Kumru Kaan, Yao Zi, Holmes Brandon B, Zhao Fangzhu, Zhang Yun, Ferrara Emilio, Peters-Clarke Trenton M, Leung Kevin K, Wells James A
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
bioRxiv. 2025 Sep 2:2025.09.02.673832. doi: 10.1101/2025.09.02.673832.
Extracellular targeted protein degradation (eTPD) is as an important new modality for manipulating the extracellular proteome. However, most eTPD receptors are expressed broadly or are restricted to the liver. Cytokine receptor targeting chimeras (kineTACs) are genetically encoded bispecifics for eTPD that fuse a natural ligand like CXCL12 to an antibody, directing soluble or membrane proteins for lysosomal degradation using the widely expressed chemokine receptor CXCR7 (Pance K, Gramespacher JA., Byrnes, JR, Salangsang F., Serrano JAC, Cotton AD, Steri V, and Wells JA, , 41, 273-281). Here, we dramatically expand the kineTAC toolbox by constructing 81 new kineTACs based on an unbiased list of cytokines, chemokines and growth factors. Remarkably, 55 of these expressed at suitable levels for analysis without any optimization. Many of these kineTACs bind receptors that have unique cell-type expression profiles, allowing for eTPD in specific cells and tissues and some were more potent than the original CXCL12-based kineTAC. We further show the internalizing capability of a kineTAC can enhance the performance of antibody drug conjugates. We believe these simple, genetically encoded tools will be useful for expanding the applications for optimized or cell type-selective eTPD.
细胞外靶向蛋白降解（eTPD）是一种操纵细胞外蛋白质组的重要新方法。然而，大多数eTPD受体广泛表达或仅限于肝脏。细胞因子受体靶向嵌合体（kineTACs）是用于eTPD的基因编码双特异性分子，它将天然配体（如CXCL12）与抗体融合，利用广泛表达的趋化因子受体CXCR7将可溶性或膜蛋白导向溶酶体降解（潘斯K，格拉梅斯帕彻JA，伯恩斯JR，萨朗桑F，塞拉诺JAC，科顿AD，斯特里V和韦尔斯JA，，41，273 - 281）。在这里，我们通过基于细胞因子、趋化因子和生长因子的无偏列表构建81种新的kineTAC，极大地扩展了kineTAC工具箱。值得注意的是，其中55种在无需任何优化的情况下表达水平适合分析。这些kineTAC中有许多结合具有独特细胞类型表达谱的受体，从而允许在特定细胞和组织中进行eTPD，并且有些比原始的基于CXCL12的kineTAC更有效。我们进一步表明，kineTAC的内化能力可以提高抗体药物偶联物的性能。我们相信这些简单的、基因编码的工具将有助于扩展优化的或细胞类型选择性的eTPD的应用。
