The physiological interactome of TCR-like antibody therapeutics in human tissues

Estelle Marrer-Berger, Annalisa Nicastri, Angelique Augustin, Vesna Kramar, Hanqing Liao, Lydia Jasmin Hanisch, Alejandro Carpy, Tina Weinzierl, Evelyne Durr, Nathalie Schaub, Ramona Nudischer, Daniela Ortiz-Franyuti, Ekaterina Breous-Nystrom, Janick Stucki, Nina Hobi, Giulia Raggi, Lauriane Cabon, Emmanuelle Lezan, Pablo Umaña, Isaac Woodhouse, Alexander Bujotzek, Christian Klein () and Nicola Ternette ()
Additional contact information
Estelle Marrer-Berger: Roche Innovation Center Basel
Annalisa Nicastri: Old Road Campus Research Building
Angelique Augustin: Roche Innovation Center Basel
Vesna Kramar: Roche Innovation Center Zürich
Hanqing Liao: Old Road Campus Research Building
Lydia Jasmin Hanisch: Roche Innovation Center Zürich
Alejandro Carpy: Roche Innovation Center Munich
Tina Weinzierl: Roche Innovation Center Zürich
Evelyne Durr: Roche Innovation Center Basel
Nathalie Schaub: Roche Innovation Center Basel
Ramona Nudischer: Roche Innovation Center Basel
Daniela Ortiz-Franyuti: Roche Innovation Center Basel
Ekaterina Breous-Nystrom: Roche Innovation Center Basel
Janick Stucki: Swiss Organs-on-Chip Innovation
Nina Hobi: Swiss Organs-on-Chip Innovation
Giulia Raggi: Swiss Organs-on-Chip Innovation
Lauriane Cabon: Roche Innovation Center Basel
Emmanuelle Lezan: Roche Innovation Center Basel
Pablo Umaña: Roche Innovation Center Zürich
Isaac Woodhouse: Old Road Campus Research Building
Alexander Bujotzek: Roche Innovation Center Munich
Christian Klein: Roche Innovation Center Zürich
Nicola Ternette: Old Road Campus Research Building

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Selective binding of TCR-like antibodies that target a single tumour-specific peptide antigen presented by human leukocyte antigens (HLA) is the absolute prerequisite for their therapeutic suitability and patient safety. To date, selectivity assessment has been limited to peptide library screening and predictive modeling. We developed an experimental platform to de novo identify interactomes of TCR-like antibodies directly in human tissues using mass spectrometry. As proof of concept, we confirm the target epitope of a MAGE-A4-specific TCR-like antibody. We further determine cross-reactive peptide sequences for ESK1, a TCR-like antibody with known off-target activity, in human liver tissue. We confirm off-target-induced T cell activation and ESK1-mediated liver spheroid killing. Off-target sequences feature an amino acid motif that allows a structural groove-coordination mimicking that of the target peptide, therefore allowing the interaction with the engager molecule. We conclude that our strategy offers an accurate, scalable route for evaluating the non-clinical safety profile of TCR-like antibody therapeutics prior to first-in-human clinical application.

Date: 2024
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DOI: 10.1038/s41467-024-47062-5

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