SCI
13 October 2024
Transferrin receptor targeting chimeras for membrane protein degradation
(Nature; IF:50.5)
Zhang D, Duque-Jimenez J, Facchinetti F, Brixi G, Rhee K, Feng WW, Jänne PA, Zhou X: Transferrin receptor targeting chimeras for membrane protein degradation. Nature 2024.
Correspondence to: xin_zhou1@dfci.harvard.edu
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 transferrin. Leveraging this phenomenon and the fast endocytosis rate of TfR1, 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.
癌细胞需要高水平的铁才能快速增殖,这导致细胞表面转铁蛋白受体1 (TfR1)显著上调,而TfR1通过与载铁蛋白转铁蛋白结合来介导铁摄取。利用这一现象和TfR1的快速内吞速率,我们开发了转铁蛋白受体靶向嵌合体(TransTACs),一种用于膜蛋白降解的异源双特异性抗体模式。TransTACs被设计用于驱动目标蛋白和TfR1从细胞表面快速内化,并使目标蛋白进入溶酶体降解途径。我们的研究表明,TransTACs可以有效地降解多种单通道、多通道、天然或合成的膜蛋白,包括表皮生长因子受体、程序性细胞死亡配体1、分化簇20和嵌合抗原受体。在应用示例中,TransTACs实现了对人初级嵌合抗原受体T细胞的可逆性控制,以及在小鼠异种移植模型中,利用外显子19缺失/T790M/C797S突变靶向耐药的表皮生长因子受体驱动的肺癌。TransTACs代表了一个有前景的双功能抗体新家族,可用于精确调控膜蛋白和靶向肿瘤治疗。