美国丹娜-法伯癌症研究所Xin Zhou课题组发现，靶向转铁蛋白受体的嵌合体可用于膜蛋白降解。该研究于2024年9月25日在线发表于国际一流学术期刊《自然》。

研究人员表示，癌细胞为了快速增殖需要大量铁，导致细胞表面转铁蛋白受体1（TfR1）显著上调，TfR1通过与携铁蛋白转铁蛋白结合来介导铁的摄取。

利用这一现象以及TfR1的快速内吞率，研究人员开发了转铁蛋白受体靶向嵌合体（TransTAC），这是一种用于膜蛋白降解的异双特异性抗体模式。TransTAC被设计用于驱动感兴趣的靶蛋白与TfR1从细胞表面共同内吞，并促使靶蛋白进入溶酶体降解途径。

研究人员展示了TransTAC能够有效降解多种单跨膜、多跨膜、天然或合成的膜蛋白，包括表皮生长因子受体、程序性死亡1配体1、分化簇20以及嵌合抗原受体。

在示例应用中，TransTAC实现了人类原代嵌合抗原受体T细胞的可逆控制，并靶向具有外显子19缺失/T790M/C797S突变的，耐药性表皮生长因子受体驱动的肺癌小鼠异种移植模型。TransTAC代表了一类有前景的新型双功能抗体家族，可用于精确调控膜蛋白和靶向癌症治疗。

附：英文原文

Title: Transferrin receptor targeting chimeras for membrane protein degradation

Author: Zhang, Dingpeng, Duque-Jimenez, Jhoely, Facchinetti, Francesco, Brixi, Garyk, Rhee, Kaitlin, Feng, William W., Jnne, Pasi A., Zhou, Xin

Issue&Volume: 2024-09-25

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 transferrin1,2,3. 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.

DOI: 10.1038/s41586-024-07947-3

Source: https://www.nature.com/articles/s41586-024-07947-3