小柯机器人

美国基因泰克公司Felipe de Sousa e Melo、Nicholas J. Agard等研究人员合作开发出用于受体降解的E3泛素连接酶的抗体靶向。该项研究成果于2022年9月21日在线发表在《自然》杂志上。

研究人员报道了蛋白分解靶向抗体（PROTAB）的开发，它将细胞表面的E3泛素连接酶拴在跨膜蛋白上，导致目标在体外和体内的降解。研究人员专注于锌和环指3（ZNRF3），一种Wnt反应性连接酶，表明这种方法可以实现结直肠癌特异性降解。值得注意的是，通过研究其他细胞表面E3泛素连接酶和跨膜受体的矩阵，研究人员证明这种技术可以修正为“按需”降解。此外，研究人员通过设计优化的抗体格式，对管理目标降解的基本规则进行了深入研究。总之，这项工作描述了一种快速开发细胞表面蛋白的有效、生物可用和组织选择性降解剂的策略。

据了解，目前大多数针对质膜受体的治疗方法都是通过拮抗配体结合或酶的活性来发挥作用。然而，典型的哺乳动物蛋白由多个结构域组成，这些结构域执行不连续但协调的活动。因此，对一个结构域的抑制往往不能完全抑制一个蛋白质的功能。事实上，靶向蛋白降解技术，包括蛋白分解-靶向嵌合体（PROTAC），已经强调了靶向降解比抑制的重要临床优势。然而，以高亲和力与两个目标结合的异功能化合物的产生是复杂的，特别是在需要口服生物利用度的时候。

附：英文原文

Title: Antibody targeting of E3 ubiquitin ligases for receptor degradation

Author: Marei, Hadir, Tsai, Wen-Ting K., Kee, Yee-Seir, Ruiz, Karen, He, Jieyan, Cox, Chris, Sun, Tao, Penikalapati, Sai, Dwivedi, Pankaj, Choi, Meena, Kan, David, Saenz-Lopez, Pablo, Dorighi, Kristel, Zhang, Pamela, Kschonsak, Yvonne T., Kljavin, Noelyn, Amin, Dhara, Kim, Ingrid, Mancini, Andrew G., Nguyen, Thao, Wang, Chunling, Janezic, Eric, Doan, Alexander, Mai, Elaine, Xi, Hongkang, Gu, Chen, Heinlein, Melanie, Biehs, Brian, Wu, Jia, Lehoux, Isabelle, Harris, Seth, Comps-Agrar, Laetitia, Seshasayee, Dhaya, de Sauvage, Frederic J., Grimmer, Matthew, Li, Jing, Agard, Nicholas J., de Sousa e Melo, Felipe

Issue&Volume: 2022-09-21

Abstract: Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins comprise multiple domains that execute discrete but coordinated activities. Thus, inhibition of one domain often incompletely suppresses the function of a protein. Indeed, targeted protein degradation technologies, including proteolysis-targeting chimeras1 (PROTACs), have highlighted clinically important advantages of target degradation over inhibition2. However, the generation of heterobifunctional compounds binding to two targets with high affinity is complex, particularly when oral bioavailability is required3. Here we describe the development of proteolysis-targeting antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo. Focusing on zinc- and ring finger 3 (ZNRF3), a Wnt-responsive ligase, we show that this approach can enable colorectal cancer-specific degradation. Notably, by examining a matrix of additional cell-surface E3 ubiquitin ligases and transmembrane receptors, we demonstrate that this technology is amendable for ‘on-demand’ degradation. Furthermore, we offer insights on the ground rules governing target degradation by engineering optimized antibody formats. In summary, this work describes a strategy for the rapid development of potent, bioavailable and tissue-selective degraders of cell-surface proteins.

DOI: 10.1038/s41586-022-05235-6

Source: https://www.nature.com/articles/s41586-022-05235-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html