Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

A current challenge is the emergence of SARS-CoV-2 variants, such as BQ.1.1 and XBB.1.5, that can evade immune defenses, thereby limiting antibody drug effectiveness. Emergency-use antibody drugs, including the widely effective bebtelovimab, are losing their benefits. One potential approach to addre...

Full description

Saved in:
Bibliographic Details
Published in:iScience 2024-04, Vol.27 (4), p.109363-109363, Article 109363
Main Authors: Inoue, Tetsuya, Yamamoto, Yuichiro, Sato, Kaoru, Okemoto-Nakamura, Yuko, Shimizu, Yoshimi, Ogawa, Motohiko, Onodera, Taishi, Takahashi, Yoshimasa, Wakita, Takaji, Kaneko, Mika K., Fukasawa, Masayoshi, Kato, Yukinari, Noguchi, Kohji
Format: Article
Language:English
Subjects:
Biochemistry
Biological sciences
Immunology
Microbiology
Natural sciences
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:A current challenge is the emergence of SARS-CoV-2 variants, such as BQ.1.1 and XBB.1.5, that can evade immune defenses, thereby limiting antibody drug effectiveness. Emergency-use antibody drugs, including the widely effective bebtelovimab, are losing their benefits. One potential approach to address this issue are bispecific antibodies which combine the targeting abilities of two antibodies with distinct epitopes. We engineered neutralizing bispecific antibodies in the IgG-scFv format from two initially non-neutralizing antibodies, CvMab-6 (which binds to the receptor-binding domain [RBD]) and CvMab-62 (targeting a spike protein S2 subunit epitope adjacent to the known anti-S2 antibody epitope). Furthermore, we created a bispecific antibody by incorporating the scFv of bebtelovimab with our anti-S2 antibody, demonstrating significant restoration of effectiveness against bebtelovimab-resistant BQ.1.1 variants. This study highlights the potential of neutralizing bispecific antibodies, which combine existing less effective anti-RBD antibodies with anti-S2 antibodies, to revive the effectiveness of antibody therapeutics compromised by immune-evading variants. [Display omitted] •Anti-SARS-CoV-2 bispecific Abs can be generated by combining non-neutralizing Abs•Anti-S2 antibody CvMab-62 recognizes a novel epitope upstream of S2 stem helix•Bispecific antibodies can inhibit spike-mediated membrane fusogenic mechanism•Bispecific Abs restore antiviral activity against bebtelovimab-resistant BQ.1.1 Natural sciences; Biological sciences; Biochemistry; Immunology; Microbiology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2024.109363