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.

通过溶酶体递送靶向降解细胞表面和细胞外蛋白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、组织靶向受限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 (KineTAC)，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感兴趣蛋白质的靶标结合臂组成。我们表明，含有细胞因子 CXCL12 的 KineTAC 可以使用诱饵回收受体 CXCR7 将多种靶蛋白靶向溶酶体进行降解。其他 KineTAC 旨在利用其他 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，KineTAC 代表了一种通用的、模块化的、选择性的和简单的基因编码策略，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。