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.

靶向蛋白质降解已成为一种非常有前途的治疗方法，用于调节传统小分子难以靶向的蛋白质。这种方法最近已扩展到包括改变细胞外蛋白水平和活性——包括分泌蛋白和膜蛋白。现在，Zhang 等人利用癌细胞中细胞表面转铁蛋白受体 1 （TfR1） 的上调及其快速的内吞作用速率来开发转铁蛋白受体靶向嵌合体 （TransTAC）。这些是诱导靶膜蛋白内化和溶酶体降解的异双特异性抗体。

该团队研究了 TransTAC 消除表面嵌合抗原受体 （CAR） 的能力。尽管经历了内化，但 CAR 不会降解;相反，它被贩运到回收内体。为了解决这个问题，该团队加入了 TfR1 抗体结合剂和组织蛋白酶 B 切割接头，以促进 CAR 进入溶酶体降解途径。CAR TransTACs 可有效抑制 Jurkat 和人原代 CAR T 细胞的活化，以及 IFNγ 的分泌。此外，靶标范围扩大到包括靶向耐药肺癌的表皮生长因子受体 （EGFR） 以及 PD-L1 和 CD20，证明了 TransTACs 有效内化和降解结构和功能不同的膜蛋白的能力。