Wang Yafeng, Zhang Guiquan, Rong Ping, Guo Panpan, Huang Shisheng, Hang Yang, Wang Pei, Tang Lin, Li Xiaojing, Tang Xiaojun, Ding Shuai, Huang Xingxu, Liu Jianghuai, Sun Lingyun
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing 210008, China.
The Second People's Hospital of Changzhou, the Third Affiliated Hospital of Nanjing Medical University, Changzhou 213000, China; College of Life Sciences, Nanjing Medical University, Changzhou 213000, China.
Mol Ther. 2025 Aug 6;33(8):3644-3661. doi: 10.1016/j.ymthe.2025.05.002. Epub 2025 May 7.
Molecular tether-mediated extracellular targeted protein degradation (eTPD) presents an innovative technology and underlies a promising drug modality. However, to precisely implement eTPD within specific cell compartments remains a significant challenge. As eTPD depends on the degrader molecule expression and activity, we first seek to expand the panel of potential eTPD degraders. To this end, more than 50 receptors with variable tissue distributions are screened for identification of those with substantial endocytic rates. We subsequently assemble the bispecific, "Selected endocytic carrier-targeting chimeras (SecTAC)," and validate their efficacies to program the target cells to internalize membrane/extracellular protein cargos (or nucleic acids). Moreover, administration of a SecTAC for removal of excessive immunoglobulin G via a currently validated, emerging degrader (CD71) leads to evident therapeutic effect in a mouse lupus model. To further enhance cell-targeting specificity, we next develop logic-gated eTPD (LOG-eTPD) based on a combination of chimeras that indirectly couple cargo and degrader via another cell surface gating marker. Particularly, we find that a selective surface marker from the neighboring cells also may be exploited as input for LOG-eTPD in a therapeutically relevant context. Taken together, the present work has laid a strong foundation for developing eTPD agents that combine high potency with precision and safety.
分子栓介导的细胞外靶向蛋白质降解（eTPD）是一项创新技术，也是一种很有前景的药物模式的基础。然而，在特定细胞区室中精确实施eTPD仍然是一项重大挑战。由于eTPD取决于降解分子的表达和活性，我们首先试图扩大潜在的eTPD降解剂的范围。为此，我们筛选了50多种具有不同组织分布的受体，以鉴定那些具有较高内吞率的受体。随后，我们组装了双特异性的“选定内吞载体靶向嵌合体（SecTAC）”，并验证了它们将靶细胞编程为内化膜/细胞外蛋白质货物（或核酸）的功效。此外，通过目前已验证的新型降解剂（CD71）施用SecTAC以去除过量的免疫球蛋白G，在小鼠狼疮模型中产生了明显的治疗效果。为了进一步提高细胞靶向特异性，我们接下来基于嵌合体的组合开发了逻辑门控eTPD（LOG-eTPD），这些嵌合体通过另一种细胞表面门控标记间接连接货物和降解剂。特别地，我们发现来自邻近细胞的选择性表面标记也可以在治疗相关背景下用作LOG-eTPD的输入。综上所述，本研究为开发兼具高效性、精准性和安全性的eTPD药物奠定了坚实基础。
