IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern

Matthew R. Chang, Luke Tomasovic, Natalia A. Kuzmina, Adam J. Ronk, Patrick O. Byrne, Rebecca Johnson, Nadia Storm, Eduardo Olmedillas, Yixuan J. Hou, Alexandra Schäfer, Sarah R. Leist, Longping V. Tse, Hanzhong Ke, Christian Coherd, Katrina Nguyen, Maliwan Kamkaew, Anna Honko, Quan Zhu, Galit Alter, Erica Ollmann Saphire, Jason S. McLellan, Anthony Griffiths, Ralph S. Baric, Alexander Bukreyev and Wayne A. Marasco ()
Additional contact information
Matthew R. Chang: Dana-Farber Cancer Institute
Luke Tomasovic: Dana-Farber Cancer Institute
Natalia A. Kuzmina: University of Texas Medical Branch
Adam J. Ronk: University of Texas Medical Branch
Patrick O. Byrne: University of Texas
Rebecca Johnson: Boston University, School of Medicine
Nadia Storm: Boston University, School of Medicine
Eduardo Olmedillas: La Jolla Institute for Immunology
Yixuan J. Hou: University of North Carolina at Chapel Hill
Alexandra Schäfer: University of North Carolina at Chapel Hill
Sarah R. Leist: University of North Carolina at Chapel Hill
Longping V. Tse: University of North Carolina at Chapel Hill
Hanzhong Ke: Dana-Farber Cancer Institute
Christian Coherd: Dana-Farber Cancer Institute
Katrina Nguyen: Dana-Farber Cancer Institute
Maliwan Kamkaew: Dana-Farber Cancer Institute
Anna Honko: Boston University, School of Medicine
Quan Zhu: Dana-Farber Cancer Institute
Galit Alter: MIT and Harvard
Erica Ollmann Saphire: La Jolla Institute for Immunology
Jason S. McLellan: University of Texas
Anthony Griffiths: Boston University, School of Medicine
Ralph S. Baric: University of North Carolina at Chapel Hill
Alexander Bukreyev: University of Texas Medical Branch
Wayne A. Marasco: Dana-Farber Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Monoclonal antibodies are a promising approach to treat COVID-19, however the emergence of SARS-CoV-2 variants has challenged the efficacy and future of these therapies. Antibody cocktails are being employed to mitigate these challenges, but neutralization escape remains a major challenge and alternative strategies are needed. Here we present two anti-SARS-CoV-2 spike binding antibodies, one Class 1 and one Class 4, selected from our non-immune human single-chain variable fragment (scFv) phage library, that are engineered into four, fully-human IgG-like bispecific antibodies (BsAb). Prophylaxis of hACE2 mice and post-infection treatment of golden hamsters demonstrates the efficacy of the monospecific antibodies against the original Wuhan strain, while promising in vitro results with the BsAbs demonstrate enhanced binding and distinct synergistic effects on neutralizing activity against circulating variants of concern. In particular, one BsAb engineered in a tandem scFv-Fc configuration shows synergistic neutralization activity against several variants of concern including B.1.617.2. This work provides evidence that synergistic neutralization can be achieved using a BsAb scaffold, and serves as a foundation for the future development of broadly reactive BsAbs against emerging variants of concern.

Date: 2022
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DOI: 10.1038/s41467-022-33030-4

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