Abstract
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).
【초록키워드】 COVID-19, SARS-CoV-2, coronavirus, monoclonal antibody, variant, Cryo-electron microscopy, drug, in vitro, omicron, Protein, SARS-CoV-2 variants, clinical evaluation, therapeutic, experiment, hamster, targeted therapy, escape mutation, binding, mAb, fatality, Analysis, ACE2 binding, Support, acute respiratory syndrome, trimer, Standard-of-care, DARPin, inhibit, reduced, in viral, the spike protein, engage, infected with SARS-CoV-2, 【제목키워드】 SARS-CoV-2 variant, DARPin, inhibit,