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

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.

SUBMITTER: Marrer-Berger E

PROVIDER: S-EPMC11021511 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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

Marrer-Berger Estelle E Nicastri Annalisa A Augustin Angelique A Kramar Vesna V Liao Hanqing H Hanisch Lydia Jasmin LJ Carpy Alejandro A Weinzierl Tina T Durr Evelyne E Schaub Nathalie N Nudischer Ramona R Ortiz-Franyuti Daniela D Breous-Nystrom Ekaterina E Stucki Janick J Hobi Nina N Raggi Giulia G Cabon Lauriane L Lezan Emmanuelle E Umaña Pablo P Woodhouse Isaac I Bujotzek Alexander A Klein Christian C Ternette Nicola N

Nature communications 20240416 1

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 ...[more]

PMID: 38627373

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Dataset Information

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

Publications

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

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