Receptor Crosslinking: A General Method to Trigger Internalization and Lysosomal Targeting of Therapeutic Receptor:Ligand Complexes.
Receptor Crosslinking: A General Method to Trigger Internalization and Lysosomal Targeting of Therapeutic Receptor:Ligand Complexes.
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DOI：
10.1038/mt.2015.178
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Jones AT
中科院分区：
文献类型：
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作者：
Moody PR;Sayers EJ;Magnusson JP;Alexander C;Borri P;Watson P;Jones AT
一个主要的未满足的临床需求是一种通用的亚细胞靶向溶酶体的生物活性分子的方法。递送到这个细胞器可以降解在癌症中过度表达的致癌受体，或者从抗体-药物偶联物中释放前药。在这里，我们描述了一种使用受体交联来触发内吞作用的一般方法，并随后将受体货物复合物的运输从其预期路线重新定向到溶酶体。通过用生物素化的货物培养质膜受体，随后将链霉亲和素添加到交联受体：货物-生物素复合物中，我们实现了快速和选择性的溶酶体靶向转铁蛋白，一种抗mhc I类抗体，以及临床批准的抗her2抗体曲妥珠单抗。这三种蛋白质配体各自靶向一种具有不同细胞功能和细胞内运输特征的受体。重要的是，我们证实了曲妥珠单抗交联增加了其同源致癌受体Her2在乳腺癌细胞系SKBR3和BT474中的溶酶体降解。这些数据表明，交联可以用于广泛的靶受体，通过内溶酶体途径导航治疗，获得显著的治疗效果。
A major unmet clinical need is a universal method for subcellular targeting of bioactive molecules to lysosomes. Delivery to this organelle enables either degradation of oncogenic receptors that are overexpressed in cancers, or release of prodrugs from antibody–drug conjugates. Here, we describe a general method that uses receptor crosslinking to trigger endocytosis and subsequently redirect trafficking of receptor:cargo complexes from their expected route, to lysosomes. By incubation of plasma membrane receptors with biotinylated cargo and subsequent addition of streptavidin to crosslink receptor:cargo–biotin complexes, we achieved rapid and selective lysosomal targeting of transferrin, an anti-MHC class I antibody, and the clinically approved anti-Her2 antibody trastuzumab. These three protein ligands each target a receptor with a distinct cellular function and intracellular trafficking profile. Importantly, we confirmed that crosslinking of trastuzumab increased lysosomal degradation of its cognate oncogenic receptor Her2 in breast cancer cell lines SKBR3 and BT474. These data suggest that crosslinking could be exploited for a wide range of target receptors, for navigating therapeutics through the endolysosomal pathway, for significant therapeutic benefit.