We have recently shown that a dominant-negative mutant of CXCL8, dnCXCL8, with increased glycosaminoglycan (GAG) binding affinity and inactivated GPCR signaling function is able to efficiently prevent neutrophil infiltration into murine lungs (Adage et al., 2015). Here we present evidence that chemical PEGylation of dnCXCL8 with 20 kDa and 40 kDa PEG does not significantly interfere with GAG binding affinity, nor does it influence the mutant's disabled chemotaxis function, while it strongly improved bioavailability and serum half-life of the chemokine mutant. In a murine model of lung inflammation, only the 40 kDa PEGylated dnCXCL8 showed a significant reduction of neutrophils in bronchoalveolar lavage (BAL) fluid. In combination with an almost three-fold increase (compared to non-PEGylated dnCXCL8) in plasma half-life after intravenous administration, our results prove that PEGylation of chemokine-derived biologics is an amenable way for the treatment of chronic inflammatory conditions.

中文翻译：

---

糖胺聚糖结合显性失活 CXCL8 突变体的聚乙二醇化在体外和体内保持生物活性

我们最近表明，具有增加的糖胺聚糖 (GAG) 结合亲和力和失活的 GPCR 信号功能的 CXCL8 显性失活突变体 dnCXCL8 能够有效防止中性粒细胞浸润到鼠肺中（Adage 等，2015）。在这里，我们提供的证据表明 dnCXCL8 与 20 kDa 和 40 kDa PEG 的化学聚乙二醇化不会显着干扰 GAG 结合亲和力，也不会影响突变体的禁用趋化功能，同时它极大地提高了趋化因子突变体的生物利用度和血清半衰期。在肺部炎症的小鼠模型中，只有 40 kDa 聚乙二醇化的 dnCXCL8 显示支气管肺泡灌洗液 (BAL) 中的中性粒细胞显着减少。