小柯机器人

美国加州大学旧金山分校James A. Wells团队近期取得重要工作进展，他们研究开发了模块化的细胞因子受体靶向嵌合体，可用于定向降解细胞表面和细胞外蛋白。该项研究成果2022年9月22日在线发表于《自然—生物技术》杂志上。

研究人员描述了一种溶酶体降解策略，称为细胞因子受体靶向嵌合体（KineTACs），它解决了这些限制。KineTAC是完全基因编码的双特异性抗体，由结合其同源细胞因子受体的细胞因子臂和目标蛋白质的靶标结合臂组成。研究人员发现，含有细胞因子CXCL12的KineTAC可以使用诱饵回收受体CXCR7，将多种靶蛋白靶向到溶酶体进行降解。另外的KineTACs被设计用来驾驭其他CXCR7靶向细胞因子，CXCL11和vMIPII，以及白细胞介素-2（IL-2）受体靶向细胞因子IL-2。因此，KineTAC代表了一种通用的、模块化的、选择性的和简单的遗传编码策略，用于诱导具有广泛或组织特异性分布的细胞外和细胞表面靶标的溶酶体递送。

据介绍，通过溶酶体传递靶向降解细胞表面和细胞外蛋白是调节细胞外基质生物学的重要手段。然而，由于缺乏模块化、易于开发、受限的组织靶向以及对细胞表面和细胞外蛋白的适用性，这些方法具有局限性。

附：英文原文

Title: Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins

Author: Pance, Katarina, Gramespacher, Josef A., Byrnes, James R., Salangsang, Fernando, Serrano, Juan-Antonio C., Cotton, Adam D., Steri, Veronica, Wells, James A.

Issue&Volume: 2022-09-22

Abstract: Targeted degradation of cell surface and extracellular proteins via lysosomal delivery is an important means to modulate extracellular biology. However, these approaches have limitations due to lack of modularity, ease of development, restricted tissue targeting and applicability to both cell surface and extracellular proteins. We describe a lysosomal degradation strategy, termed cytokine receptor-targeting chimeras (KineTACs), that addresses these limitations. KineTACs are fully genetically encoded bispecific antibodies consisting of a cytokine arm, which binds its cognate cytokine receptor, and a target-binding arm for the protein of interest. We show that KineTACs containing the cytokine CXCL12 can use the decoy recycling receptor, CXCR7, to target a variety of target proteins to the lysosome for degradation. Additional KineTACs were designed to harness other CXCR7-targeting cytokines, CXCL11 and vMIPII, and the interleukin-2 (IL-2) receptor-targeting cytokine IL-2. Thus, KineTACs represent a general, modular, selective and simple genetically encoded strategy for inducing lysosomal delivery of extracellular and cell surface targets with broad or tissue-specific distribution.

DOI: 10.1038/s41587-022-01456-2

Source: https://www.nature.com/articles/s41587-022-01456-2

Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex