Transferrin receptor targeting chimeras for membrane protein degradation
成果类型：
Article
署名作者：
Zhang, Dingpeng; Duque-Jimenez, Jhoely; Facchinetti, Francesco; Brixi, Garyk; Rhee, Kaitlin; Feng, William W.; Janne, Pasi A.; Zhou, Xin
署名单位：
Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
刊物名称：
Nature
ISSN/ISSBN：
0028-2111
DOI：
10.1038/s41586-024-07947-3
发表日期：
2025-02-20
关键词：
摘要：
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. Transferrin receptor targeting chimeras have been developed that enable targeting of drug resistance in epidermal growth factor receptor-driven lung cancer and reversible control of human primary chimeric antigen receptor T cells, representing a promising new family of bifunctional antibodies for targeted cancer therapy.