Multivalency transforms SARS-CoV-2 antibodies into broad and ultrapotent neutralizers

Rujas, E.; Kucharska, I.; Tan, Y. Z.; Benlekbir, S.; Cui, H.; Zhao, T.; Wasney, G. A.; Budylowski, P.; Guvenc, F.; Newton, J. C.; Sicard, T.; Semesi, A.; Muthuraman, K.; Nouanesengsy, A.; Prieto, K.; Bueler, S. A.; Youssef, S.; Liao-Chan, S.; Glanville, J.; Christie-Holmes, N.; Mubareka, S.; Gray-Owen, S. D.; Rubinstein, J. L.; Treanor, B.; Julien, J.-P.

doi:10.1101/2020.10.15.341636

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bioRxiv · 10.1101/2020.10.15.341636

Multivalency transforms SARS-CoV-2 antibodies into broad and ultrapotent neutralizers

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Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), has caused a global pandemic. Antibodies are powerful biotherapeutics to fight viral infections; however, discovery of the most potent and broadly acting clones can be lengthy. Here, we used 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 x 10-14 M were achieved as a result of up to 10,000-fold potency enhancements. 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 Ig-like in vivo bioavailability. This MULTi-specific, multi-Affinity antiBODY (Multabody; or MB) platform contributes a new class of medical countermeasures against COVID-19 and an efficient approach to rapidly deploy potent and broadly-acting therapeutics against infectious diseases of global health importance. One Sentence Summarymultimerization platform transforms antibodies emerging from discovery screens into potent neutralizers that can overcome SARS-CoV-2 sequence diversity.

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Rujas, E., Kucharska, I., Tan, Y. Z., Benlekbir, S., Cui, H., Zhao, T., Wasney, G. A., Budylowski, P., Guvenc, F., Newton, J. C., Sicard, T., Semesi, A., Muthuraman, K., Nouanesengsy, A., Prieto, K., Bueler, S. A., Youssef, S., Liao-Chan, S., Glanville, J., Christie-Holmes, N., Mubareka, S., Gray-Owen, S. D., Rubinstein, J. L., Treanor, B., Julien, J.-P.. 2020-10-16. Multivalency transforms SARS-CoV-2 antibodies into broad and ultrapotent neutralizers. https://doi.org/10.1101/2020.10.15.341636

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