Multivalency transforms SARS-CoV-2 antibodies into ultrapotent neutralizers

Rujas, Edurne; Kucharska, Iga; Tan, Yong Zi; Benlekbir, Samir; Cui, Hong; Zhao, Tiantian; Wasney, Gregory A.; Budylowski, Patrick; Guvenc, Furkan; Newton, Jocelyn C.; Sicard, Taylor; Semesi, Anthony; Muthuraman, Krithika; Nouanesengsy, Amy; Aschner, Clare Burn; Prieto, Katherine; Bueler, Stephanie A.; Youssef, Sawsan; Liao-Chan, Sindy; Glanville, Jacob; Christie-Holmes, Natasha; Mubareka, Samira; Gray-Owen, Scott D.; Rubinstein, John L.; Treanor, Bebhinn; Julien, Jean-Philippe

SARS-CoV-2, the virus responsible for COVID-19, has caused a global pandemic. Antibodies can be powerful biotherapeutics to fight viral infections. Here, we use the human apoferritin protomer as a modular subunit to drive oligomerization of antibody fragments and transform antibodies targeting SARS-CoV-2 into exceptionally potent neutralizers. Using this platform, half-maximal inhibitory concentration (IC(50)) values as low as 9 × 10(−)(14) M are achieved as a result of up to 10,000-fold potency enhancements compared to corresponding IgGs. Combination of three different antibody specificities and the fragment crystallizable (Fc) domain on a single multivalent molecule conferred the ability to overcome viral sequence variability together with outstanding potency and IgG-like bioavailability. The MULTi-specific, multi-Affinity antiBODY (Multabody or MB) platform thus uniquely leverages binding avidity together with multi-specificity to deliver ultrapotent and broad neutralizers against SARS-CoV-2. The modularity of the platform also makes it relevant for rapid evaluation against other infectious diseases of global health importance. Neutralizing antibodies are a promising therapeutic for SARS-CoV-2.