Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
EpiBiologics, Inc., San Carlos, CA, USA.
Nat Biotechnol. 2023 Feb;41(2):273-281. doi: 10.1038/s41587-022-01456-2. Epub 2022 Sep 22.
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.
通过溶酶体递送来靶向降解细胞表面和细胞外蛋白质是调节细胞外生物学的重要手段。然而，由于缺乏模块化、易于开发、限制组织靶向性以及对细胞表面和细胞外蛋白质的适用性，这些方法存在局限性。我们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），该策略解决了这些限制。KineTACs 是完全遗传编码的双特异性抗体，由细胞因子臂组成，该臂结合其同源细胞因子受体，以及针对感兴趣的蛋白质的靶结合臂。我们表明，包含细胞因子 CXCL12 的 KineTAC 可以利用诱饵回收受体 CXCR7 将各种靶蛋白靶向溶酶体进行降解。另外设计了 KineTAC 以利用其他 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，KineTACs 代表了一种通用、模块化、选择性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。
