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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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The physiological interactome of TCR-like antibody therapeutics in human tissues

Estelle Marrer-Berger1, Annalisa Nicastri2,3, Angelique Augustin1

  • 1Roche Pharma Research & Early Development, Roche Innovation Center Basel, 4070, Basel, Switzerland.

Nature Communications
|April 16, 2024
PubMed

Insights

Developing novel TCR-like antibodies requires rigorous safety testing. This study presents a new mass spectrometry platform to identify antibody interactomes in human tissues, ensuring therapeutic safety and efficacy before clinical trials.

Area of Science:

  • Immunology and Cancer Therapeutics
  • Proteomics and Mass Spectrometry

Background:

  • Therapeutic T-cell receptor (TCR)-like antibodies must selectively bind tumor-specific antigens presented by human leukocyte antigens (HLA) for safety and efficacy.
  • Current methods for assessing antibody selectivity, such as peptide library screening and predictive modeling, have limitations.
  • Accurate assessment of off-target interactions is crucial for patient safety in TCR-like antibody development.

Purpose of the Study:

  • To develop and validate an experimental platform for identifying TCR-like antibody interactomes directly in human tissues.
  • To assess the selectivity and potential off-target activities of TCR-like antibodies using mass spectrometry.
  • To provide a reliable method for evaluating the non-clinical safety profile of TCR-like antibody therapeutics.

Main Methods:

  • Development of a novel experimental platform utilizing mass spectrometry for de novo interactome identification.
  • Application of the platform to confirm the target epitope of a MAGE-A4-specific TCR-like antibody.
  • Determination of cross-reactive peptide sequences for the ESK1 TCR-like antibody in human liver tissue.

Main Results:

  • The platform successfully confirmed the target epitope of a MAGE-A4-specific TCR-like antibody.
  • Cross-reactive peptide sequences for the ESK1 antibody were identified in human liver tissue, confirming known off-target activity.
  • Off-target interactions were linked to T-cell activation and tissue damage, mediated by a specific amino acid motif.
  • The identified motif mimics the target peptide's interaction within the HLA structural groove.

Conclusions:

  • The developed mass spectrometry-based platform provides an accurate and scalable method for evaluating TCR-like antibody safety.
  • This strategy enables comprehensive assessment of antibody selectivity and off-target interactions in relevant human tissues.
  • The findings support the pre-clinical safety evaluation of TCR-like antibody therapeutics prior to clinical application.

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