2. Academic Validation
  3. Proteolysis-Targeting Chimeras Enhance T Cell Bispecific Antibody-Driven T Cell Activation and Effector Function through Increased MHC Class I Antigen Presentation in Cancer Cells

Proteolysis-Targeting Chimeras Enhance T Cell Bispecific Antibody-Driven T Cell Activation and Effector Function through Increased MHC Class I Antigen Presentation in Cancer Cells

  • J Immunol. 2021 Jul 15;207(2):493-504. doi: 10.4049/jimmunol.2000252.
Vittoria Massafra 1,  Sofia Tundo 1,  Aline Dietzig 1,  Axel Ducret 2,  Christian Jost 3,  Christian Klein 3,  Roland E Kontermann 4,  Hendrik Knoetgen 5,  Martin Steegmaier 6,  Andrea Romagnani 1,  Yvonne A Nagel 7
Affiliations

Affiliations

  • 1 Molecular Targeted Therapy-Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • 2 Pharmaceutical Sciences-Biomarkers, Bioinformatics, and Omics, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
  • 3 Cancer Immunotherapy-Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center Zurich, F. Hoffmann-La Roche Ltd., Schlieren, Switzerland.
  • 4 Institute of Cell Biology and Immunology, Stuttgart University, Stuttgart, Germany.
  • 5 Therapeutic Modalities, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and.
  • 6 Large Molecule Research, Roche Pharma Research and Early Development, Roche Innovation Center Munich, F. Hoffmann-La Roche Ltd., Penzberg, Germany.
  • 7 Molecular Targeted Therapy-Discovery Oncology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland; yvonne_alice.nagel@roche.com.
PMID: 34215653 DOI: 10.4049/jimmunol.2000252
Abstract

The availability of Ags on the surface of tumor cells is crucial for the efficacy of Cancer immunotherapeutic approaches using large molecules, such as T cell bispecific Abs (TCBs). Tumor Ags are processed through intracellular proteasomal protein degradation and are displayed as Peptides on MHC class I (MHC I). Ag recognition through TCRs on the surface of CD8+ T cells can elicit a tumor-selective immune response. In this article, we show that proteolysis-targeting chimeras (PROTACs) that target bromo- and extraterminal domain proteins increase the abundance of the corresponding target-derived peptide Ags on MHC I in both liquid and solid tumor-derived human cell lines. This increase depends on the engagement of the E3 Ligase to bromo- and extraterminal domain protein. Similarly, targeting of a doxycycline-inducible Wilms tumor 1 (WT1)-FKBP12F36V fusion protein, by a mutant-selective FKBP12F36V degrader, increases the presentation of WT1 Ags in human breast Cancer cells. T cell-mediated response directed against Cancer cells was tested on treatment with a TCR-like TCB, which was able to bridge human T cells to a WT1 peptide displayed on MHC I. FKBP12F36V degrader treatment increased the expression of early and late activation markers (CD69, CD25) in T cells; the secretion of granzyme β, IFN-γ, and TNF-α; and Cancer cell killing in a tumor-T cell coculture model. This study supports harnessing targeted protein degradation in tumor cells, for modulation of T cell effector function, by investigating for the first time, to our knowledge, the potential of combining a degrader and a TCB in a Cancer Immunotherapy setting.

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