Nature: Multivalency Transforms SARS-CoV-2 Antibodies into Ultrapotent Neutralizers
Nature | 16 JUNE 2021
Edurne Rujas1,2,3, Iga Kucharska1, Yong Zi Tan 1, Samir Benlekbir1, Hong Cui1, Tiantian Zhao4, Gregory A. Wasney1,5, Patrick Budylowski6,7, Furkan Guvenc6,8, Jocelyn C. Newton1, Taylor Sicard1,2, Anthony Semesi1, Krithika Muthuraman1, Amy Nouanesengsy1,2, Clare Burn Aschner1, Katherine Prieto1, Stephanie A. Bueler1, Sawsan Youssef9, Sindy Liao-Chan9, Jacob Glanville9, Natasha Christie-Holmes6, Samira Mubareka10,11, Scott D. Gray-Owen8, John L. Rubinstein1,2,12, Bebhinn Treanor4,13,14 & Jean-Philippe Julien1,2,4
Abstract
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 (IC50) 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.
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