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Access through your institution Buy or subscribe Targeted protein degradation has emerged as a highly promising therapeutic approach to modulate proteins that are difficult to target with
conventional small molecules. This approach has recently been expanded to include alteration of extracellular protein levels and activity — including both secreted and membrane proteins.
Now, Zhang et al. have exploited the upregulation of cell surface transferrin receptor 1 (TfR1) in cancer cells and its rapid endocytosis rate to develop transferrin receptor targeting
chimeras (TransTACs). These are heterobispecific antibodies that induce internalization and lysosomal degradation of target membrane proteins. The team investigated the capacity of TransTACs
to eliminate surface chimeric antigen receptor (CAR). Despite undergoing internalization, CAR is not subjected to degradation; instead, it is trafficked to the recycling endosomes. To
address this the team incorporated an antibody binder to TfR1 and a cathepsin B cleavage linker to facilitate CAR entry into the lysosomal degradation pathway. CAR TransTACs can effectively
inhibit the activation of Jurkat and human primary CAR T cells, as well as secretion of IFNγ. Furthermore, the target scope was expanded to include epidermal growth factor receptor (EGFR)
for targeting drug-resistant lung cancer, as well as PD-L1 and CD20, demonstrating the capacity of TransTACs to efficiently internalize and degrade structurally and functionally distinct
membrane proteins. This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Access Nature and 54 other Nature Portfolio journals
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ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Nature Communications
https://www.nature.com/ncomms/ Irene Serrano Authors * Irene Serrano View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence
to Irene Serrano. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Serrano, I. Bridging the gap in protein targeting. _Nat Chem Biol_ 20, 1387 (2024).
https://doi.org/10.1038/s41589-024-01766-3 Download citation * Published: 22 October 2024 * Issue Date: November 2024 * DOI: https://doi.org/10.1038/s41589-024-01766-3 SHARE THIS ARTICLE
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