The recent advancements on membrane protein degraders (MPDs) have broadened the applicability of proteolysis-targeting chimeras (PROTACs) beyond intracellular proteins to include the previously “undruggable” cell-surface targets. However, the potential toxicity of MPDs caused by undesired off-target degradation poses a significant challenge to clinical deployment, mirroring concerns associated with PROTACs. Here, we introduce a conditionally activatable membrane protein degrader (Pro-MPD), which leverages the specificity and high affinity of biparatopic nanobodies combined with a tumor microenvironment-activated cell-penetrating peptide (Pro-CPP) to achieve on-target activated internalization and degradation of PD-L1 within tumor sites. This modularly designed Pro-MPD demonstrated a high target degradation efficiency and T cell reactivation, as well as sustained inhibition of tumor growth in xenograft models, highlighting its potential as a safer and highly efficient MPD for in vivo applications. Our work provides a general strategy for the development of conditionally activatable MPDs, which offers a new avenue for reducing the undesired systemic toxicity of MPDs due to the off-tumor degradation.

中文翻译：

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用于肿瘤特异性膜蛋白降解的条件可激活嵌合体


膜蛋白降解剂 （MPD） 的最新进展将蛋白水解靶向嵌合体 （PROTAC） 的适用性扩大到细胞内蛋白之外，包括以前“不可成药”的细胞表面靶标。然而，由意外脱靶降解引起的 MPD 的潜在毒性对临床部署构成了重大挑战，反映了与 PROTAC 相关的担忧。在这里，我们介绍了一种条件可激活的膜蛋白降解剂 （Pro-MPD），它利用双旁生位纳米抗体的特异性和高亲和力与肿瘤微环境激活的细胞穿透肽 （Pro-CPP） 相结合，实现肿瘤部位内 PD-L1 的靶向激活内化和降解。这种模块化设计的 Pro-MPD 在异种移植模型中表现出高靶标降解效率和 T 细胞再激活，以及持续抑制肿瘤生长，突出了其作为更安全、更高效的体内应用 MPD 的潜力。我们的工作为开发条件可激活的 MPD 提供了一种通用策略，这为减少 MPD 由于非肿瘤降解而导致的不良全身毒性提供了一条新途径。