Transferrin receptor targeting chimeras for membrane protein degradation

  • Nature. 2024 Sep 25. doi: 10.1038/s41586-024-07947-3.
Dingpeng Zhang  1  2 ,  Jhoely Duque-Jimenez  1 ,  Francesco Facchinetti  3  4  5 ,  Garyk Brixi  6 ,  Kaitlin Rhee  1  2 ,  William W Feng  3  4  5 ,  Pasi A Jänne  3  4  5  7 ,  Xin Zhou  8  9
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4. Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 5. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6. Harvard University, Boston, MA, USA.
  • 7. Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 9. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 39322661 DOI: 10.1038/s41586-024-07947-3
Abstract

Cancer cells require high levels of iron for rapid proliferation, leading to significant upregulation of cell-surface Transferrin Receptor 1 (TfR1), which mediates iron uptake by binding to the iron-carrying protein transferrin1-3. Leveraging this phenomenon and the fast endocytosis rate of TfR1 (refs. 4,5), we developed Transferrin Receptor targeting chimeras (TransTACs), a heterobispecific antibody modality for membrane protein degradation. TransTACs are engineered to drive rapid co-internalization of a target protein of interest and TfR1 from the cell surface, and to enable target protein entry into the lysosomal degradation pathway. We show that TransTACs can efficiently degrade a diverse range of single-pass, multi-pass, native or synthetic membrane proteins, including epidermal growth factor receptor, programmed cell death 1 ligand 1, cluster of differentiation 20 and chimeric antigen receptor. In example applications, TransTACs enabled the reversible control of human primary chimeric antigen receptor T cells and the targeting of drug-resistant epidermal growth factor receptor-driven lung Cancer with the exon 19 deletion/T790M/C797S mutations in a mouse xenograft model. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of membrane proteins and targeted Cancer therapy.

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