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

Tetsuya Inoue; Yuichiro Yamamoto; Kaoru Sato; Yuko Okemoto-Nakamura; Yoshimi Shimizu; Motohiko Ogawa; Taishi Onodera; Yoshimasa Takahashi; Takaji Wakita; Mika K Kaneko; Masayoshi Fukasawa; Yukinari Kato; Kohji Noguchi

doi:10.1016/j.isci.2024.109363

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

iScience. 2024 Feb 29;27(4):109363. doi: 10.1016/j.isci.2024.109363. eCollection 2024 Apr 19.

Authors

Tetsuya Inoue¹, Yuichiro Yamamoto¹, Kaoru Sato¹, Yuko Okemoto-Nakamura², Yoshimi Shimizu^{2

3}, Motohiko Ogawa⁴, Taishi Onodera⁵, Yoshimasa Takahashi⁵, Takaji Wakita⁶, Mika K Kaneko^{7

8}, Masayoshi Fukasawa^{1

2}, Yukinari Kato^{7

8}, Kohji Noguchi^{1

2}

Affiliations

¹ Laboratory of Molecular Targeted Therapy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-8510, Japan.
² Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
³ Department of Pharmaceutical Sciences, Teikyo Heisei University, 4-21-2 Nakano, Nakano-ku 164-8530, Japan.
⁴ Department of Virology I, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
⁵ Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
⁶ National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
⁷ Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Miyagi 980-8575, Japan.
⁸ Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai, Miyagi 980-8575, Japan.

Abstract

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.

Keywords: Biochemistry; Biological sciences; Immunology; Microbiology; Natural sciences.