Lysosome-targeting chimeras (LYTACs) have recently been developed to facilitate the lysosomal degradation of specific extracellular and transmembrane molecular targets. However, the LYTAC particles described to date are based on glycopeptide conjugates, which are difficult to prepare and produce on a large scale. Here, we report on the development of pure protein LYTACs based on the non-glycosylated IGF2 peptides, which can be readily produced in virtually any facility capable of monoclonal antibody production. These chimeras utilize the IGF2R/CI-M6PR pathway for lysosomal shuttling and, in our illustrative example, target programmed death ligand 1 (PD-L1), eliciting physiological effects analogous to immune checkpoint blockade. Results from in vitro assays significantly exceed the effects of anti-PD-L1 antibodies alone.

中文翻译：

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基于 IGF2 肽的 LYTAC 用于细胞外和跨膜蛋白的靶向降解


最近开发了溶酶体靶向嵌合体 （LYTAC），以促进特定细胞外和跨膜分子靶标的溶酶体降解。然而，迄今为止描述的 LYTAC 颗粒是基于糖肽偶联物的，这些偶联物难以制备和大规模生产。在这里，我们报告了基于非糖基化 IGF2 肽的纯蛋白 LYTAC 的开发，它几乎可以在任何能够生产单克隆抗体的设施中轻松生产。这些嵌合体利用 IGF2R/CI-M6PR 通路进行溶酶体穿梭，在我们的说明性示例中，靶向程序性死亡配体 1 （PD-L1），引发类似于免疫检查点阻断的生理效应。体外检测的结果明显优于单独的抗 PD-L1 抗体的效果。