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^1,2,3. 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.

癌细胞需要高水平的铁才能快速增殖，导致细胞表面转铁蛋白受体 1 （TfR1） 显著上调，该受体通过与携带铁的蛋白质转铁蛋白结合来介导铁的摄取^1,2,3。利用这种现象和 TfR1 的快速内吞速率 （refs.^4,5），我们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 经过工程改造，可驱动目标靶蛋白和 TfR1 从细胞表面快速共内化，并使靶蛋白能够进入溶酶体降解途径。我们表明 TransTACs 可以有效地降解各种单通道、多通道、天然或合成膜蛋白，包括表皮生长因子受体、程序性细胞死亡 1 配体 1、分化簇 20 和嵌合抗原受体。在示例应用中，TransTAC 能够对人原代嵌合抗原受体 T 细胞进行可逆控制，并在小鼠异种移植模型中使用外显子 19 缺失/T790M/C797S 突变靶向耐药表皮生长因子受体驱动的肺癌。TransTAC 代表了一个很有前途的新型双功能抗体家族，用于膜蛋白的精确操作和靶向癌症治疗。