engage peptide-HLA complexes is essential for effective drug development, yet traditional crystallography methods can take months and require significant technical expertise. In this webinar replay, Thomas Powell from Immunocore demonstrates how chemical cross-linking combined with LC-MS/MS provides a faster, more accessible alternative for understanding TCR binding orientations. Using Protein Metrics' Byosphere platform to analyze cross-linking data from multiple enzymes and reagents, his team can now differentiate between canonical, shifted, and reverse binding modes—and integrate these insights into AI structural models with remarkable accuracy. This methodology accelerates candidate screening from months to days while maintaining the precision needed for therapeutic development.
Key Takeaways
Accelerate structural analysis dramatically by replacing months-long crystallography with days-long cross-linking MS approaches that deliver actionable binding orientation data.
Distinguish critical binding modes quickly including canonical binders, shifted binders, and reverse binders—information essential for selecting effective therapeutic candidates and avoiding those with weak or harmful immune responses.
Streamline multi-enzyme workflows in Byosphere by analyzing trypsin and chymotrypsin digestions together in a single workflow, achieving near-complete sequence coverage with consolidated, easy-to-read outputs.
Enhance AI model accuracy exponentially by incorporating just 1-4 high-confidence cross-links into computational predictions, reducing structural prediction errors from over 21 angstroms to just 2.4 angstroms—nearly matching crystal structure quality.
From the Webinar
On multi-enzyme analysis: "what's really brilliant about Byosphere, and I found quite unique, is we can analyze both these data sets using the same workflow... it's all combined into a single, easy-to-read output file, which is really brilliant." 33:40
On workflow transferability: "the workflow files are the same between BYOS and Byosphere, so... if you're using BYOS, you can use those workflows and import them into Byosphere. You don't have to create all the workflows from scratch." 45:00
On data visualization: "We see a nice, clear, extracted ion chromatogram... We can check its MS1 data... And then we can see our MS2 data as well, and... we get a very easy-to-read sequence coverage, and assignment of where the crosslinks are formed." 34:41
About the Speaker
Thomas Powell is a Senior Scientist in the Analytical Development group at Immunocore with over seven years of experience in the pharmaceutical industry. He holds a PhD from the University of Birmingham and specializes in mass spectrometry, with extensive expertise in identifying novel post-translational modifications relevant to biopharmaceuticals. More recently, he has focused on developing innovative mass spectrometry methods and integrating them into discovery pipelines in novel and impactful ways—including pioneering the use of cross-linking MS to accelerate TCR therapeutic candidate screening and enhance AI-driven structural predictions.
Recorded 9-Oct-25
Read the associated Application Note