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DARPins stack up as anti-COVID-19 agents

Molecular Partners and Novartis are teaming up to test whether biologic alternatives to antibodies called DARPins can help control COVID-19. DARPins — designed ankyrin repeat proteins — are protein scaffolds a tenth the size of monoclonal antibodies. Like other protein-scaffold biologics, DARPins promise benefits over conventional antibodies. By stringing DARPins together, for example, Molecular Partners can quickly design and screen multispecific candidates. In the case of the COVID-19, the company selected DARPin modules with high target affinity for SARS-CoV-2 and joined them with peptide linkers to form trispecific candidates. “We really own the space of multi-specificity. Mono-, bi-, tri- and tetraspecific compounds — for us it’s really all the same,” says Molecular Partners CEO Patrick Amstutz. The resulting multi-DARPins can bind more than one epitope at once. In contrast, the over ten monoclonal antibody therapeutics in clinical testing for SARS-CoV-2 target a single site on the spike protein used by the virus to bind and enter host cells. Because mutations at this site might lead to viral escape, some antibody developers have turned to antibody cocktails to get around this possible limitation. These combinations, however, bring optimization, manufacturing and regulatory challenges of their own. Instead, Molecular Partners’ lead multi-DARPins for treating COVID-19 bind different epitopes on the spike protein. The MP0420 molecule binds three epitopes on the spike’s receptor-binding domain (RBD); MP0423 targets one epitope on the spike’s RBD, one on its S1 N-terminal domain and another on its S2 domain.

A phase 1 trial of MP0420 started in November. Novartis paid $22 million up front, acquired $44 million in equity and committed up to $165 million in future milestone payments to collaborate on the development of these biologics for COVID-19. Earlier in the year, the US Food and Drug Administration rejected Molecular Partners, AbbVie and Allergan’s VEGF-targeting DARPin abicipar pegol, for wet age-related macular degeneration, citing concerns with intraocular inflammation.

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DARPins stack up as anti-COVID-19 agents. Nat Biotechnol 38, 1369 (2020). https://doi.org/10.1038/s41587-020-00771-w

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