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

Authors :
Misasi J
Wei RR
Wang L
Pegu A
Wei CJ
Oloniniyi OK
Zhou T
Moliva JI
Zhao B
Choe M
Yang ES
Zhang Y
Boruszczak M
Chen M
Leung K
Li J
Yang ZY
Andersen H
Carlton K
Godbole S
Harris DR
Henry AR
Ivleva VB
Lei QP
Liu C
Longobardi L
Merriam JS
Nase D
Olia AS
Pessaint L
Porto M
Shi W
Wallace SM
Wolff JJ
Douek DC
Suthar MS
Gall JG
Koup RA
Kwong PD
Mascola JR
Nabel GJ
Sullivan NJ
Source :
Science translational medicine [Sci Transl Med] 2024 Oct 09; Vol. 16 (768), pp. eado9026. Date of Electronic Publication: 2024 Oct 09.
Publication Year :
2024

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.

Details

Language :
English
ISSN :
1946-6242
Volume :
16
Issue :
768
Database :
MEDLINE
Journal :
Science translational medicine
Publication Type :
Academic Journal
Accession number :
39383243
Full Text :
https://doi.org/10.1126/scitranslmed.ado9026