A multispecific antibody against SARS-CoV-2 prevents immune escape in vitro and confers prophylactic protection in vivo

Despite effective countermeasures, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists worldwide because of its ability to diversify and evade human immunity. This evasion stems from amino acid substitutions, particularly in the receptor binding domain (RBD) of the spike protein that confers resistance to vaccine-induced antibodies and antibody therapeutics. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different RBD sites into multispecific antibodies. Here, we describe multispecific antibodies, including a trivalent trispecific antibody that potently neutralized diverse SARS-CoV-2 variants and prevented virus escape more effectively than single antibodies or mixtures of the parental antibodies. Despite being generated before the appearance of Omicron, this trispecific antibody neutralized all major Omicron variants through BA.4/BA.5 at nanomolar concentrations. Negative stain electron microscopy suggested that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated binding across more than one spike protein. Moreover, a tetravalent trispecific antibody containing the same variable regions as the trivalent trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2, and BA.5 challenge, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. These results demonstrated that multispecific antibodies have the potential to provide broad SARS-CoV-2 coverage, decrease the likelihood of escape, simplify treatment, and provide a strategy for antibody therapies that could help eliminate pandemic spread for this and other pathogens.

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Publication Details

Journal
Science Translational Medicine
Published
2024-10-09
DOI
https://doi.org/10.1126/scitranslmed.ado9026
Citations
2
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
0.78
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article

A multispecific antibody against SARS-CoV-2 prevents immune escape in vitro and confers prophylactic protection in vivo

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2 citations
Science Translational Medicine
SARS-CoV-2 and COVID-19 Research
0.78
article

A multispecific antibody against SARS-CoV-2 prevents immune escape in vitro and confers prophylactic protection in vivo

Shannon M. Wallace, Tongqing Zhou, Nancy J. Sullivan, Richard A. Koup, Adam S. Olia, Amarendra Pegu, Kevin Carlton, Lindsay Longobardi, Mehul S. Suthar, Daniel C. Douek, Olamide K. Oloniniyi, Peter D. Kwong, Eun Sung Yang, Lingshu Wang, Cuiping Liu, Marika Boruszczak, Danielle Nase, Ronnie R. Wei, Kwanyee Leung, Q. Paula Lei, Gary J. Nabel, Misook Choe, M. Chen, Juan I. Moliva, John R. Mascola, Jason G. Gall, Amy R. Henry, Vera B. Ivleva, Chih‐Jen Wei, Laurent Pessaint, Wei Shi, John Misasi, Jeremy J. Wolff, Maciel Porto, Darcy R. Harris, Sucheta Godbole, Jonah S. Merriam, Yi Zhang, Bingchun Zhao, Juan Li, Hanné Andersen, Zhi-Yong Yang
article en
2 citations

Abstract

Despite effective countermeasures, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists worldwide because of its ability to diversify and evade human immunity. This evasion stems from amino acid substitutions, particularly in the receptor binding domain (RBD) of the spike protein that confers resistance to vaccine-induced antibodies and antibody therapeutics. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different RBD sites into multispecific antibodies. Here, we describe multispecific antibodies, including a trivalent trispecific antibody that potently neutralized diverse SARS-CoV-2 variants and prevented virus escape more effectively than single antibodies or mixtures of the parental antibodies. Despite being generated before the appearance of Omicron, this trispecific antibody neutralized all major Omicron variants through BA.4/BA.5 at nanomolar concentrations. Negative stain electron microscopy suggested that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated binding across more than one spike protein. Moreover, a tetravalent trispecific antibody containing the same variable regions as the trivalent trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2, and BA.5 challenge, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. These results demonstrated that multispecific antibodies have the potential to provide broad SARS-CoV-2 coverage, decrease the likelihood of escape, simplify treatment, and provide a strategy for antibody therapies that could help eliminate pandemic spread for this and other pathogens.

Science Translational MedicineVol. 16(768)
National Institutes of Health (US), Emory University (US), Experimental Pathology Laboratories (US), Opexa Therapeutics (United States) (US), Bioqual (US), National Institute of Allergy and Infectious Diseases (US)
Good health and well-being
Openalex Percentile: Top 27%
SARS-CoV-2 and COVID-19 Research
0.78
DOISourceOpenAlex
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