The trispecific DARPin ensovibep inhibits diverse SARS-CoV-2 variants
). This cooperative binding of multiple paratopes is a hallmark of the trispecific nature of ensovibep, differentiating the molecule from mAb candidates by affording full neutralization of even the highly mutated SARS-CoV-2 variants, such as Omicron BA.1 and BA.2.
Ensobibep’s high level of protection against viral escape mutations was also demonstrated in a viral passaging experiment. The single mAbs and the monovalent DARPin R2 were overcome by escape mutants, whereas ensovibep maintained potency similar to a clinically validated mAb cocktail. Translatability of the observed in vitro activity of ensovibep against SARS-CoV-2 was evaluated in a COVID-19 model using highly susceptible Roborovski dwarf hamsters. Using this in vivo model, we confirmed the therapeutic benefit of ensovibep, with outcomes similar to a clinically validated antibody cocktail. In a late intervention scenario, ensovibep treatment yielded prolonged survival of animals and reduced inflammation of the lungs when compared to mAb-treated and placebo-treated animals.
In conclusion, ensovibep has shown highly potent neutralization against the most frequent SARS-CoV-2 variants to date due to its cooperative and complementary binding to a highly conserved epitope region on the spike RBD. In vitro and in vivo single-agent efficacies closely match the performance of a clinically validated mAb cocktail.
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