Evolvable and rapidly adaptable monobodies: a broad-spectrum antiviral platform

Antibodies are immune system proteins that attach to foreign substances (antigens) and help the body get rid of them. Monobodies (Mobs) are engineered protein binders that can act like antibodies. They are promising candidates for antiviral drug development. The EU-funded EvaMobs project intends to deliver a platform for the development of evolvable and rapidly adaptable antivirals based on Mobs to improve Europe’s preparedness for future viral outbreaks with pandemic potential. The process will leverage deep learning-powered computational design tools and a high-throughput screening platform. Candidates will proceed through preclinical and Phase I clinical trials, supported by demonstrated production processes following good manufacturing practices.

Objective
With progress in globalization, expansion of human populations into natural habitats, and aggravation of climate change comes an increased risk of viral outbreaks. As demonstrated by the COVID-19 pandemic, not being prepared for such events has devastating consequences on public health, society and the economy. EvaMobs will improve preparedness of the European Union (EU) for the next viral outbreak(s) of pandemic potential by developing a platform for the discovery, development, production and validation of evolvable and rapidly adaptable antivirals. These innovative medicines will be based on small human-derived proteins called monobodies (Mobs). As Mobs can be engineered to have high binding affinity for virtually any viral protein, this platform can be easily adapted to a broad range of viruses, including newly emerging viruses and viral variants.
To demonstrate the capacity of this platform it will first be applied to four pathogenic viruses with epidemic and/or pandemic potential: Influenza A, SARS-CoV-2, respiratory syncytial virus, and Zika virus. Deep-learning and computational design tools will allow generation of tailor-made Mobs with cryo-EM elucidating the molecular details of their binding interaction. Simple bacterial expression of Mobs, the development of a semi-automated high-throughput screening platform for evaluation of the Mobs’ stability and target affinity and streamlined in vitro and in vivo preclinical validation, will allow rapid development and selection of stable and potently neutralizing candidates. The Mob with the best preclinical indicators will then be tested in a phase I clinical trial after implementing a stable formulation and GMP production.
The optimized platform can then be adapted to other viruses. Therefore, EvaMobs provides an innovative, robust and flexible platform for antiviral biologics development as well as a diverse portfolio of validated drugs, strengthening the EU’s pandemic preparedness.