Transferrin receptor targeting chimeras for membrane protein degradation

Dingpeng Zhang, Jhoely Duque-Jimenez, Francesco Facchinetti, Garyk Brixi, Kaitlin Rhee, William W. Feng, Pasi A. Jänne and Xin Zhou ()
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Dingpeng Zhang: Dana-Farber Cancer Institute
Jhoely Duque-Jimenez: Dana-Farber Cancer Institute
Francesco Facchinetti: Dana-Farber Cancer Institute
Garyk Brixi: Harvard University
Kaitlin Rhee: Dana-Farber Cancer Institute
William W. Feng: Dana-Farber Cancer Institute
Pasi A. Jänne: Dana-Farber Cancer Institute
Xin Zhou: Dana-Farber Cancer Institute

Nature, 2025, vol. 638, issue 8051, 787-795

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-024-07947-3

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