Spiez Laboratory, Austrasse, Spiez, Switzerland.
Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
Nat Biotechnol. 2022 Dec;40(12):1845-1854. doi: 10.1038/s41587-022-01382-3. Epub 2022 Jul 21.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19).
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）变体的出现对现有药物具有潜在的耐药性，这强调了需要具有广泛变异性活性的新治疗方式。在这里，我们展示了 ensovibep，一种三特异性 DARPin（设计的锚蛋白重复蛋白）临床候选药物，能够与 SARS-CoV-2 的三个刺突蛋白三聚体结合，并通过冷冻电镜分析显示出对 ACE2 结合的高抑制活性。协同结合和三个 DARPin 模块的互补性使 ensovibep 能够抑制频繁出现的 SARS-CoV-2 变体，包括奥密克戎亚系 BA.1 和 BA.2。在感染 SARS-CoV-2 的罗伯罗夫斯基仓鼠中，ensovibep 降低了死亡率，与标准护理的单克隆抗体（mAb）鸡尾酒相似。当作为单一药物在体外病毒传代实验中使用时，ensovibep 以类似于相同 mAb 鸡尾酒的方式减少了逃逸突变的出现。这些结果支持进一步评估 ensovibep 作为一种广泛的替代现有针对 2019 年冠状病毒病（COVID-19）的靶向治疗药物的临床评估。
